Process for preparing substituted glycines

A new process is disclosed for the preparation of N-acyl-.alpha.-aromatic and N-acyl-.alpha.-heteroaromatic glycines by reaction of an .alpha.-ester or ether of an N-acylglycine ester or acid with an aromatic or heteroaromatic compound. Also disclosed are new intermediates for preparing N-acyl-.alpha.-aromatic and N-acyl-.alpha.-heteroaromatic glycines.

This invention relates to a process for preparing N-acyl-.alpha.-aromatic 
and N-acyl-.alpha.-heteroaromatic glycines and to intermediates for 
preparing said compounds. In particular, the invention relates to a 
process for preparing compounds of formula III by reacting an 
.alpha.-ester or ether of an N-acylglycine ester or acid (I) with an 
aromatic or heteroaromatic compound (II). 
##STR1## 
In the above formulas I-III, R.sup.1 Y is any group which with adjacent 
carbonyl group forms an amine protective group removable under conditions 
which are mild enough not to affect the remainder of the molecule. R.sup.1 
can therefore be straight or branched chain lower alkyl of one to four 
carbon atoms, .beta. ,.beta.,.beta.-trichloroethyl or substituted or 
unsubstituted benzyl. Y can be O or S. The substituents on benzyl can be 
halo, alkyl, alkoxy or nitro. Preferred groups are those where R.sup.1 Y 
is t-butoxy, .beta.,.beta. ,.beta.-trichloroethoxy and benzyloxy. 
ZR.sup.3 is any ester or ether group readily replaceable by an 
electron-rich aromatic or heteroaromatic group. Z can therefore be O, S or 
##STR2## 
and R.sup.3 can be straight or branched chain lower alkyl of one to four 
carbon atoms; halomethyl such as trifluoromethyl; aryl such as phenyl, 
which may be unsubstituted or substituted with one or two halo, lower 
alkyl, hydroxy, lower alkoxy, nitro, amino or acetamido groups; or aralkyl 
such as benzyl, which may be unsubstituted or substituted in the same 
manner as phenyl. Preferred groups are those where ZR.sup.3 is lower 
alkanoyloxy such as 
##STR3## 
LOWER ALKOXY SUCH AS OCH.sub.3 (methoxy) and OC.sub.4 H.sub.9 (butoxy), 
SCH.sub.2 C.sub.6 H.sub.5 (benzylthio), OC.sub.6 H.sub.5 (phenoxy) and 
lower alkylthio such as SCH.sub.3 (methylthio). 
R.sup.2 is hydrogen, except when ZR.sup.3 is phenoxy, or any carboxyl 
protective group which is easily removable or is itself usable in the 
acylation reaction in which the product glycine compound is used. R.sup.2 
can therefore be hydrogen, except when ZR.sup.3 is phenoxy, straight or 
branched chain lower alkyl of one to four carbon atoms, haloalkyl such as 
.beta.,.beta. ,.beta.-trichloroethyl, benzyl or substituted benzyl such as 
p-nitrobenzyl or p-methoxybenzyl. In addition, R.sup.2 can be any 
activated ester known to the art to be usable for the acylation of 
peptides, penicillins or cephalosporins. 
Ar can be any aromatic or heteroaromatic group that is sufficiently 
electron-rich to replace the ZR.sup.3 group Ar can be phenyl, thienyl, 
furyl, pyrryl, napththyl, innolyl, purinyl, tetrazolyl, oxadiazolyl or 
thiadiazolyl. Ar can be unsubstituted or substituted with one or two lower 
alkyl, lower alkoxy, lower alkylthio halo, hydroxy, mercapto, nitro or 
amino groups, or any other groups that do not by their reactivity or 
election-withdrawing character prevent the replacement reaction from 
proceeding satisfactorily. The only certain limitation on the nature of 
the Ar group is that it must possess an unsubstituted position which can 
bond to the .alpha.-carbon atom of the glycine molecule. 
A subgeneric group of processes are those above described in which the 
compound having an aromatc or heteroaromatic group is phenyl lithium, 
anisole, resorcinol, 2-acetamidophenol, indole, purine, furan, phenol, 
chlorophenol, fluorophenol, pyrrole, thioanisole, thiophene or 
2,6-dimethylphenol; R.sup.1 Y is t-butoxy, 
.beta.,.beta.,.beta.-trichloroethoxy, benzyloxy, p-nitrobenzyloxy or 
p-methoxybenzyloxy; ZR.sup.3 is lower alkoxy, benzylthio, phenoxy or lower 
alkylthio and R.sup.2 is lower alkyl, .beta.,.beta.,.beta.-trichloroethyl, 
benzyl, p-nitrobenzyl, p-methoxybenzyl, or hydrogen, except when ZR.sup.3 
is phenoxy. 
When used herein, the terms "lower alkyl", "lower alkoxy" and "lower 
alkanoyl" are intended to refer to straight or branched chain groups 
contaning from one to four carbon atoms. The term "halo" is intended to 
refer to fluoro, chloro, bromo and iodo. 
N-Acyl-.alpha.-aromatic and N-acyl-.alpha.-heteroaromatic glycines are 
intermediates useful for preparing antibacterial aromatic and 
heteroaromatic glycinamidopenicillins and cephalosporins. Examples of such 
antibacterial compounds are described in U.S. Pat. Nos. 2,985,648, 
3,507,861 and 3,560,489 and Belgian Pat. No. 784,995. The penicillin and 
cephalosporins are prepared by acylation of the penicillin or 
cephalosporin nucleus with the aromatic or heteroaromatic glycine. Prior 
to the acylation reaction, the amino group of the glycine moiety is 
normally protected with any of a variety of well-known and easily-removed 
amine protective groups. Thus, one normally must prepare the aromatic or 
heteroaromatic glycine compound and then protect the amino group prior to 
the acylation reaction. The advantage of the present process is that the 
protection of the amino group can be accomplished in the same reaction in 
which the aromatic or heteroaromatic glycine is itself prepared. 
The process of this invention whereby the ZR.sup.3 leaving group is 
replaced by the Ar group is carried out by combining the .alpha.-ester or 
ether of formula I with at least an equimolar amount of the aromatic or 
heteroaromatic compound (Ar). The reaction is generally carried out using 
an acid catalyst, including Lewis acids, among which boron trifluoride as 
its etherate, aluminum chloride formic acid and trifluoroacetic acid are 
preferred. Highly election-rich aromatic reactants such as indole, purine 
and pyrrole require no catayst. When the aromatic moiety is insufficiently 
election-rich to replace the .alpha.-ester or ether, even with an acid 
catalyst, it is used as a metal salt. Thus, when Ar is phenyl, the 
reaction is best carried out using phenyl lithium as a reactant. When the 
leaving group (ZR.sup.3) is a thioether, mercuric acetate is used in 
addition to the acid catalyst. 
The reaction is carried out in the liquid phase. A solvent is generally 
preferred; among those being usable are such non-polar organic solvents as 
benzene, toluene, xylene, carbon tetrachloride, ethyl acetate, dioxane, 
tetrahydrofuran, ether, methylene chloride and chloroform. The aromatic 
reactant may be employed in large excess and thus itself serve as the 
solvent. The temperature of the reaction will depend upon the nature of 
the reactants. When the aromatic moiety is especially sensitive or 
reactive, the temperature should be kept low, in the case of phenyl 
lithium and furan, as low as -78.degree. C. Otherwise, the temperature 
should be approximately between 0.degree. C and ambient temperature (ca 
25.degree. C) and the reaction should be allowed to proceed until it is 
substantially complete, as indicated by thin layer chromatography. This 
time will vary from approximately 15 minutes to 24 hours. In cases where 
an aromatic moiety is sluggish in reacting, high temperatures, including 
those reached only by heating in the absence of solvent, may be required. 
The product is then isolated and purified according to standard methods, 
including solvent extraction, chromatography and recrystallization. 
The esters of formula III obtained by this process may be hydrolyzed or 
used directly in acylating penicillin and cephalosporin intermediates by 
well-known methods. Use of a base such as sodium bicarbonate or sodium 
carbonate in aqueous methanol or dioxane is preferred for hydrolysis. 
The compounds of formula I which are reacted with the aromatic nuclei to 
give compounds of formula III are themselves prepared by condensing an 
amide of formula IV, a glyoxylic ester of formula V and an acid, alcohol 
or mercaptan of formula VI, as shown below: 
##STR4## 
An anhydride may be used instead of an acid. R.sup.1, R.sup.2, R.sup.3, Y 
and Z are as defined above. This reaction is carried out either using one 
of the reactants as a solvent or in an organic solvent such as dioxane, 
benzene, xylene or toluene. The temperature of the reaction will vary with 
the reactants, but it is preferable to carry it out at the reflux 
temperature of the solvent unless lower temperatures are necessary to 
prevent serious decomposition. 
Compounds of formula I where ZR.sup.3 is acyloxy are new and are considered 
part of the present invention. Among the preferred compounds of this group 
are those where R.sup.1 Y is t-butoxy, .beta.,.beta. 
,.beta.-trichloroethoxy or benzyloxy; R.sup.2 is hydrogen or lower alkyl 
and ZR.sup.3 is lower alkanoyloxy. The p-nitrobenzyl and p-methoxybenzyl 
glyoxylic acid esters are prepared according to known procedures, for 
example, by treating glyoxylic acid with a p-nitrobenzyl or 
p-methoxybenzyl halide in the presence of base. 
It will be recognized that, due to the asymmetric .alpha.-carbon atom in 
the glycine compounds of formulas I and III, optical isomers will exist. 
The resolved glycines are readily obtained, when desired, by resolution of 
the racemic compounds by well-known methods including fractional 
crystallization of a salt formed with an optically active acid or base. 
Both the resolved and racemic compounds are usable and obtainable in the 
process of the invention and both are comprehended by the definition of 
the claimed intermediate glycines. 
Many examples of .alpha.-substituted N-acylgylcines and glycine esters are 
found in the prior art. Various .alpha.-alkoxy-N-benzoylglycines and 
glycine esters are described in Zhur. Obschch. Khim., 25, 1360 (1955), 
Bull. Soc. Chim. Fr., 530 (1959), Doklady Akad. Nauk. S.S.S.R., 106,675 
(1956) and 137, 1377 (1961) and Nippon Kagaku Zasshi, 76, 1022 (1955). 
N-Phenylacetyl-.alpha.-methoxyglycine is disclosed in U.S. Pat. No. 
2,523,621, while N-phenylacetyl-.alpha.-benzyloxyglycine is described in 
Experientia, 21, 317 (1965). The corresponding methyl and benzyl esters 
are found in J. Chem. Soc. C, 14, 1264 (1967) and Ann. Chim. (Rome), 60, 
259 (1970), respectively. 
Huisgen and Blaschke have prepared N-ethoxycarbonyl-.alpha.-benzoylglycine 
ethyl ester [Chem. Ber., 98, 29585 (1965)]. The preparations of 
.alpha.-hydroxy, .alpha.-amino (for example, unsubstituted and substituted 
anilino, benzylamino and morpholino) and .alpha.-halo N-ethoxycarbonyl, 
N-benzoyl and N-phenylacetylglycine esters are described by 
Matthies[Pharmazie, 25, 522 (1970)]. 
Synthesis of N-.alpha.-alkoxybenzylbenzamides is described in Tetrahedron, 
23, 2869-77 (1967). Synthesis of an .alpha.-carbethoxyiminoacetic ester 
and conversion to an N-acyl-.alpha.-indolylglycine ester are described in 
Tetrahedron Letters No. 41, 4371-73 (1968). Synthesis of glycines by means 
of a Grignard reaction is described in Tetrahedron Letters No. 21, 1813-16 
(1970). 
Other references may exist describing compounds similar to those described 
in the above references. However, the inventors are aware of no disclosure 
of N-acyl-.alpha.-acyloxyglycines or of their use in preparing 
N-acyl-.alpha.-aromatic or heteroaromatic glycines.

The following examples illustrate the products and processes of the 
invention, but are not to be construed as limiting the scope thereof. 
Temperatures are in degrees Centigrade unless otherwise stated. 
EXAMPLE 1 
N-t-Butoxycarbonyl-2-acetoxyglycine n-butyl ester 
A solution of 23.4 g. (0.2 mol.) of t-butyl carbamate [Org. Syn., 48, 32 
(1968); U.S. Pat. No. 3,072,710] and 32.2 g. (0.25 mol.) of n-butyl 
glyoxylate (Org. Syn., Col. Vol. 4, 124) in 150 ml. of acetic anhydride 
was refluxed for 1.25 hours. The reaction mixture was then cooled, the 
solvent was removed in vacuo and the residue was molecularly distilled at 
130.degree./.05 mm. to give the title compound. 
Use of formic, propionic or butyric anhydride in place of the acetic 
anhydride gives the the corresponding 2-formyloxy, 2-propionyloxy or 
2-butyryloxy compound, respectively. 
EXAMPLE 2 
N-(.beta.,.beta.,.beta.-Trichloroethoxycarbonyl)-2-acetoxyglycine n -butyl 
ester 
When 38.5 g. of .beta.,.beta. ,.beta. -trichloroethyl carbamate (U.S. Pat. 
No. 3,072,210) was substituted in the procedure of Example 1 for t-butyl 
carbamate, the title compound was obtained. 
EXAMPLE 3 
Substitution of 22.6 g. of benzyl carbamate in the procedure of Example 1 
for t-butyl carbamate gave N-benzyloxycarbonyl-2-acetoxyglycine n-butyl 
ester. 
By simular use of p-methoxybenzyl carbamate and p-nitrobenzyl carbamate in 
the procedures described herein, there are prepared the corresponding 
N-(p-methoxyand p-nitrobenzyloxycarbonyl)glycines of this invention. 
EXAMPLE 4 
N-Benzyloxycarbonyl-2-n-butoxyglycine n-butyl ester 
A solution of 3.0 g. (0.02 mol.) of benzyl carbamate, 1.8 g. (0.02 mol.) of 
glyoxylic acid hydrate and 0.1 g. of p-toluenesulfonic acid in 50 ml. of 
n-butanol was slowly distilled over a 1 hour period. The last of the 
solvent was removed in vacuo to give a residue which was dissolved in 
hexane and filtered to remove the p-toluene-sulfonic acid. The filtrate 
was chromatographed on alumina (Woelm, activity II) and eluted with 
hexane. Concentration of the eluate in vacuo and molecular distillation of 
the residue at 130.degree./0.1 mm. gave the title compound. 
EXAMPLE 5 
N-Benzyloxycarbonyl-2-methoxyglycine methyl ester 
A solution of 3.0 g. (0.02 mol.) of benzyl carbamate and 1.8 g. (0.02 mol) 
of glyoxylic acid hydrate in 50 ml. of 1:1 methanol-benzene containing 0.1 
g. of p-toluenesulfonic acid was slowly distilled. During the course of 
the distillation the solvent was periodically replaced with 1:4 
methanol-benzene to keep the total volume at least 20 ml. After 1 hour, 
the reaction mixture was concentrated in vacuo and the residue was 
dissolved in 10 ml. of benzene and filtered. The filtrate was 
chromatographed on alumina (Woelm, activity II) and eluted with benzene. 
Concentration of the eluate in vacuo gave the title compound, m.p. 
74.degree.-75.degree. (benzene-hexane). 
EXAMPLE 6 
N-t-butoxycarbonyl-2-phenoxyglycine n-butyl ester 
To 2.9 g (0.01 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester 
in 10 ml. of dioxane was added a solution of sodium phenolate prepared 
from 0.94 g. of phenol and 0.54 g. of sodium methoxide in 15 ml. of 
dioxane After refluxing for 2 hours, the solvent was evaporated in vacuo 
and the residue was dissolved in ethyl acetate. The ethyl acetate solution 
was washed with cold 10% aqueous sodium hydroxide, dried (MgSO.sub.4) and 
concentrated to yield the title compound as an oil. 
Alternatively, N-t-Butoxycarbonyl-2-phenoxyglycine-n-butyl ester was 
prepared by heating a mixture of 1.5 g. (0.005 mol.) of 
N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 0.5 g. (0.005 mol.) 
of phenol at 150.degree. for 1 hour. The residue was dissolved in ethyl 
acetate and the resulting solution was washed with cold 10% aqueous sodium 
hydroxide, dried (MgSO.sub.4) and concentrated to give the title compound. 
EXAMPLE 7 
N-Benzyloxycarbonyl-2-S-benzylthioglycine 
A mixture of 15.1 g. (0.1 mol.) of benzyl carbamate, 7.4 g. (0.1 mol.) of 
glyoxylic acid hydrate and 24.0 g. (0.1 mol.) of benzyl mercaptan in 100 
ml. of toluene was refluxed for 0.5 hour. After cooling, the reaction 
mixture was filtered and the crystalline product was washed with toluene, 
dried in vacuo and recrystallized from ethyl acetate-hexane to give the 
title compound, m.p. 120.degree.-122.degree.. 
EXAMPLE 8 
N-Butoxycarbonyl-2-S-methylthioglycine 
When equivalent amounts of t-butyl carbamate and methyl mercaptan are 
substituted in the procedure of Example 7 for benzyl carbamate and benzyl 
mercaptan, respectively, the title compound is obtained. 
EXAMPLE 9 
When an equivalent amount of t-butyl thiocarbamate [F. Org. Chem. 28, 3421 
(1963); U.S. Pat. No. 3,072,710] is substituted in the procedure of 
Example 1 for t-butyl carbamate, N-t-butylthiocarbonyl-2-acetoxyglycine 
n-butyl ester is obtained. 
Similarly, substitution of an equivalent amount of benzyl thiocarbamate [J. 
Amer. Chem. Soc., 82, 4582 (1960)] in the procedure of Example 1 for 
t-butyl carbamate gives N-benzylthiocarbonyl-2-acetoxyglycine n-butyl 
ester. 
EXAMPLE 10 
N-Benzylthiocarbonyl-2-n-butoxyglycine n-butyl ester 
When an equivalent amount of benzyl thiocarbamate is substituted in the 
procedure of Example 4 for benzyl carbamate, the title compound is 
obtained. 
EXAMPLE 11 
N-Benzylthiocarbonyl-2-methoxyglycine methyl ester 
When an equivalent amount of benzyl thiocarbamate is substituted in the 
procedure of Example 5 for benzyl carbamate, the title compound is 
obtained. 
EXAMPLE 12 
N-t-butylthiocarbonyl-2-phenoxyglycine n-butyl ester 
Substitution of an equivalent amount of 
N-t-butylthiocarbonyl-2-acetoxyglycine n-butyl ester in the procedure of 
Example 6 for N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester gives the 
title compound. 
EXAMPLE 13 
N-Benzylthiocarbonyl-2-S-benzylthioglycine 
When ab equivalent amount of benzyl thiocarbamate is substituted in the 
procedure of Example 7 for benzyl carbamate, the title compound is 
obtained. 
EXAMPLE 14 
N-t-Butylthiocarbonyl-2-S-methylthioglycine 
Substitution of an equivalent amount of t-butyl thiocarbamate in the 
procedure of Example 8 for t-butyl carbamate gives the title compound. 
EXAMPLE 15 
N-Benzyloxycarbonyl-2-n-butoxyglycine 
A solution of 0.002 mol. of N-benzyloxycarbonyl-2-n-butoxyglycine n-butyl 
ester is stirred with 10 ml. of methanol and 10 ml. of5% aqueous sodium 
bicarbonatesodium carbonate solution for 5 hours at 25.degree.. The 
reaction mixture is then diluted with water and shaken with ethyl acetate. 
The layers are separated and the aqueous layer is acidified to pH 2.0 and 
extracted with ethyl acetate containing 10% ethanol. The extracts are 
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to give the title 
compound. 
In like manner, the other N-alkoxycarbonyl and N-alkylthiocarbonyl glycine 
esters described herein may be converted to the corresponding acids. 
EXAMPLE 16 
When an equivalent amount of methyl glyoxylate [Synthesis, 544 (1972)] is 
substituted in the procedure of Example 1 for n-butyl glyoxylate, 
N-t-butoxycarbonyl-2-acetoxyglycine methyl ester is obtained. 
In like manner, 
N-(.beta.,.beta.,.beta.-trichloroethoxycarbonyl)-2-acetoxyglycine methyl 
ester is prepared by substitution of an equivalent amount of methyl 
glyoxylate in the procedure of Example 2 for n-butyl glyoxylate. 
Similarly, substitution of an equivalent amount of methyl glyoxylate in the 
procedure of Example 3 for n-butyl glyoxylate gives 
N-benzyloxycarbonyl-2-acetoxyglycine methyl ester. 
Other glycine methyl esters may be prepared by substitution of methyl 
glyoxylate for n-butyl glyoxylate in the appropriate procedures. 
EXAMPLE 17 
Substitution of an equivalent amount of ethyl glyoxylate [Synthesis, 544 
(1972)] in the procedure of Example 1 for n-butyl glyoxylate gives 
N-t-butoxycarbonyl2-acetoxyglycine ethyl ester. 
In like manner, when equivalent amount of ethyl glyoxylate is substituted 
in the procedure of Example 2for n-butyl glyoxylate, 
N-(.beta.,.beta.,.beta.-trichloroethoxycarbonyl)-2-acetoxyglycine ethyl 
ester is obtained. 
When an equivalent amount of ethyl glyoxylate is substituted in the 
procedure of Example 3 for n-butyl glyoxylate, 
N-benzyloxycarbonyl-2-acetoxyglycine ethyl ester is obtained. 
Other glycine ethyl esters may be similarly prepared by substitution of an 
equivalent amount of ethyl glyoxylate for n-butyl glyoxylate in the 
appropriate procedure. 
EXAMPLE 18 
When an equivalent amount of .beta.,.beta. ,.beta.-trichloroethyl 
glyoxylate [J. Amer. Chem. Soc., 88, 852 (1966)] is substituted in the 
procedure of Example 1 for n-butyl glyoxylate, 
N-t-butoxycarbonyl-2-acetoxyglycine .beta.,.beta.,.beta.-trichloroethyl 
ester is obtained. 
Similarly, substitution of an equivalent amount of 
.beta.,.beta.,.beta.-trichloroethyl glyoxylate in the procedure of Example 
2 for n-butyl glyoxylate gives 
N-(.beta.,.beta.,.beta.-trichlorothoxycarbonyl)-2-acetoxyglycine 
.beta.,.beta.,.beta.-trichloroethyl ester. 
In like manner, when an equivalent amount of 
.beta.,.beta.,.beta.-trichloroethyl glyoxylate is substituted in the 
procedure of Example 3 for n-butyl glyoxylate, 
N-benzyloxycarbonyl-2-acetoxyglycine .beta.,.beta.,.beta.-trichloroethyl 
ester is obtained. 
Likewise, other glycine .beta.,.beta.,.beta.-trichloroethyl esters may be 
prepared by substitution of an equivalent amount of 
.beta.,.beta.,.beta.-trichloroethyl glyoxylate for n-butyl glyoxylate in 
the appropriate procedures. 
EXAMPLE 19 
Substitution of an equivalent amount of benzyl glyoxylate in the procedure 
of Example 1 for n-butyl glyoxylate gives 
N-t-butoxycarbonyl-2-acetoxyglycine benzyl ester. 
In like manner, when an equivalent amount of benzyl glyoxylate is 
substituted in the procedure of Example 2 for n-butyl glyoxylate, 
N-(.beta.,.beta.,.beta.-trichloroethoxycarbonyl)-2-acetoxyglycine benzyl 
ester is obtained. 
When an equivalent amount of benzyl glyoxylate is substituted in the 
procedure of Example 3 for n-butyl glyoxylate, 
N-benzyloxycarbonyl-2-acetoxyglycine benzyl ester is obtained. 
Other glycine benzyl esters may be similarly prepared by substitution of an 
equivalent amount of benzyl glyoxylate for n-butyl glyoxylate in the 
appropriate procedure. 
Similarly, use of p-methoxybenzyl glyoxylate or p-nitrobenzyl glyoxylate in 
place of benzyl glyoxylate in the above procedures gives the corresponding 
glycine p-methoxybenzyl and p-nitrobenzyl esters. 
EXAMPLE 20 
When an equivalent amount of N-t-butoxycarbonyl-2-acetoxyglycine methyl 
ester is substituted in the procedure of Example 6, 
N-t-butoxycarbonyl-2-phenoxyglycine methyl ester is obtained. 
In like manner, N-t-butoxycarbonyl-2-phenoxyglycine ethyl ester is obtained 
by substitution of an equivalent amount of 
N-t-butoxycarbonyl-2-acetoxyglycine ethyl ester in the procedure of 
Example 6. 
Similarly, when an equivalent amount of N-t-butoxycarbonyl-2-acetoxyglycine 
.beta.,.beta.,.beta.-trichloroethyl ester is substituted in the procedure 
of Example 6, N-t-butoxycarbonyl-2-phenoxyglycine 
.beta.,.beta.,.beta.-trichloroethyl ester is obtained. 
EXAMPLE 21 
N-t-Butoxycarbonyl-2-phenylglycine n-butyl ester 
A solution containing 2.4 mmol. of phenyl lithium in benzene-ether was 
added dropwise at -78.degree. under argon to a solution of 700 mg. (2.4 
mmol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 15 ml. of 
dry ether. The mixture was stirred for 2 hours at -78.degree., then for 1 
hour at 25.degree.. The mixture was diluted with water, the layers were 
separated and the ether layer was washed with water, dried (Na.sub.2 
SO.sub.4) and concentrated in vacuo. The residue was chromatographed on 
silica gel with methylene chloride to give a crude product which was 
rechromatographed on basic alumina to give the title compound. 
Use of 2-formyloxy, 2-propionyloxy, or 2-butyryloxy starting materials 
gives the same product. 
EXAMPLE 22 
N-t-Butoxycarbonyl-2-(4-methoxyphenyl)glycine n-butyl ester 
A solution of 290 mg. (1 mmol.) of N-t-butoxycarbonyl-2-acetoxyglycine 
n-butyl ester, 0.5 ml. of anisole and 3 drops of boron trifluoride 
etherate in 5 ml. of methylene chloride was stirred at 25.degree. for 4 
hours. The solvent was removed and the residue was chromatographed on 
silica gel and eluted with 1:1 chloroform-hexane to give the title 
compound. 
EXAMPLE 23 
N-t-Butoxycarbonyl-2-(2,4-dihydroxyphenyl)glycine 
To a stirred mixture of 11.0 g. (0.1 mol.) of resorcinol and 24.7 g. (0.085 
mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 250 ml. of 
methylene chloride at 0.degree. was added 1 ml. of boron trifluoride 
etherate. The reaction mixture was allowed to warm to room temperature 
during a 30 minute period, then it was stirred for an additional 3 hours. 
The reaction mixture was washed five times with equal volumes of water, 
dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to give 
N-t-butoxycarbonyl-2-(2,4-dihydroxyphenyl)glycine n-butyl ester. 
To a boiling solution of 23 g. (0.067 mol.) of 
N-t-butoxycarbonyl-2-(2,4-dihydroxyphenyl)glycine n-butyl ester in 300 ml. 
of methanol was slowly added a solution of 23 g. of sodium bicarbonate in 
300 ml. of water. During addition, the reaction mixture was kept under a 
nitrogen atmosphere and the methanol was allowed to distill from the 
mixture. When all the methanol had been distilled the mixture was cooled, 
adjusted to pH 7.0 with phosphoric acid and extracted with ethyl acetate. 
The aqueous phase was acidified to pH 4.0 and again extraced with ethyl 
acetate. The extract was dried (Na.sub.2 SO.sub.4) and concentrated in 
vacuo to give the title compound. 
EXAMPLE 24 
N-t-Butoxycarbonyl-2-(3-acetamido-4-hydroxyphenyl)glycine and 
N-t-butoxycarbonyl-2-(3-acetamido-2-hydroxyphenyl)-glycine. 
To a stirred mixture of 20.0 g. (0.069 mol.) of 
N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester, 11.5 g. (0.076 mol.) of 
2-acetamidophenol and 200 ml. of methylene chloride was added 11.0 g. of 
boron trifluoride etherate under a nitrogen atmosphere. After 20 minutes 
the reaction mixture was shaken with sufficient aqueous sodium carbonate 
to bring the final pH of the aqueous phase to 7-8. The organic phase was 
dried (Na.sub.2 SO.sub.4) and concentrated to give a residue which was 
hydrolyzed with sodium carbonate according to the procedure described in 
Example 23. The hydrolysis product, a mixture of 
N-t-butoxycarbonyl-2-(3-acetamido-4-hydroxyphenyl)glycine and 
N-t-butoxycarbonyl-2-(3-acetamido-2-hydroxyphenyl)glycine, was 
chromatographed on silica gel with 3:1 methylene chloride-ethyl acetate 
containing 1% acetic acid followed by 2:1 ethyl acetate-acetone containing 
1% acetic acid to effect separation of the compounds, m.p. 
178.degree.-179.degree. (4-hydroxy isomer from tetrahydrofuran-hexane); 
m.p. 171.degree.-172.degree. (2-hydroxy isomer from ethyl 
acetate-hexane.). 
EXAMPLE 25 
.alpha.-(N-t-Butoxycarbonylamino)indole-3-acetic acid 
A solution of 20.2 g. (0.070 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine 
n-butyl ester and 8.8 g. (0.075 mol.) of indole in 300 ml. of toluene was 
slowly distilled over a 30 minute interval with periodic replacement of 
the toluene with fresh solvent. After an additional 45 minutes the 
reaction mixture was cooled and the solvent was evaporated in vacuo. The 
residue was triturated with hexane to give 
.alpha.-(N-t-butoxycarbonylamino)indole-3-acetic acid n-butyl ester, m.p. 
127.degree.-128.degree. (ether-hexane). 
A suspension of 5.9 g. (0.017 mol.) of the ester in 70 ml. of 5% aqueous 
sodium carbonate and 30 ml. of dioxane was refluxed for 2.5 hours. The 
cooled reaction mixture was concentrated in vacuo and 30 ml. of water was 
added to the residue. The aqueous solution was extracted with methylene 
chloride, cooled and acidified to pH 2.0 with hydrochloric acid. The 
resulting solid was collected and recrystallized from ethyl acetate-hexane 
to give the title compound, m.p. 143.5.degree.. 
EXAMPLE 26 
.alpha.-(N-t-Butoxycarbonylamino)purine-7-acetic acid n-butyl ester and 
.alpha.-(N-t-butoxycarbonylamino)-9H-purine-9-acetic acid n-butyl ester 
A mixture of 2.9 g. (0.01 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine 
n-butyl ester and 1.2 g. (0.012 mol.) of purine was stirred under vacuum 
at 150.degree.-160.degree. until cessation of acetic acid evolution. 
The cooled reaction mixture was taken up in 20 ml. of methylene chloride 
and the solution was filtered. Chromatography of the filtrate, containing 
a mixture of the title compounds, on 120 g. of silica gel with methylene 
chloride containing increasing amounts of acetone gave 
.alpha.-(N-t-butoxycarbonylamino)purine-7-acetic acid, m.p. 
135.degree.-136.degree. (acetone) and 
.alpha.-(N-t-butoxycarbonylamino)-9H-purine-9-acetic acid, m.p. 
164.degree.-165.degree. (acetone). 
EXAMPLE 27 
.alpha.-(N-t-Butoxycarbonylamino)furan-2-acetic acid n-butyl ester 
A solution of 1.6 g. (0.006 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine 
n-butyl ester and 0.7 g. (0.01 mol.) of redistilled furan in 75 ml. of 
methylene chloride was cooled to -78.degree. and four drops of boron 
trifluoride etherate was added with stirring. The reaction mixture was 
warmed to room temperature and left for 3 hours. Chromotography on silica 
gel with methylene chloride and methylene chloride containing increasing 
amounts of ethyl acetate gave the title compound. 
EXAMPLE 28 
N-t-Butoxycarbonyl-2-(4-hydroxyphenyl)glycine and 
N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine. 
A solution of 1.5 g (0.005 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine 
n-butyl ester in 10 ml. of methylene chloride was slowly added over a 1 
hour period to a stirred solution of 0.6 g. (0.006 mol.) of phenol and 0.1 
ml. of boron trifluoride etherate in 15 ml. of methylene chloride. After 3 
hours the reaction mixture was chromatographed on 50 g. of silica gel and 
eluted with methylene chloride containing increasing amounts of ethyl 
acetate to give N-t-butoxycarbonyl-2-(4-hydroxyphenyl)-glycine n-butyl 
ester and N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine n-butyl ester. 
A solution of 0.5 g. (1.5 mmol). of 
N-t-butoxycarbonyl-2-(4-hydroxyphenyl)glycine n-butyl ester in 20 ml. of 
methanol and 30 ml. of 5% aqueous sodium carbonate was heated at reflux 
for 30 minutes. The solvent was removed in vacuo and the aqueous residue 
was extracted with ethyl acetate. The aqueous phase was acidified to pH 
3.0 with phosphoric acid and again extracted with ethyl acetate. The 
extract was dried (Na.sub.2 SO.sub.4) and concentrated to give 
N-t-butoxycarbonyl-2-(4-hydroxyphenyl)glycine, m.p. 
112.degree.-114.degree. (methanol-water). 
Similarly, N-t-butoxycarbonyl-2-(2-hydroxyphenyl)-glycine n-butyl ester was 
hydrolyzed to give N-t-butoxycarbonyl-2-(2-hydroxyphenyl)glycine, m.p. 
125.degree. (methylene chloride-water). 
EXAMPLE 29 
.alpha.-(N-t-Butoxycarbonylamino)pyrrole-2-acetic acid n-butyl ester. 
A solution of 14.5 g. (0.05 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine 
n-butyl ester and 10 ml. of redistilled pyrrole in 75 ml. of toluene was 
slowly distilled with replacement of fresh toluene to maintain the volume 
at 50-75 ml. After 30 minutes the reaction mixture was cooled and 
concentrated in vacuo. The residue was dissolved in hexane and 
chromatographed on alumina (Woelm, activity II) with hexane-benzene 
followed by benzene to give the title compound. 
EXAMPLE 30 
N-Benzyloxycarbonyl-2-(4-hydroxyphenyl)glycine and 
N-benzyloxycarbonyl-2-(2-hydroxphenyl)glycine 
To a solution of 1.73 g. (0.010 mol.) of phenol and 0.2 ml. of boron 
trifluoride etherate in 20 ml. of methylene chloride was added dropwise 
with stirring over a 15 minute interval 3.37 g. (0.011 mol.) of 
N-benzyloxycarbonyl-2-acetoxyglycine n-butyl ester. After 3 hours the 
reaction mixture was cooled and the precipitate collected by filtration to 
give N-benzyloxycarbonyl-2-(4-hydroxyphenyl)glycine n-butyl ester, m.p. 
143.degree.-144.degree.. 
The filtrate was concentrated in vacuo and the residue was dissolved in 
benzene and chromatographed on silica gel. Elution with benzene containing 
increasing amounts of ethyl acetate gave 
N-benzyloxycarbonyl-2-(2-hydroxyphenyl)glycine n-butyl ester, m.p. 
114.degree.-117.degree. (ethyl acetate-hexane) and additional amounts of 
the 4-hydroxy isomer. 
By the same procedure, substitution of an equivalent amount of 
N-benzyloxycarbonyl-2-n-butoxyglycine n-butyl ester for 
N-benzyloxycarbonyl-2-acetoxyglycine n-butyl ester gave 
N-benzyloxycarbonyl-2-(4-hydroxyphenyl)-glycine n-butyl ester and 
N-benzyloxycarbonyl-2-(2-hydroxyphenyl)glycine n-butyl ester. 
Hydrolysis of N-benzyloxycarbonyl-2-(4-hydroxyphenyl)glycine n-butyl ester 
as described in Example 29 gave 
N-benzyloxycarbonyl-2-(4-hydroxyphenyl)glycine, m.p. 
188.degree.-190.degree. (dec.). 
Similarly, N-benzyloxycarbonyl-2-(2-hydroxyphenyl)glycine n-butyl ester was 
hydrolyzed to give N-benzyloxycarbonyl-2-(2-hydroxyphenyl)glycine, m.p. 
145.degree.-148.degree. (dec.). 
N-Benzyloxycarbonyl-2-(4-hydroxyphenyl)glycine was also obtained from 
treatment of a cold solution of 3.3 g. (0.01 mol.) of 
N-benzyloxycarbonyl-2-S-benzylthioglycine and 1.9 g. (0.02 mol.) of phenol 
in 20 ml. of methylene chloride with 1 ml. of boron trifluoride etherate 
and 6.4 g (0.02 mol.) of mercuric acetate. The reaction mixture was 
stirred at 25.degree. for 18 hours, then hydrogen sulfide was added to 
decompose the mercuric salts and the mixture was shaken with 5% aqueous 
sodium bicarbonate-ether. The aqueous phase was acidified to pH 2.0 with 
5% hydrochloric acid and extracted with ethyl acetate. The extract was 
washed with water, dried (Na.sub.2 SO.sub.4) and concentrated in vacuo to 
give N-benzyloxycarbonyl-2-(4-hydroxyphenyl)glycine, crystallized from 
ethyl acetate-hexane; m.p. 182.degree.-185.degree. (dec.). 
EXAMPLE 31 
N-Benzyloxycarbonyl-2-(4-methoxyphenyl)glycine n-butyl ester 
When an equivalent amount of N-benzyloxycarbonyl-2-acetoxyglycine n-butyl 
ester was substituent in the procedure of Example 22 for 
N-t-butoxycarbonyl-2-acetoxy glycine n-butyl ester, the title compound was 
obtained. 
EXAMPLE 32 
N-Benzyloxycarbonyl-2-(4-methylthiophenyl)glycine n-butyl ester 
A solution of 1.6 g. (5.0 mmol.) of N-benzyloxycarbonyl-2-acetoxyglycine 
n-butyl ester, 1.0 g. (8.0 mmol.) of thioanisole and 10 drops of boron 
trifluoride etherate in 10 ml. of methylene chloride was stirred at 
25.degree. for 2 hours. The reaction mixture was diluted with hexane and 
chromatographed on silica gel with hexane followed by 1:1 
chloroform-hexane to give the title compound. 
EXAMPLE 33 
.alpha.-(N-Benzyloxycarbonylamino)thiophene-2-acetic acid n-butyl ester 
A solution of 1.6 g. (5.0 mmol.) of N-benzyloxycarbonyl-2-acetoxyglycine 
n-butyl ester ad 1.0 ml. of thiophene in 10 ml. of methylene chloride was 
treated with three drops of boron trifluoride etherate and left to stir at 
25.degree. for 16 hours. The reaction mixture was concentrated in vacuo 
and the residue was dissolved in methylene chloride and chromatographed on 
silica gel with methylene chloride containing increasing amounts of ethyl 
acetate to give the title compound, m.p. 37.degree.. 
EXAMPLE 34 
.alpha.-(N-Benzyloxycarbonylamino)pyrrole-2-acetic acid n-butyl ester 
Substitution of an equivalent amount of 
N-benzyloxycarbonyl-2-acetoxyglycine n-butyl ester in the procedure of 
Example 29 for N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester gave the 
title compound. 
EXAMPLE 35 
N-(.beta.,.beta.,.beta.-Trichloroethoxycarbonyl)-2-(4-methoxyphenyl)-glycin 
e n-butyl ester 
A solution of 0.91 g. (3.0 mmol.) of 
N-(.beta.,.beta.,.beta.-trichloroethoxycarbonyl)-2-acetoxyglycine n-butyl 
ester and 0.3 g. (2.8 mmol.) of anisole in 20 ml. of methylene chloride 
containing two drops of boron trifluoride etherate was maintained at 
25.degree. for 5 hours. The solvent was then evaporated in vacuo and 2:1 
hexane-methylene chloride was added. Chromatography on silica gel with 
methylene chloride containing increasing amounts of ethyl acetate gave the 
title compound. 
Alternatively, the title compound was obtained by substitution of 10 ml. of 
toluene containing 0.3 ml. of trifluoroacetic acid in the procedure 
described above for methylene chloride and boron trifluoride etherate 
followed by refluxing the reaction mixture was 1.75 hours and 
chromotography as described. 
EXAMPLE 36 
N-(.beta.,.beta.,.beta.-Trichloroethoxycarbonyl(-2-(4-hydroxy-3,5-dimethylp 
henyl)glycine n-butyl ester 
A solution of 1.8 g. (6 mmol.) of 
N-(.beta.,.beta.,.beta.-trichloroethoxycarbonyl(-2-acetoxyglycine n-butyl 
ester and 1.2 g. (10 mmol.) of 2,6-dimethylphenol in 20 ml. of methylene 
chloride containing three drops of boron trifluoride etherate was stirred 
at 25.degree. for 3 hours. The reaction mixture was concentrated in vacuo, 
5 ml. of 2:1 hexane-methylene chloride was added and the resulting 
solution was chromatographed on silica gel. Elution with 2:1 
hexane-methylene chloride then with methylene chloride containing 
increasing amounts of ethyl acetate gave the title compound. 
In like manner, the title compound was prepared by substituting an 
equivalent amount of formic acid or trifluoroacetic acid in the procedure 
described above for methylene chloride and boron trifluoride etherate 
followed by refluxing the reaction mixture was 1 hour and chromatography 
as described. 
EXAMPLE 37 
.alpha.-(N-.beta.,.beta.,.beta.-Trichloroethoxycarbonylamino)pyrrole-2-acet 
ic acid 
When an equivalent amount of 
N-(.beta.,.beta.,.beta.-trichloroethoxycarbonyl)-2-acetoxyglycine n-butyl 
ester was substituted in the procedure of Example 29 for 
N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester, 
.alpha.-(N-.beta.,.beta..beta.-trichloroethoxycarbonylamino)pyrrole-2-acet 
ice acid n-butyl ester, m.p. 51.5.degree. (hexane) was obtained. 
A suspension of 3.7 g. of the ester in 5% aqueous sodium bicarbonate and 
200 ml. of methanol was stirred at 25.degree. for 48 hours. The reaction 
mixture was concentrated in vacuo and the remaining aqueous solution was 
extracted with methylene chloride. The aqueous phase was cooled acidified 
to pH 3.0 with phosphoric acid and extracted with ethyl acetate. The 
extract was dried (Na.sub.2 SO.sub.4) and concentrated to give the title 
compound, m.p. 111.degree. (hexane). 
EXAMPLE 38 
.alpha.-(N-.beta.,.beta.,.beta.-Trichloroethoxycarbonylamino)purine-7-aceti 
c acid n-butyl ester 
When an equivalent amount of 
N-(.beta.,.beta.,.beta.-trichloroethoxycarbonyl(-2-acetoxyglycine n-butyl 
ester was substituted in the procedure of Example 26 for 
N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester, the title compound was 
ultimately obtained, m.p. 114.degree.-116.degree. (major product; 
acetone-hexane).