N.sup.2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

N.sup.2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

EXAMPLE 1 
(A) N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginine: 
To a well stirred solution of 83.6 g of L-arginine in 800 ml of 10% 
potassium carbonate solution was added 112.7 g of 
2-dibenzothiophenesulfonyl chloride in 800 ml of benzene. The reaction 
mixture was stirred at 60.degree. C for 5 hours, during which time the 
product precipitated. After one hour at room temperature, the precipitate 
was filtered and washed successively with benzene and water to give 127 g 
(76 percent) of N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginine. 
(B) N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginyl chloride: 
A suspension of 4.21 g of N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginine in 
20 ml of thionyl chloride was stirred for 2 hours at room temperature. 
Addition of cold dry diethyl ether resulted in a precipitate which was 
collected by filtration and washed several times with dry diethyl ether to 
give N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginyl chloride. 
(C) N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine tert-butyl 
ester: 
To a stirred solution of 2.67 g of N-butylglycine tert-butyl ester in 20 ml 
of chloroform was carefully added N.sup.2 
-(2-dibenzothienylsulfonyl)-L-arginyl chloride obtained above. The 
reaction mixture was allowed to stand at room temperature for one hour. 
At the end of this period, the reaction mixture was washed twice with 20 ml 
of saturated sodium chloride solution and evaporated to dryness. 
The residue was triturated with a small amount of diethyl ether to give an 
amorphous solid. This was collected by filtration and reprecipitated from 
ethanol-ethyl ether to give 3.1 g (49 percent) of N.sup.2 
-(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester. 
I.R. (KBr): 3350, 1740, 1625 cm.sup.-1 
Analysis - Calcd. for C.sub.28 H.sub.39 O.sub.5 N.sub.5 S.sub.2.1/2H.sub.2 
SO.sub.3 (percent): C, 53.31; H, 6.39; N, 11.10 Found (percent): C, 53.21; 
H, 6.46; N, 10.89 
(D) N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine: To a 
solution of 2.00 g of N.sup.2 
-(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester in 
20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction 
mixture was stirred for 5 hours at room temperature. At the end of this 
period, the reaction mixture was evaporated to dryness. The residue was 
washed several times with dry diethyl ether and chromatographed on 80 ml 
of Daiaion .RTM. SK 102 ion exchange resin (200-300 mesh, H.sup.30 form, 
manufactured by Mitsubishi Chemical Industries Limited) packed in water, 
washed with water and eluted with 3% ammonium hydroxide solution. 
The fraction eluted from 3% ammonium hydroxide solution was evaporated to 
dryness to give 0.9 g (53 percent) of N.sup.2 
-(2-dibenzothienylsulfonyl)-L-arginyl-N-butylglycine as an amorphous 
solid, I.R. (KBr): 3350, 1640, 1270 cm.sup.-1 
Analysis-Calcd. for C.sub.24 H.sub.31 N.sub.5 O.sub.5 S.sub.2 (percent): C, 
54.01; H, 5.86; N, 13.12 Found (percent): C, 53.78; H, 5.97; N, 12.96 
EXAMPLE 2 
(A) N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine 
ethyl ester 
To a stirred solution of 2.42 g of N-(2-methoxyethyl) glycine ethyl ester 
and 4.0 ml of triethylamine in 50 ml of chloroform, which was cooled in an 
ice-salt bath, was added in portions N.sup.2 
-(2-dibenzothienylsulfonyl)-L-arginyl chloride obtained above. The 
reaction mixture was stirred overnight at room temperature. At the end of 
this period, 50 ml of chloroform was added and the chloroform solution was 
washed twice with 25 ml of saturated sodium chloride solution, dried over 
anhydrous sodium sulfate and evaporated in vacuo. The oily residue was 
washed with ethyl ether to give 5.5 g of powdery N.sup.2 
-(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl 
ester 
Analysis calcd for C.sub.25 H.sub.23 O.sub.6 N.sub.5 S.sub.2.1/2 H.sub.2 
SO.sub.3 (percent): C, 50.49; H, 4.07; N, 11.78 Found (percent): C, 50.22; 
H, 4.18; N, 11.51 
(B) N.sup.2 
-(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine: 
A solution of 5.5 g of N.sup.2 
-(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine ethyl 
ester in 15 ml of methanol and 15 ml of 2N-NaOH solution was warmed to 
40.degree. C and held at that temperature for 10 hours. At the end of this 
period, the reaction mixture was concentrated and chromatographed on 200 
ml of Daiaion .RTM. SK 102 ion exchange resin (200-300 mesh, H.sup.30 
form, manufactured by Mitsubishi Chemical Industries Limited) packed in 
water, washed with ethanol-water (1 : 4) and eluted with 
ethanol-water-NH.sub.4 OH (10 : 9 : 1). The main fraction was evaporated 
to dryness and washed with ethyl ether to give 3.05 g (62 percent) of 
N.sup.2 -(2-dibenzothienylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine as 
an amorphous solid. I.R. (KBr): 3,400, 1,630, 1,280 cm.sup.-1 
Analysis-Calcd for C.sub.23 H.sub.29 O.sub.6 N.sub.5 S.sub.2 (percent): C, 
51.57; H, 5.46; N, 13.08 Found (percent): C, 51.35; H, 5.63; N, 12.86 
EXAMPLE 3 
(A) N.sup.G -nitro-N.sup.2 -(tert-butoxycarbonyl)-L-arginyl-N-butylglycine 
benzyl ester 
To a stirred solution of 28.4 g of N.sup.G -nitro-N.sup.2 
-(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran were 
added in turn 12.4 ml of triethylamine and 12.4 ml of isobutyl 
chloroformate while keeping the temperature at -5.degree. C. After 15 
minutes, to this were added 35.0 g of N-butylglycine benzyl ester 
p-toluenesulfonate, 12.4 ml of triethylamine and dry tetrahydrofuran, and 
then the mixture was stirred for 15 minutes at -5.degree. C. At the end of 
this period, the reaction mixture was warmed to room temperature. The 
solvent was evaporated and the residue taken in 400 ml of ethyl acetate, 
and washed successively with 200 ml of water, 100 ml of 5% sodium 
bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of 
water. The ethyl acetate solution was dried over anhydrous sodium sulfate. 
Upon evaporation of the solvent, the residue was dissolved in 20 ml of 
chloroform, and the solution was applied to a column (80 cm .times. 6 cm) 
of 500 g of silica gel packed in chloroform. 
The product was eluted first with chloroform, and then 3% 
methanol-chloroform. The fraction eluted from 3% methanol-chloroform was 
evaporated to dryness to give 26.0 g (56 percent) of N.sup.G 
-nitro-N.sup.2 -(tert-butoxycarbonyl)-L-arginyl-N-butylglycine benzyl 
ester in the form of a syrup. I.R. (KBr): 3,300, 1,740, 1,690 cm.sup.-1 
(B) N.sup.G -nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride: 
To a stirred solution of 26.0 g of N.sup.G -nitro-N.sup.2 
-(tertbutoxycarbonyl)-L-arginyl-N-butylglycine benzyl ester in 50 ml of 
ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0.degree. C. 
After 3 hours, to this solution was added 200 ml of dry ethyl ether to 
precipitate a viscous oily product. This was filtered and washed with dry 
ethyl ether to give 20.8 g of N.sup.G -nitro-L-arginyl-N-butylglycine 
benzyl ester hydrochloride as an amorphous solid. 
(C) N.sup.G -nitro-N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine benzyl 
ester: 
To a stirred solution of 2.33 g of N.sup.G -nitro-L-arginyl-N-butylglycine 
benzyl ester hydrochloride in 10 ml of water and 40 ml of dioxane were 
added in turn 1.26 g of sodium bicarbonate, and 2.2 g of 
3-cyclohexyl-4-methoxyphenylsulfonyl chloride at 5.degree. C, and stirring 
was continued for 3 hours at room temperature. At the end of this period, 
the solvent was evaporated and the residue dissolved in 100 ml of ethyl 
acetate, and washed successively with 10 ml of 1N hydrochloric acid 
solution, 20 ml of water, 20 ml of 5% sodium bicarbonate and 10 ml of 
water. 
The ethyl acetate solution was dried over anhydrous sodium sulfate. Upon 
evaporation of the solvent, the residue was chromatographed on 50 g of 
silica gel packed in chloroform, washed with chloroform and eluted with 3% 
methanol-chloroform. The fraction eluted from 3% methanol-chloroform was 
evaporated to give 2.6 g (77 percent) of N.sup.G -nitro-N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine benzyl 
ester in the form of an amorphous solid. I.R. (KBr): 3,300, 2,920, 1,740, 
1,640, 1,250 cm.sup.-1 
Analysis - Calcd. for C.sub.32 H.sub.46 O.sub.8 N.sub.6 S (percent): C, 
56.95; H, 6.87; N, 12.46 Found (percent): C, 56.49; H, 6.63; N, 12.38 
(D) N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine 
To a solution of 3.00 g of N.sup.G -nitro-N.sup.2 
-(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine benzyl 
ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water was 
added 0.5 g of palladium-black and then the mixture was shaken in a 
hydrogen atmosphere for 50 hours at room temperature. At the end of this 
period, the ethanol solution was filtered to remove the catalyst and 
evaporated to dryness. The residue was washed several times with dry ethyl 
ether and chromatographed on 80 ml of Daiaion.RTM. SK 102 ion exchange 
resin (200-300 mesh, H.sup.+ form, manufactured by Mitsubishi Chemical 
Industries Limited) packed in water, washed with water, and eluted with 3% 
ammonium hydroxide solution. The fraction eluted from 3% ammonium 
hydroxide solution was evaporated to dryness to give 1.5 g (72%) of 
N.sup.2 -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-butylglycine 
as an amorphous solid. I.R. (KBr): 3,350, 2,920, 1,630, 1,250 cm.sup.-1 
Analysis - Calcd. for C.sub.25 H.sub.41 N.sub.6 O.sub.5 S.sub.1 (percent): 
C, 55.63; H, 7.66; N, 12.98 Found (percent): C, 55.32; H, 7.39; N, 12.84 
EXAMPLE 4 
(A) N.sup.2 
-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl 
chloride hydrochloride: 
A suspension of 2.00 g of N.sup.2 
-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine in 
20 ml of thionyl chloride was stirred for 2 hours at room temperature. 
Addition of cold dry ethyl ether resulted in a precipitate which was 
collected by filtration and washed several times with dry ethyl ether to 
give N.sup.2 
-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl 
chloride hydrochloride. 
(B) N.sup.2 
-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine 
m-tolyl ester hydrochloride: 
A mixture of 2.00 g of m-cresol and N.sup.2 
-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycyl 
chloride hydrochloride obtained above was heated at 90.degree. C for 50 
minutes. At the end of this period, the reaction mixture was cooled, 
washed several times with dry ethyl ether, and then dissolved in 10 ml of 
dry ethyl alcohol. Addition of cold dry ethyl ether resulted in a 
precipitate which was washed several times with dry ethyl ether to give 
2.12 g (86 percent) of N.sup.2 
-(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxyethyl)glycine 
m-tolyl ester hydrochloride in the form of a powder. I.R. (KBr): 3,250, 
3,100, 1,740, 1,640 cm.sup.-1. Various other N.sup.2 
-arylsulfonyl-L-argininamides or acid addition salts thereof were 
synthesized in accordance with the procedures of the above examples, and 
the test results are summarized in Table 2. 
TABLE 2 
__________________________________________________________________________ 
Sam- 
##STR529## time by acoagulationprolong the required 
toConcentration 
processrationPrepa- 
Physical 
Upper: 
CalculatedElemental 
analysis I.R. 
ple Addition 
factor of two 
(Ex. 
proper- 
Lower: 
(KBr) 
No. 
Ar R moiety 
(.mu.M) No. ties C H N (cm.sup.-1) 
__________________________________________________________________________ 
1 
##STR530## 
##STR531## 20 3 53.82 53.59 
6.21 6.11 
13.08 
3,350, 1,630 
1,270, 1,160 
2 
##STR532## 
##STR533## 38 3 57.02 56.69 
6.81 6.65 
12.79 12.84 
3,400, 1,630 
1,260 
3 
##STR534## 
##STR535## 5 3 55.63 55.32 
7.66 7.39 
12.98 12.84 
3,350, 2,920 
1,630, 1,250 
4 
##STR536## 
##STR537## 3 49.57 49.24 
6.66 6.79 
17.34 17.48 
3,400, 1,640 
1,530, 1,160 
5 
##STR538## 
##STR539## 3 46.95 46.67 
5.71 5.79 
19.17 18.87 
3,400, 1,680 
1,630, 1,380 
6 
##STR540## 
##STR541## 2 50.89 50.79 
5.96 5.98 
14.13 13.86 
3,400, 1,740 
1,630 
7 
##STR542## 
##STR543## 19 3 52.70 52.66 
6.32 6.19 
17.56 17.82 
8 
##STR544## 
##STR545## 2 54.32 54.08 
5.70 5.96 
15.84 15.73 
3,400 1,635 
1,510 
9 
##STR546## 
##STR547## 2 52.44 52.43 
5.69 5.86 
12.74 12.58 
3,400 1,630 
1,290 
10 
##STR548## 
##STR549## 1/2H.sub.2 SO.sub.3 
2 50.49 50.22 
4.07 4.18 
11.78 11.51 
3,350 1,735 
1,620 
11 
##STR550## 
##STR551## 2 51.57 51.35 
5.46 5.63 
13.08 12.86 
3,400 1,630 
1,280 
12 
##STR552## 
##STR553## 2 
13 
##STR554## 
##STR555## 1 54.01 53.78 
5.86 5.97 
13.12 12.96 
3,350 1,640 
1,270 
14 
##STR556## 
##STR557## 2 54.22 54.08 
5.50 5.36 
13.18 12.95 
3,400 1,700 
1,635 
__________________________________________________________________________ 
EXAMPLE 5 
Tablets suitable for oral administration 
Tablets containing the ingredients indicated below may be prepared by 
conventional techniques. 
______________________________________ 
Amount 
per 
tablet 
Ingredient (mg) 
______________________________________ 
N.sup.2 -(3-cyclohexyl-4-methoxy- 
250 
phenylsulfonyl)- 
L-arginyl-N-butylglycine 
Lactose 140 
Corn starch 35 
Talcum 20 
Magnesium stearate 5 
Total 450 mg 
______________________________________ 
EXAMPLE 6 
Capsules for oral administration 
Capsules of the below were made up by thoroughly mixing together batches of 
the ingredients and filling hard gelatin capsules with the mixture. 
______________________________________ 
Amount 
per 
capsule 
Ingredient (mg) 
______________________________________ 
N.sup.2 -(3-cyclohexyl-4-methoxy- 
250 
phenylsulfonyl)- 
L-arginyl-N-butylglycine 
Lactose 250 
Total 500 mg 
______________________________________ 
EXAMPLE 7 
Sterile solution for infusion 
The following ingredients are dissolved in water for intravenous perfusion 
and the resulting solution is then sterilized. 
______________________________________ 
Ingredients Amount (g) 
______________________________________ 
N.sup.2 -(3-cyclohexyl-4-methoxy- 
25 
phenylsulfonyl)- 
L-arginyl-N-butylglycine 
Buffer system As desired 
Glucose 25 
Distilled water 500 
______________________________________ 
PREATION A 
Arylsulfonyl chlorides 
(A) Sodium 6,7-dimethoxy-2-naphthalenesulfonate 
To a well stirred solution of 70.8 g of sodium 
6,7-dihydroxy-2-naphthalenesulfonate and 77.2 g of sodium hydroxide in 450 
ml of water was added dropwise 230 ml of dimethyl sulfate at 60.degree. C 
over a period of 1 hour, during which time the product precipitated. To 
this reaction mixture was added in portions 38.8 g of sodium hydroxide, 
and stirring was continued for one hour. After one hour at room 
temperature, the precipitate was filtered, washed with ethanol and dried 
to give 50 g of sodium 6,7-dimethoxy-2-naphthalenesulfonate. 
(B) 6,7-dimethoxy-2-naphthalenesulfonyl chloride 
To a stirred suspension of 50 g of finely divided sodium 
6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide was 
added dropwise 62.2 ml of thionyl chloride at room temperature. After 30 
minutes, the reaction mixture was poured into 1 l of ice water, and the 
precipitate filtered and then dissolved into 250 ml of benzene. The 
benzene solution was repeatedly washed with water and dried over anhydrous 
sodium sulfate. The solvent was evaporated to dryness in vacuo, and the 
residue was recrystallized from benzene-n-hexane (1:1) to give 32 g of 
6,7-dimethoxy-2-naphthalenesulfonyl chloride, M.P. 
127.5.degree.-129.5.degree. C 
Analysis - Calcd. for C.sub.12 H.sub.11 O.sub.4 SCl (percent): C, 50.26; H, 
3.87; Cl, 12.37 Found (percent): C, 50.45; H, 4.00; Cl, 12.33 
The following arylsulfonyl chlorides not previously reported in the 
chemical literature were synthesized by the aforementioned procedure which 
is essentially that as described in E. H. Rodd, "Chemistry of Carbon 
Compounds", Elsevier Publishing Company, 1954, Vol III, P. 441-469. 
______________________________________ 
No. Arylsulfonyl Chloride M.P. (.degree. C) 
______________________________________ 
##STR558## 118 - 119.5 
2 
##STR559## 136.5 - 138.5 
3 
##STR560## 137 - 139 
______________________________________ 
PREATION B 
Amino acid derivatives 
(A) N-butylglycine tert-butyl ester 
To 36.5 g of butylamine was added with stirring 15.05 g of tert-butyl 
chloroacetate over a period of 30 minutes, while maintaining the 
temperature at 30.degree.-70.degree. C. The reaction mixture was held at 
70.degree. C for an additional one hour. At the end of this period, the 
excess butyl amine was evaporated in vacuo, and the residue was taken up 
in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a 
separatory funnel and well shaken. The benzene solution was separated, 
washed with water, dried over anhydrous sodium sulfate and filtered. After 
evaporation of benzene, the residue was distilled under reduced pressure 
to give 17.0 g (90.9 percent) of N-butylglycine tert-butyl ester, B.P. 
76.degree. C/4 mmHg. 
The following amino acid tert-butyl esters not previously reported in the 
chemical literature were synthesized by the aforementioned procedure which 
is essentially that as taught by A. J. Speziale et al., J. Org. Chem. 25, 
731 (1960). 
______________________________________ 
No. Amino Acid Derivative 
B.P. 
______________________________________ 
##STR561## 95.degree. C/20 mmHg 
2 
##STR562## 65.degree. C/5 mmHg 
3 
##STR563## 89 - 90.degree. C/2.5 mmHg 
4 
##STR564## 83 - 5.degree. C/1.5 mmHg 
5 
##STR565## 125 - 130.degree. C/4 mmHg 
6 
##STR566## 61 - 2.degree. C/2 mmHg 
7 
##STR567## 94.degree. C/3 mmHg 
8 
##STR568## 60 - 3.degree. C/3 mmHg 
9 
##STR569## 95 - 7.degree. C/5 mmHg 
10 
##STR570## 102.degree. C/4 mmHg 
11 
##STR571## 166.degree. C/10 mmHg 
12 
##STR572## 106 - 9.degree. C/1.5 mmHg 
13 
##STR573## 97.degree. C/2.5 mmHg 
14 
##STR574## 101.degree. C/5 mmHg 
15 
##STR575## 101.degree. C/5 mmHg 
16 
##STR576## 105.degree. C/4 mmHg 
17 
##STR577## 129 - 130.degree. C/8 mmHg 
18 
##STR578## 145.degree. C/15 mmHg 
19 
##STR579## 156.degree. C/10 mmHg 
20 
##STR580## 93.degree. C/26 mmHg 
21 
##STR581## 110.degree. C/27 mmHg 
22 
##STR582## 124.degree. C/26 mmHg 
23 
##STR583## 88 - 90.degree. C/6 mmHg 
24 
##STR584## 116 - 8.degree. C/2 mmHg 
25 
##STR585## 167.degree. C/16 mmHg 
26 
##STR586## 125.degree. C/16 mmHg 
27 
##STR587## 141.degree. C/15 mmHg 
28 
##STR588## 89.degree. C/3 mmHg 
29 
##STR589## 111.degree. C/1 mmHg 
30 
##STR590## 91 - 2.degree. C/1 mmHg 
31 
##STR591## 115.degree. C/2 mmHg 
32 
##STR592## 82 - 84.degree. C/2 mmHg 
33 
##STR593## 150.degree. C/0.5 mmHg 
34 
##STR594## 95 - 6.degree. C/2 mmHg 
35 
##STR595## 
______________________________________ 
(B) N-(2-methoxyethyl)glycine ethyl ester 
To a stirred solution of 165.2 g of 2-methoxyethylamine and 202.4 g of 
triethylamine in 1 l of benzene was added dropwise a solution of 334.0 g 
of ethyl bromoacetate in 200 ml of benzene in one hour at room 
temperature. At the end of this period, the mixture was heated at reflux 
for 2 hours to complete the reaction. Upon chilling, the triethylamine 
hydrobromide was removed by filtration and washed with benzene. After 
removal of the solvent, the product was distilled in vacuo to yield 242.8 
g (75.3 percent) of N-(2-methoxyethyl)glycine ethyl ester, B.P. 
73.degree.-5.degree. C/4 mmHg. 
The following amino acid ethyl esters not previously reported in the 
chemical literature were synthesized by the aforementioned procedure which 
is essentially that as taught by A. J. Speziale et al., J. Org. Chem., 25 
731 (1960). 
______________________________________ 
M.P. (.degree. C) or B.P. 
No. Amino Acid Ethyl Ester 
(.degree. C/mmHg) 
______________________________________ 
##STR596## 57 - 8.degree. C/3 mmHg 
2 
##STR597## 63 - 4.degree. C/3 mmHg 
3 
##STR598## 91 - 3.degree. C/2 mmHg 
4 
##STR599## 101 - 2.degree. C 
5 
##STR600## 113 - 6.degree. C/3 mmHg 
6 
##STR601## 116 - 7.degree. C/1 mmHg 
7 
##STR602## 78 - 80.degree. C/2 mmHg 
8 
##STR603## 63 - 4.degree. C 
______________________________________ 
(C) N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate 
To a solution of 55.8 g of N-(2-methoxyethyl)glycine tert-butyl ester in 
200 ml of benzene was added 63.8 g of benzyl alcohol and 72.9 g of 
p-toluenesulfonic acid monohydrate. The mixture was heated at reflux for 
10 hours with the continuous removal of water through a Dean-Stark water 
trap. At the end of this period, the solution was concentrated in vacuo, 
and to the residue was added 300 ml of dry ethyl ether. After 2 hours at 
room temperature, the formed precipitate was filtered, washed with dry 
ethyl ether and then recrystallized from ethyl acetate to yield 99.2 g (85 
percent) of N-(2-methoxyethyl)glycine benzyl ester p-toluenesulfonate, 
M.P. 95.degree.-6.degree. C. 
The following amino acid benzyl ester p-toluenesulfonate not previously 
reported in the chemical literature were synthesized by the aforementioned 
procedure. 
______________________________________ 
Amino Acid Benzyl Ester 
No. p-Toluenesulfonate M.P. (.degree. C) 
______________________________________ 
##STR604## 97 - 9 
2 
##STR605## 122 - 4 
3 
##STR606## 94 - 5 
4 
##STR607## 66 - 8 
5 
##STR608## 101 - 2 
6 
##STR609## 140 - 3 
7 
##STR610## 154 - 6 
8 
##STR611## 133 - 5 
9 
##STR612## 133 - 5 
10 
##STR613## 133 - 8 
11 
##STR614## 103 - 6 
12 
##STR615## 92 - 4 
13 
##STR616## 123 - 6 
14 
##STR617## 119 - 123 
______________________________________ 
Having now fully described the invention, it will be apparent to one of 
ordinary skill in the art that many changes and modifications can be made 
thereto without departing from the spirit of the invention as set forth 
herein.