The known blood platelet antiaggregative agent 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one is prepared in high yield via an improved process involving a novel intermediate of the Formula ##STR1## in which R.sup.1 is (lower)alkyl and X is bromo, chloro or iodo. Two processes for the preparation of compounds of the Formula III are disclosed, one of which involves the novel intermediate ##STR2##

SUMMARY OF THE INVENTION 
This application relates to a new and improved process for the preparation 
of the known blood platelet antiaggregative compound 
6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one of Formula I 
##STR3## 
from a (lower)alkyl N-(6-amino-2,3-dichlorobenzyl)glycine of Formula II 
##STR4## 
in which R.sup.1 is (lower)alkyl, via a novel (lower)alkyl 
5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate hydrohalide 
intermediate of Formula III 
##STR5## 
in which R.sup.1 is (lower)alkyl and X is bromo, chloro or iodo. 
DESCRIPTION OF THE PRIOR ART 
U.S. Pat. No. 3,932,407 discloses compounds of the formula 
##STR6## 
IN WHICH R.sup.1 is H, phenyl or (lower)alkyl, R.sup.2 and R.sup.3 when 
alike are H, chloro, bromo, fluoro, (lower)alkyl, hydroxy or 
(lower)alkoxy, R.sup.2 and R.sup.3 when different are H, chloro, bromo, 
fluoro, SO.sub.3 H, CF.sub.3, hydroxy, nitro, amino, phenyl, (lower)alkyl 
of 1 to 3 carbon atoms or (lower)alkoxy of 1 to 3 carbon atoms, or when 
taken together R.sup.2 and R.sup.3 are methylenedioxy or the residue of a 
phenyl ring, and n is an integer of 1 or 2; and pharmaceutically 
acceptable acid addition salts thereof. The compounds, which are disclosed 
as hypotensive, blood platelet antiaggregative and/or bronchodilator 
agents, are prepared inter alia by a multistep process ending the reaction 
of CNBr with an ethanol solution of a compound of the formula 
##STR7## 
in which R.sup.1, R.sup.2, R.sup.3 and n are as described above, and 
R.sup.4 is (lower)alkyl. Although the above patent generically discloses 
the compound of Formula I as being prepared by the above process, its 
preparation is specifically exemplified only by chlorination of the 
compound of the formula

COMPLETE DISCLOSURE 
When a compound of Formula II is reacted in alcoholic solution with CNBr 
according to the prior art process, the compound of Formula I is formed 
directly. We have unexpectedly found that much higher yields of Compound I 
may be obtained by reacting Compound II with CNBr, CNCl or CNI in an 
inert, aprotic organic solvent and isolating the novel intermediate of 
Formula III. Intermediate III is then treated with a base to produce the 
compound of Formula I. Surprisingly, the yield of Compound I obtained in 
this two-step procedure typically is about four times greater than the 
yield obtained in the one-step process. 
According to one embodiment of the present invention there is provided a 
compound of the formula 
##STR9## 
wherein R.sup.1 is (lower)alkyl and X is chloro, bromo or iodo. In a 
preferred embodiment X is bromo and R.sup.1 is methyl, ethyl, n-propyl, 
isopropyl or n-butyl. In a more preferred embodiment X is bromo and 
R.sup.1 is methyl, ethyl or n-propyl. In a most preferred embodiment X is 
bromo and R.sup.1 is ethyl. 
According to another embodiment of the present invention there is provided 
a process for the preparation of a compound of the Formula 
##STR10## 
wherein R.sup.1 is (lower)alkyl and X is chloro, bromo or iodo, which 
process comprises reacting a compound of the Formula 
##STR11## 
wherein R.sup.1 is as defined above with a compound of the Formula CNX 
wherein X is as defined above, in an aprotic, reaction-inert organic 
solvent, at a temperature up to about 200.degree.. A preferred temperature 
range is from about 50.degree. to about 150.degree. and a more preferred 
range is from about 80.degree. to about 120.degree.. It is preferred to 
use at least one mole of CNX per mole of Compound II and it is more 
preferred to use about an equimolar amount. 
Suitable aprotic, reaction-inert, organic solvents for use in this reaction 
will be apparent to those skilled in the art. Such solvents include 
benzene, toluene, xylene, hexane, heptane, octane, nonane, 
2,2,4-trimethylpentane, cyclopentane, cyclohexane, cycloheptane, 
tetrahydrofuran, dioxane, chloroform, carbon tetrachloride, di-n-propyl 
ether and di-n-butyl ether. A preferred solvent is toluene. 
Intermediate III is readily converted to the compound of Formula I by 
reaction with about an equimolar amount of a base, and preferably an 
organic base, and most preferably a tertiary amine such as triethylamine, 
N,N-dimethylaniline or the like. The reaction is conducted in an 
non-reactive solvent and preferably in a (lower)alkanol such as ethanol, 
propanol, 2-methoxyethanol or the like. 
Preparation of Starting Materials 
The preparation of starting compounds of Formula II by two different routes 
is given below, as exemplified by the preparation of the compound of 
Formula II in which R.sup.1 is ethyl. 
##STR12## 
2,3,4-Trichloronitrobenzene 
A 12 liter resin pot equipped with an efficient mechanical stirrer and a 
thermometer was charged with 90% (sp. gr. 1.4826) nitric acid (3.6 
liters). An iced-water bath was used to keep the temperature between 
25.degree. and 30.degree. while 1,2,3-trichlorobenzene (1.89 kg, 10.4 mol) 
was added in portions over 30 minutes. The resulting mixture was stirred 
for 30 minutes and then poured into a 9.5 liter battery jar equipped with 
an efficient stirrer and containing about 5 kg of ice. The resulting solid 
was filtered off and washed well with water. 
This solid cannot be dried in a vacuum oven because it sublimes. Therefore, 
it was taken up in CH.sub.2 Cl.sub.2 (about 3 liters) and the water layer 
was separated. The CH.sub.2 Cl.sub.2 solution was washed with water (500 
ml) and with saturated aqueous NaCl (500 ml), and then dried over 
MgSO.sub.4. The drying agent was filtered off and the filtrate was 
concentrated in vacuo. Before the residue solidified it was poured into a 
crystallizing dish. Then it was dried in a desiccator at ca. 1 mm Hg 
pressure over P.sub.2 O.sub.5. Yield 2237 g (95%); mp. 
52.degree.-54.5.degree.. 
2,3-Dichloro-6-nitrobenzonitrile 
Under a nitrogen atomosphere, pyridine (42 ml, 0.52 mol) was spread evenly 
over a mixture of 2,3,4-trichloronitrobenzene (225 g, 1 mol) and cuprous 
cyanide (89.6 g, 1 mol). The mixture was heated to 100.degree. and held at 
this temperature until it became stirrable. Then the stirred mixture was 
heated to 165.degree. over 1.5 hours, and held at this temperature for 30 
minutes. The dark mixture was allowed to cool, then concentrated HCl (500 
ml) and toluene (250 ml) were added. The mixture was vigorously stirred 
for 1.5 hours. The layers were separated and the aqueous phase was 
extracted with toluene (3 .times. 250 ml). The combined toluene extracts 
were washed with concentrated HCl (3 .times. 250 ml), water (250 ml) and 
saturated aqueous NaCl (2 .times. 250 ml). The toluene solution was dried 
over Na.sub.2 SO.sub.4, filtered and stripped to obtain 185 g (85%) of the 
title benzonitrole. The product was 87% pure and contained about 7% 
trichloronitrobenzene. Recrystallization from methanol (2.1 ml/g) gave a 
product of 99% purity. 
2,3-Dichloro-6-nitrobenzylamine 
To a solution of recrystallized 2,3-dichloro-6-nitrobenzonitrile (434 g, 2 
mol) in tetrahydrofuran (THF) (2.4 liters), under N.sub.2, was added a 
solution of borane in THF (4 liters of a 1 molar solution). The addition 
was made over about 1.25 hours and the reaction temperature rose to 
61.degree. (reflux). The solution was refluxed for 2 hours after the 
addition was complete. 
The solution was cooled to 16.degree. and 1 liter of water added. The 
addition was made very cautiously at first because the first few 
milliliters of water produced a lot of foam. Then concentrated HCl (470 
ml) was added and the solution was stirred overnight. 
The solution was concentrated in vacuo to remove THF, filtered and the 
residue washed with diethyl ether. The filtrate was extracted with diethyl 
ether (3 .times. 500 ml). Then the aqueous solution was chilled and 
basified (pH 8) with 40% aqueous NaOH (about 600 ml). The alkaline 
solution was extracted with diethyl ether (3 .times. 500 ml). The ethereal 
extracts were combined and washed with H.sub.2 O (250 ml), then with 
saturated aqueous NaCl (250 ml) and then dried over Na.sub.2 SO.sub.4. 
Filtration and evaporation of the solvent gave 305 g (69%) of the title 
product as an orange, crystalline solid. Gas chromatography indicated that 
the product was about 77% pure, but it was used as such in the next step. 
An analytical sample of the above product (obtained via purification of 
its hydrochloride) melted at 51.degree.-53.degree.. 
Ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride 
A solution of ethyl bromoacetate (157 ml, 1.41 mols) in dioxane (1 liter) 
was added dropwise to a refluxing solution of 
2,3-dichloro-6-nitrobenzylamine (306.2 g, 1.38 mols) and triethylamine 
(193 ml, 1.38 mols) in dioxane (1 liter). The addition took 2 hours and 
the mixture was refluxed for 16 hours after the addition was complete. The 
cooled mixture was filtered to remove TEA.HBr, the residue was washed with 
dioxane and the filtrate and washings were combined and stripped of 
solvent. The residue was suspended in absolute ethanol (2 liters) and the 
mixture was cooled in an iced water bath while being saturated with 
gaseous HCl. Anhydrous ether (2 liters) was added and the resulting 
mixture was stirred for about 1 hour, then filtered. The residue was 
washed with anhydrous ether, then dried under pump vacuum (0.5-1 mm Hg). A 
yield of 238 g (50%) was obtained. Chromatography of the free base showed 
no contaminants. An analytical sample, obtained by recrystallization from 
an ethanol-ether mixture, melted at 203.degree.-205.degree.. 
N-(6-Amino-2,3-dichlorobenzyl)glycine Ethyl Ester 
A solution of stannous chloride dihydrate (1051.4 g., 5.06 mol) in 
concentrated HCl (3.8 liters) was added briskly (35 minutes) to a cooled 
solution of ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine hydrochloride (344 
g., 1.00 mol) in concentrated HCl (2.8 liters). The temperature was held 
at 22.degree. .+-. 5.degree. during the addition. The mixture was slowly 
(approximately 0.5 hour) heated to 40.degree. after the addition and held 
at that temperature for one hour. After being stirred briefly without 
being heated the mixture was cooled to 15.degree. and then filtered 
through a sintered glass filter. The residue was washed with a little ice 
cold water. 
The solid was suspended in water (3.5 liters) and the mixture basified with 
ammonium hydroxide while being chilled in an iced water bath. The 
resulting mixture was extracted with ether (3 .times. 1 liter). The ether 
extracts were combined and washed with water (250 ml) and saturated 
aqueous NaCl (250 ml) and then dried over Na.sub.2 SO.sub.4. Filtering and 
stripping gave 242 g. (87%) of the title product, mp 
56.degree.-60.degree.. This material was 92% pure by chromatography. 
##STR13## 
iso-Nitroso-m-chloroacetanilide 
This material was prepared in 91% yield by the procedure of A. E. Senear, 
et al., J. Am. Chem. Soc., 68, 2695 (1946). 
4-Chloroisatin 
A mixture of the 4-chloro and 6-chloro isomers was prepared by the 
procedure of Senear, et al., above. After separation of the isomers by the 
method of P. W. Sadler, J. Org. Chem., 21, 169 (1956), recrystallization 
of 4-chloroisatin from ethanol gave a 23% yield of product. In a large 
scale run, the 4-chloro isomer was obtained in 42% yield and did not 
require recrystallization. 
4,5-Dichloroisatin 
Chlorination of 4-chloroisatin with sulfuryl chloride by the method of B. 
R. Baker, et al., J. Org. Chem., 17, 149 (1952), gave a 70% yield of the 
title compound. 
5,6-Dichloroanthranilic Acid 
This material was obtained from 4,5-dichloroisatin in 91% yield by the 
method of B. R. Baker, et al., J. Org. Chem., 17, 141 (1952). 
6-Amino-2,3-Dichlorobenzyl Alcohol 
A solution of borane (0.55 mol) in 550 ml of tetrahydrofuran was slowly 
added, over a period of 1 hour, to a solution of 5,6-dichloroanthranilic 
acid (44.5 g, 0.216 mol) in tetrahydrofuran (1200 ml). The solution was 
heated at reflux for 18 hours, cooled and treated slowly with 550 ml of 1N 
HCl. The tetrahydrofuran was removed in vacuo at 30.degree. and the 
aqueous mixture was washed with ether and then made basic with 
concentrated NH.sub.4 OH. The resulting solid was extracted with ether, 
dried (K.sub.2 CO.sub.3) and the solvent was evaporated to leave 31.5 g. 
(76%) of the title compound as light pinkish needles, m.p. 
133.5.degree.-135.degree.. An analytical sample was prepared by 
recrystallization from benzene; white needles, m.p. 
134.degree.-135.5.degree.. 
Calcd. for C.sub.7 H.sub.7 Cl.sub.2 NO: C, 43.78; H, 3.67; N, 7.30. Found: 
C, 43.79; H, 3,87; N, 7.17. 
N-(6-Amino-2,3-dichlorobenzyl)glycine Ethyl Ester 
A solution of 6-amino-2,3-dichlorobenzyl alcohol (10.0 g., 0.0521 mol) in 
250 ml. of boiling benzene was treated with a slow-stream of dry hydrogen 
chloride for 0.5 hour. The finely divided suspension was cooled slightly, 
thionyl chloride (12.4 g, 0.104 mol) was added in one portion, and reflux 
was continued for 2.5 hours. The solution was evaporated in vacuo to 
remove excess thionyl chloride and hydrogen chloride, and the residue was 
redissolved in 250 ml. benzene. This solution was added over 1 hour to a 
reluxing mixture of glycine ethyl ester hydrochloride (29.1 g, 0.208 mol) 
and triethylamine (31.6 g, 0.313 mol) in 600 ml. CH.sub.2 Cl.sub.2. Reflux 
was continued for 1 hour, the mixture was allowed to stand overnight and 
was then extracted with 1N HCl. The extract was washed with CH.sub.2 
Cl.sub.2 and ether, made slightly alkaline with concentrated NH.sub.4 OH 
and extracted with ether. After drying (K.sub.2 CO.sub.3) and evaporation 
there remained 8.3 g (58%) of the title product as a light yellow oil 
which crystallized. The analytical sample was obtained from Skellysolve B 
as white needles, mp. 60.degree.-61.degree. C. 
Calcd. for C.sub.11 H.sub.14 Cl.sub.2 N.sub.2 O.sub.2 : C, 47.67; H, 5.09; 
N, 10.11. Found: C, 47.75; H, 5.18; N, 10.34. 
COMATIVE PREATION 1 
6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one Hydrochloride 
Prepared Via The One-Step Prior Art Procedure 
A solution of cyanogen bromide (3.2 g, 0.030 mol) in 100 ml. 
2-methoxyethanol was added to a solution of 
N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester (8.2 g, 0.030 mol) in 
250 ml. 2-methoxyethanol. The solution was stirred at room temperature for 
1 hour, heated at reflux for 22 hours, and cooled. The precipitate was 
filtered off, washed with ether and air dried to give 3.11 gms. of the 
crude title product (31% yield as the hydrobromide salt). 
Recrystallization from ethanolic HCl gave the pure title product in 71% 
recovery (22% overall yield); m.p. &gt;250.degree.. 
Calcd. for C.sub.10 H.sub.7 Cl.sub.2 N.sub.3 O.HCl.0.5H.sub.2 O: C, 39.82; 
H, 3.01; N, 13,93. Found: C, 39.58; H, 3.19; N, 13.32. 
As stated above, the compound of Formula I is a known blood platelet 
antiaggregative agent. Table I compares the activities of the compound of 
Formula I and other known blood platelet antiaggregative agents in various 
antiaggregative and antithrombosis tests. Although the compounds of 
Formula III are primarily intended as intermediates in the preparation of 
the compound of Formula I, they themselves have blood platelet 
antiaggregative properties. For comparison purposes, one of the compounds 
of Formula III (R.sup.1 = ethyl, X = bromo) is included in Table I. The 
tests referred to in Table I were conducted as set out in detail in J. S. 
Fleming, et al., Journal of Pharmacology and Experimental Therapeutics, 
194, 435 (1975). 
SLIDE II 
__________________________________________________________________________ 
Antiaggregative and Antithrombosis Tests in Various In Vitro, Ex Vivo 
And In Vivo Experimental Systems 
Aggregometry - Rabbit - PRP 
In Vivo Animal Models ED50's (mg/kg) 
In Vitro EC50 
Ex Vivo ED50 
Rabbit 
Dog Rat 
(.mu.g/ml) (mg/kp ip) Biolaser 
Electrical 
Endotoxin 
Compound ADP Collagen 
ADP Collagen 
Thrombosis 
Thrombosis 
Shock 
__________________________________________________________________________ 
Aspirin &gt;512 7 &gt;100 3 &gt;60 iv 
50 po 
&gt;256 po 
Dipyridamole 
&gt;512 245 &gt;100 &gt;100 &gt;60 iv 
&gt;35 ip 
&gt;256 po 
Sulfinpyrazone 
&gt;512 62 &gt;100 3 &gt;60 iv 
&gt;100 po 
&gt;128 po 
Compound I 0.3 0.08 1.25 1 2.5 po 
1.5 po 
25 po 
Compound III 
9 3.6 Not Tested 
-- -- -- -- 
(R.sup.1 = ethyl, X = Br) 
__________________________________________________________________________ 
PRP = Platelet-rich plasma 
ADP = Adenosine diphosphate 
As used herein, the term (lower)alkyl refers to a straight or branched 
chain alkyl group containing from 1 to 6 carbon atoms. All temperatures 
given herein are in degrees centigrade. 
The following examples illustrate, but in no way limit, the present 
invention. 
EXAMPLE 1 
Ethyl 5,6-Dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
Hydrobromide 
A solution of cyanogen bromide (0.53 gm. 5 mmol) in toluene (10 ml.) was 
added to a solution of N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester 
(1.39 gm, 5 mmol) in toluene (10 ml.) and stirred at room temperature. 
There was an almost immediate precipitate. Stirring was continued for 30 
minutes, and the reaction mixture was then heated to reflux and refluxed 
for 18 hours. After cooling, the solid was filtered off, washed with 
toluene and dried to give 1.81 gm (94.5%) of the title product. A portion 
of the product was recrystallized from ethanol, washed with ethanol and 
ether, and dried in vacuo at 78.degree. to give an analytical sample as 
golden crystals. 
Calcd. for C.sub.12 H.sub.13 Cl.sub.2 N.sub.3 O.sub.2.HBr: C, 37.62; H, 
3.68; N, 10.97. Found: C, 37.59; H, 3.57; N, 10.80. 
EXAMPLE 2 
Ethyl 5,6-Dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
Hydrobromide 
A solution of cyanogen bromide (89.6 g, 0.85 mol) in toluene (1.6 liters) 
was poured into a solution of N-(6-amino-2,3-dichlorobenzyl)glycine ethyl 
ester (231 g, 0.834 mol) in toluene (1.6 liters). The temperature rose 
quickly from 18.degree. to 31.degree.. The mixture was slowly (1 hour) 
heated to reflux and refluxed for 12 hours. The mixture was cooled to room 
temperature and filtered, the product being washed with toluene both by 
decantation and on the filter. The residue was washed with ether and then 
dried under pump vacuum (0.5-1 mm Hg) over P.sub.2 O.sub.5. A yield of 290 
g (91%) of the title product was obtained as a brown powder. When heated 
this powder decomposed over a wide temperature range: 
200.degree.-300.degree.. 
Its infrared and nmr spectra were consistent with the desired product. 
Infrared peaks were at 3140 (broad), 1745 (--C.dbd.O), 1661 (--C.dbd.N--), 
1636, 1550, 1471 and 1215 cm.sup.-1. Nmr peaks (TMS standard) were at 
.delta. 8.24 (broads s), 7.25 (AB, q, 2H), 4.69 (s, 2H), 4.55 (s, 2H), 
4.27 (q, 2H) and 1.32 (t, 3H). 
EXAMPLE 3 
6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one 
A mixture of ethyl 
5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate hydrobromide 
(289.6 g, 0.756 mol), absolute ethanol (4.5 liters) and triethylamine (106 
ml, 0.758 mol) was refluxed for 4 hours. The mixture was cooled and as 
much of the ethanol as possible decanted off. The solid was suspended in 
fresh absolute ethanol and, after the mixture was stirred for 0.5 hour, 
filtered off. Then the solid was suspended in a mixture of absolute 
ethanol (600 ml.) and 95% ethanol (2.4 liters) and refluxed for 4 hours. 
The mixture was filtered while warm. The solid was dried under pump vacuum 
(0.5-1 mm Hg) over P.sub.2 O.sub.5. This gave 179 g (92%) of the title 
product as an ivory colored solid. 
Infrared peaks were at 1702 (weak), 1638, 1554, 1468, and 1440 cm.sup.-1. 
Nmr peaks (TFA) were at .delta. 7.33 (AB, q, 2H), 4.97 (s, 2H) and 4.59 
(s, 2H). 
EXAMPLE 4 
6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one 
Monohydrochloride Monohydrate 
6,7-Dichloro-1,5-dihydroimidazo[2,1-b]-quinazolin-2(3H)-one (94.0 g, 0.367 
mol) was added to 2.82 liters of boiling methanol. To the suspension was 
added 77 ml. (0.92 mol) of concentrated hydrochloric acid. A nearly 
complete solution resulted. Darco G-60 was added, the mixture was boiled 
for ca. 3 minutes and then filtered. The filtrate was reheated to boiling 
to effect solution, then cooled slightly, and 1.9 liters of ether added 
cautiously. The mixture was stirred at ambient temperature for 2 hours and 
the solid was filtered off. (Crop A). 
Some material tended to crystallize in the funnel during the charcoal 
treatment step; the charcoal and solids therefore were suspended in hot 
methanol and filtered. This filtrate was combined with the filtrate from 
Crop A, and the combined filtrates were concentrated in vacuo to about 1.3 
liters and heated to boiling to effect complete solution. After filtration 
and slight cooling, 800 mls. of ether were added and the mixture was 
stirred at room temperature for 1 hour. The resulting solid was filtered 
off (Crop B). Chromatography showed both crops to be of very high purity. 
They were combined and dried in vacuo (ca. 1 mm Hg) overnight. Total 
weight of product was 88.1 gm. Karl Fischer analysis indicated 2.27% 
water. The material was placed in a desiccator over saturated aqueous 
Ca(NO.sub.3).sub.2 (ca. 50% relative humidity) and analyzed for water 
daily. After 4 days analysis showed 5.64% water (5.80% theoretical for 
monohydrate). The weight of product was 91.9 gm (80.6% of theoretical). 
EXAMPLE 5 
The general procedure of Example 1 is repeated, except that the cyanogen 
bromide utilized therein is replaced by an equimolar amount of cyanogen 
chloride, and there is thereby produced ethyl 
5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate hydrochloride. 
EXAMPLE 6 
The general procedure of Example 1 is repeated, except that the cyanogen 
bromide utilized therein is replaced by an equimolar amount of cyanogen 
iodide, and there is thereby produced ethyl 
5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate hydroiodide. 
EXAMPLE 7 
The general procedure of Example 1 is repeated, except that the 
N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester utilized therein is 
replaced by an equimolar amount of 
N-(6-amino-2,3-dichlorobenzyl)glycine methyl ester, 
N-(6-amino-2,3-dichlorobenzyl)glycine n-propyl ester, 
N-(6amino-2,3-dichlorobenzyl)glycine isopropyl ester and 
N-(6-amino-2,3-dichlorobenzyl)glycine n-butyl ester, respectively, 
and there is thereby produced 
methyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydrobromide, 
n-propyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydrobromide, 
isopropyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydrobromide and 
n-butyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydrobromide, respectively. 
EXAMPLE 8 
The general procedure of Example 5 is repeated, except that the 
N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester utilized therein is 
replaced by an equimolar amount of 
N-(6-amino-2,3-dichlorobenzyl)glycine methyl ester, 
N-(6-amino-2,3-dichlorobenzyl)glycine n-propyl ester, 
N-(6-amino-2,3-dichlorobenzyl)glycine isopropyl ester and 
N-(6-amino-2,3-dichlorobenzyl)glycine n-butyl ester, respectively, 
and there is thereby produced 
methyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydrochloride, 
n-propyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydrochloride, 
isopropyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydrochloride and 
n-butyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydrochloride, respectively. 
EXAMPLE 9 
The general procedure of Example 6 is repeated, except that the 
N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester utilized therein is 
replaced by an equimolar amount of 
N-(6-amino-2,3-dichlorobenzyl)glycine methyl ester, 
N-(6-amino-2,3-dichlorobenzyl)glycine n-propyl ester, 
N-(6-amino-2,3-dichlorobenzyl)glycine isopropyl ester and 
N-(6-amino-2,3-dichlorobenzyl)glycine n-butyl ester, respectively, 
and there is thereby produced 
methyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydroiodide, 
n-propyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydroiodide, 
isopropyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydroiodide and 
n-butyl 5,6-dichloro-3,4-dihydro-2(1H)-iminoquinazoline-3-acetate 
hydroiodide, respectively.