Note: Descriptions are shown in the official language in which they were submitted.
1 321 592
H-380(2)
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This invention relates to a process for the preparation
of pharmacologically active thiazolobenzimidazoles and
to the intermediates used therein. More particularly
this inveniton relates to a process for the preparation
of thiazolo[3,2-a]benzimidazoles and to furo[2 ,3 :-
4,5]thiazolo[3,2-a]benzimidazolone intermediates formed
in said process.
Thiazolo[3,2-a]benzimidazoles are disclosed in US
Patent No. 4,214,089, published 22 July 1980, as
antineoplastic agents and/or as enhancers of the immune
response. Many other compounds possess the ability to
inhibit growth of neoplastic tissue, however,
cytotoxicity is a major side effect injuring other
tissues in the body. These
thiazolo-[3,2-a]benzimidazoles are noted for their low
incidence of side effects, particularly their low
thyrotoxic liability. One of the compounds exemplified
and claimed therein has the name
3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic
acid. This compound and related thiazolo[3,2-a]benzim-
idazoles are also disclosed in US Patent No. 4,361,574
published 30 November 1982, as inhibitors of mammalian
collagenase. Collagen is a major organic component of
the surface tissue of the cornea, skin,
gastrointestinal viscera, joint mucosa and other areas
of the body. Collagenases are capable of breaking down
collagen; thereby destroying collagen-based tissue
which constitutes the major organic component of the
areas previously noted. Hence collagen inhibitors are
useful in the treatment of diseases where destruction
of collagen connective tissue plays a central role,
such as for example periodontal disease, rheumatoid
arthritis corneal ulcerations and so forth.
1 32 1 592 ~{-380
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In US Patent Nos. 4,214,089 and 4,361,574 the process
for preparing the th;azolo[3,2-a]-benzimidazoles
described involves the dehydration of a corresponding
2,3-dihydro-3-hydroxy-thiazolo[3,2-a]benzimidazole by
warming at reflux temperature in an aqueous acid,
dioxane mixture.
Accordingly the reaction may be represented by the
scheme below:
;.)n C(~ l,R
l~x ~ ,"eo~s ~c~ xa ne
~q~ ,~(CH2)"CO~,R
in which formulae n is 1 or 2, R is hydrogen or lower
alkyl and R1 is hydrogen, lower alkyl, lower alkoxy,
trifluoromethyl or halo. In the case of
3-(p-chlorophenyl)thiazolo[3,2-a]benzimidazole itself,
Example 1 of US Patent No. 4,361,574 illustrates the
preparation in only 42% yield using 6N HCl and dioxane
as solvent and heating at reflux for 18 hours. Indeed
it has been found that this process for preparing
compounds of formula I gives relatively poor yields
ranging from 20 to 50 per cent and furthermore the
reaction product is difficult to purify without a
further significant loss in yield. The yield for this
same process as described in Journal of Medicinal
Chemistry, 1976, Vol, 19, No.4. pps 524-530 is only
23%.
1 32 1 5~2 ~l-380
It has now surprîsingl.y been found that by carrying out
the reaction, with heating if necessary, in the
presence of a strong acid selected from the group
consisting of sulphuric and phosphoric acids or
mixtures thereof then the yield of the aforementioned
reaction may be substantially improved and a cleaner
product obtained.
Accordingly this invention provides a process for
preparing thiazolo[3,2-a]benzimidazoles of formula I as
defined above or a salt thereof wherein R is hydrogen
which comprises dehydrating a compound of formula II as
defined above wherein COOR is an acid or ester function
in the presence of acid sel.ected from the group
consisting of sulphuric and phosphoric acids or
mixtures thereof and if desired or required an inert
solvent provided that if water is present then the
amount of water is less than about 15% by vol.ume of the
acid, the reaction being carried out with heating if
necessary.
If the reaction is carried out using a liquid acid then
solvent is not required but can be present.
It is most preferred to carry out the reaction under
substantially anhydrous conditions but small amounts of
water may be present eg. up to about 15% v/v based on
1 32 1 592 ~1-380t2)
acid. Preferably the amount is not more than about 10%
by volume based on acid, most preferably less than
about 5/O v/v. When sulphuric acid is used it is
preferred to have some water present to prevent
charring; eg. up to about 4% v/v based on acid.
The reaction is conveniently carried out at room
temperature and for a sufficient time to achieve
optimum product yield. For example when concentrated
sulphuric acid is used reaction times of 3-S hours and
reaction temperatures of from 5 to 25C provide high
yields (eg. 95 + 5%) of product. It has been found
that the ratio of compound of formula II to acid
affects reaction times being favoured by excess
quantities of acid. For example by changing the ratio
of reactants reaction times may be between a rew
minutes up to 24 hours or longer. Typically the ratio
of acid to compound of formula II is within a range
from about 12:1 to about 0.3:1 volume by weight, eg.
from about 10:1 to about 0.5:1. Reaction times may be
shortened by applying heat to the reaction mixture.
Inert solvents may be employed in the reaction but
generally reaction temperature and or reaction times
must be raised to achieve optimum yields to compensate.
Examples of inert solvents are alkanoic acids eg.
acetic acid. Since the reaction can proceed without
heating it provides a substantial saving in energy
costs over the previously disclosed route. A further
important advantage is that product yield can be
virtually quantitative as may be seen from the Examples
herein.
/
The starting materials of formula II and methods for
making them are also disclosed in US Patent No.
3,704,239. Other ester analogues may be prepared by
analogous processes. Preferably R is hydrogen or lower
alkyl.
1 32 1 592 H380
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The following Examples illustrate this invention:
Example 1
3-(p-Chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic
acid
A solution of sulphuric acid (4.0 1) was cooled to 5C
then 3-(p-chlorophenyl)-2,3 -dihydro-3-hydroxythiazolo-
[3,2-a]benzimidazole-2-acetic acid hydrochloride salt
(1.66 kg, 4.18 mol.) was added portionwise over one
hour maintaining a temperature range of 15-20C. The
mixture was stirred for an additional three hours at
2 o
5 C.
Water (6.0 1) was heated to 45C and the reaction
mixture added to it over forty-five minutes maintaining
a temperature range of 5S-60C. The mixture was
stirred for thirty minutes at 55-60C and then cooled
to 35C. The sulphate salt of 3-(p-chlorophenyl)-
thiazolo[3,2-a]benzimidazole-2-acetic acid was isolated
by centrifugation and washed with water (6.0 1~. The
filter cake was spun down for fifteen minutes.
The wet sulphate was combined with water (10.0 1),
heated to 60C and stirred for one hour. The slurry
was cooled to 35C and the crude product isolated by
centrifugation. The solids were washed with water
tS.0 1~ and the filtercake spun down for fifteen
minutes.
The wet filtercake was combined with water (10.5 1) and
stirred at 20-25C while basifying to a pH of about
9.5 with concentrated ammonium hydroxide (0.4 1). The
solution was stirred for fifteen minutes before line
filtering through a 0.2 ~ line filter. The residual
solids were rinsed with water (1.0 1).
1 32 1 5q2 H-380(2)
The product solution was acidified over a twenty minute
period to a pH of 5.5 at 20-25C by adding glacial
acetic acid (.380 l). The slurry was stirred for
thirty minutes. The title compound was isolated by
centrifugation, washed with water t4.0 L), spun down
for 30 minutes and dried in a forced air oven at
55-60C . A yield of 1334 g or 93% of theory was
obtained, mp 242-244C.
HPLC Assay: 99.6%
Non Acidic Titration: 99.8%
Total Impurities: 0.02%
Example 2
3-(p-Chlorophenyl)thiazolo[3,2-a]benzimidazole-
2-acetic acid
Concentrated sulphuric acid (200 ml) was cooled to 0C,
and to it was added portionwise a total of 100 g of
3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo-
[3,2-a]benzimidazole-2-acetic acid, hydrobromic acid
salt keeping the temperature of the reaction mixture
under 10C. After all was added , the resulting dark
red solution was stirred until the temperature of the
reaction mixture reached 25C. The solution was then
stirred for 3 hours at 25C until the colour of the
solution became a light yellow.
The light yellow solution was added dropwise to 300 ml
of hot water (50C) so as not to exceed the temperature
over 60C.
After the addition was complete the mixture was stirred
at 60C for 1 hour. White solids were collected by
filtration at 60C, reslurried in 550 ml of hot water
(60C) and stirred for 30 minutes at 60C. The solids
1 32 1 5~2 H-380(2)
were removed by filtration at 60C and washed with
water (200 ml).
To -the solids in H20 (500 ml~, with stirring was added
19 ml of concentrated ammonium hydroxide to make the pH
of the so ~ n 9~5. The solution was filtered through
a bed of cel~--t-e. to the clear filtrate, glacial acetic
acid (20 ml) was added dropwise until pH 5.5. The
precipitate was stirred for 1 hour, collected by
filtration and washed twice with water (200 mL). The
title compound was dried under vacuum at 60C for 18
hours, 68.9g, mp 242-244C.
Analysis
C17H11N2ClS02 requires: C,5g.56; H,3.24; N,8.17;
Found: C-59.48; H,3.46; N,8.08%.
Example 3
3-(p-Chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic
acid
To 40 ml of 85% phosphoric acid, 20 g of 3-(p-chloro-
phenyl)-2,3-dihydro-3-hydroxythiazo]o[3,2-a]-
benzimidazole-2-acetic acid, hydxochloric acid salt was
added portionwise. After the addition was complete,
the mixture was heated to 100C and stirred for 5 hours
at 100C. The reaction solution was then cooled to
25C and added dropwise to 100 ml of hot water (50C)
so as not to exceed a temperature of 60C.
After the addition was complete, the mixture was
stirred at 60C for 1 hour. Off white solids were
1 32 1 592 H-380(2)
_9_
collected by filtration at 60C, reslurried in 80 ml of
hot water (60C) and stirred for 30 minutes at 60C.
The off white solids were removed by filtration and
washed with 50 ml of H20. To the solids in 75 ml of
H20 was added 8.2 ml ammonium hydroxide to make pH of
the solution 9.5. The solution was filtered through a
bed of celite. To the clear solution, 4 ml of glacial
acetic acid was added dropwise until pH 5.5. The
precipitates were stirred for 1 hour, collected by
filtration and washed twice with 50 ml of H20. The
title compound was dried under vacuum at 60C for 18
hours, mp 242-244C (dec).
Example 4
3-(p-Chlorophenylthiazolo[3,2-a]benzimidazole-2-acetic
. . _
acid
A mixture of 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxy-
thiazolo[3,2-a]benzimidazole-2-acetic acid,
hydrochloric acid salt (20 g~ and orthophosphoric acid
(40 g~ was heated to 100C for 4 hours. The reaction
solution was cooled to 25C and to this 100 ml of H20
was added dropwise so as not to exceed a temperature of
60C. After the addition was complete, the mixture was
stirred at 60C for 1 hour. White solids were
collected by filtration at 60C, reslurried in 80 ml of
hot water (60C~ and stirred for 30 minutes at 60C.
The white solids were then removed by filtration and
washed with 50 ml of H20.
To the solids in 75 ml of H20, was added 8.2 ml
ammonium hydroxide to make pH of the solution 9.5.
The solution was filtered through a bed of celite. To
the clear solution, 4 ml of glacial acetic acid was
1 32 1 592 ~1-380(2)
--1 0--
added dropwise until pH 5.5. The precipi-tates were
stirred for 1 hour, collected by filtration and washed
twice with 50 ml of H20. The title compound was dried
under vacuum at 60C for 18 hours. Yield 15.2g
(88.8%); mp 242-244C (dec).
