METHODE DE PREPARATION DE 5,6,7,7A-TETRAHYDRO-4H- THIENO-[)3,2,-C]PYRIDIN-2-ONE

PROCESS FOR MAKING 5,6,7,7A-TETRAHYDRO-4H- THIENO- [)3,2,-C]PYRIDIN-2-ONE

Abrégé anglais

ABSTRACT OF THE DISCLOSURE


The present invention provides a process for the
preparation of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-pyridin-
2-one derivatives of the general formula:


Image (I)

in which R is a hydrogen atom or a phenyl radical optionally
substituted by at least one halogen atom, lower alkyl radi-
cal, lower alkoxy radical, nitro group, carboxy group,
alkoxycarbonyl radical or cyano group; R' is a hydrogen atom
or a lower alkyl radical; and n is 0, 1, 2, 3 or 4; and of
their acid addition salts with mineral and organic acids,
wherein
a) a compound of the general formula:

Image (II)

in which R, R' and n have the same meanings as above, is
treated with a solution of hydrogen peroxide in a mixture
of acetic acid and hydrobromic acid to give a brominated
derivative of the general formula:


Image (III)


in which R, R' and n have the same meanings as above;
b) the brominated derivative (III) is converted into an
organo-magnesium compound in an inert anhydrous solvent,
this organo-magnesium compound then being condensed with
tert.-butyl perbenzoate to give a compound of the general
formula:




Image
(IV)


in which R, R' and n have the same meanings as above; and
c) the compound (IV) is heated to a temperature of from 80
to 180°C. in the presence of a mineral or organic acid to
give the desired derivative of general formula (I).

Revendications

PATENT CLAIMS

1. Process for the preparation of 5,6,7,7a-tetrahydro-4H-
thieno(3,2-c)pyridin-2-one derivatives of the general formula:-

Image (I)

in which R is hydrogen or phenyl substituted by at least one
halogen, lower alkyl, lower alkoxy, nitro, carboxy, alkoxycar-
bonyl or cyano; R' is hydrogen or lower alkyl; and n is 0, 1,
2, 3 or 4, and of their acid addition salts with mineral and
organic acids, wherein a) a compound of the general formula:-



Image (II)

in which R, R' and n have the same meanings as above, is
treated with a solution of hydrogen peroxide in a mixture of
acetic acid and hydrobromic acid to give a brominated deriva-
tive of the general formula:-




Image (III)






in which R, R' and n have the same meanings as above; b) the
brominated derivative (III) is converted into an organo-
magnesium compound in an inert anhydrous solvent, this organo-
magnesium compound then being condensed with tert.-butyl
perbenzoate to give a compound of the general formula:-

Image (IV)

in which R, R' and n have the same meanings as above; and

c) the compound (IV) is heated to a temperature of from 80°
to 180°C. in the presence of a mineral or organic acid to give
the desired derivative of general formula (I).


2. Process according to claim 1, wherein the hydrogen peroxide
solution used in step a) is an alcoholic solution of hydrogen
peroxide.


3. Process according to claim 2, wherein the alcoholic solution
of hydrogen peroxide is a methanolic solution of 30% hydrogen
peroxide.



4. Process according to claim 1 wherein the mixture of acetic
acid and hydrobromic acid used in step a) contains the two
acids in a ratio of from 50/50 to 80/20.


5. Process according to claim 1 wherein the acetic acid used
is pure acetic acid.





6. Process according to claim 1, wherein the hydrobromic acid
used is 48% acid.


7. Process according to claim 1 wherein the organo-magnesium
compound prepared in step b) is obtained by reacting the
brominated derivative (III) with metallic magnesium and an
alkyl halide.


8. Process according to claim 7, wherein the alkyl halide
used is isopropyl bromide.


9. Process according to claim 1, wherein the inert solvent
used in step b) is anhydrous tetrahydrofuran.


10. Process according to claim 1, wherein the condensation
reaction with tert.-butyl perbenzoate in step b) is carried
out in the same reaction medium as that used for the prepa-
ration of the organo-magnesium compound without isolation
thereof.


11. Process according to claim 1, wherein the acid used in
step e) is p-toluenesulphonic acid.


12. Derivatives of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-
pyridin-2-one of claim 1, when prepared by the process ac-
cording to claims 1, 2 and 3.


13. Derivatives of 5,6,7,7a tetrahydro-4H-thieno(3,2-c)-
pyridin-2-one of claim 1, when prepared by the process ac-
cording to claims 4, 5 and 6.


14. Derivatives of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-
pyridin-2-one of claim 1, when prepared by the process ac-
cording to claims 7, 8 and 9.

11


15. Derivatives of 5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-
pyridin-2-one of claim 1, when prepared by the process ac-
cording to claims 10 and 11.

12

Description

The present invention is concerned with a novel
process for the preparation of 5,6,7,7a-tetrahydro-4H-thieno-
(3,2-c)-pyridin-2-one derivatives.
The 5,6,7,7a-tetrahydro~4H-thieno(3,2-c)-pyridin-2-
one derivatives with which the present invention is concerned
are compounds of the general formula:

~ ~(cHR')n-R
O ~ S ~ (I)


in which R is a hydrogen atom or a phenyl radical optionally
substituted by at least one halogen atom, lower alkyl radi-

cal, lower alkoxy radical, nitro group, carboxy group,
alkoxycarbonyl radical or cyano group; R' is a hydrogen atom
or a lower alkyl radical and n is 0, 1, 2, 3 or 4; as well as
the addition salts thereof with mineral and organic acids.
These compounds (I) have platelet anti-aggregant
properties and anti-thrombotic properties and are the subject
matter of CanO Appl. S.N. 391,052 filed Nov. 27, 1981.
Furthermore, they are included in a general formula
given in French Patent Specifications Nos. 2,215,948 and
2,345,150 in the following tautomeric form:
HO ~ ~ (CHR')n-R




in which R, R' and n have the same meanings as above.

However, none of the compounds (I) is specifically
described therein.
According to the present invention, there is pro-
vided a process for the preparation of compounds of general
formula (I), wherein
a) a compound of the general formula:

.,~

'7

,~ ~( CH:E~ ' ) n~ R

~ ~ J (II)
S




in which R, R' and n have the same meanings as above, is
treated with a solution of hydrogen peroxlde in a mixture
of acetic acid and hydrobromic acid to give a bromi.nated
derivative of the general formula:
~ ~(CHR')n-R


Br ~ S ~ (III)
in which R, R' and _ have the same meanings as above;
b) the brominated derivative (III) is converted into an
organo-magnesium compound in an inert anhydrous solvent,
this organo-magnesium compound then being condensed with
-tert.-butyl perbenzoate to give a compound of the general
formula:
_GN / ( ) n (IV)
H C CO S
c~3




in which R~ R' and n have the same meanings as above; and
c) the compound (IV) is heated to a ternperature of from 80
to 180C. in the presence of a mineral or organic acid to
give the desired derivative of general formula (I).
The mixture of acetic acid and hydrobromic acid
used in step a) is preferably within the limits of 50/50 to
80/20.
The hydrobromic acid used in step a) is preferably
48~ hydrobromic acid and the acetic acid used is preferably
pure.
The hydrogen peroxide solution employed in step a)



-- 2


is preferably an alcoholic solution of hydrogen peroxide,
such as a methanolic solution of 30% hydrogen peroxide.
In step b), the inert solvent, such as tetrahydro-
furan, may be used not only for the preparation of the
organo-magnesium compound but also for the subsequent conden-
sation of this organo-magnesium compound with tert.-butyl
perbenzoate.
The organo-magnesium compound is prepared in con-
ventional manner~ for example with the use of metallic mag-

nesium and an alkyl halide, such as isopropyl bromide, in ananhydrous medium.
It is not necessary to isolate the organo-magnesium
compound from the reaction mixture prior to condensation
thereof with tert.-butyl perbenzoate.
In step c), a mineral or organic acid is added, an
example of a preferred acid being _-toluenesulphonic acid.
The process according to the present invention may
be represented by the following reaction scheme:

~(cHR')n-R ~(CHR')n-R
J I H2O2/Hsr I N

S ~ E~r S ~`~-~'

(II) (III)




1) Mg 3 ~ /(CHR')n-R
6H5COO-t. C4Hg H3C-fo ~S ~

c~3




(IV)
The starting materials of general formula (II) may
be prepared by means of the processes described in the liter-

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ature, for example, by means of the processes described in
the above~mentioned French Patent Specifications Nos.
73 03 503 and 75 2~ 486.
The following Examples are given for the purpose of
illustrating the present lnvention.
EXAMPLE 1

5-(2-Chloro ~ )-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-
. Formula (I); R = 2-Cl.C6E14; R' - H; _ = l;
Derivative No. l
A mixture of 3 cc. 30~ hydrogen peroxide and 10 cc.
methanol is added dropwise to a solution, cooled to 0C., of
2.63 g. 5-(2-chlorobenzyl)-4,5,6,7-tetrahydro(3,2~c)-pyridine
in 10 cc. acetic acid and 6 cc. 48~ hydrobromic acid.
When the addition is finished, the reaction mixture
is stirred at ambient temperature for lO minutes, then a so-
lution of sodium hydrosulphite is added thereto, followed by
a solution of sodium carbonate, whereafter the reaction
mixture is extracted with a mixture of benzene and chloro-
form. The organic extracts are washed with water, dried with
anhydrous sodium sulphate and filtered. A solution of gase-
ous hydrogen chloride in methanol is added to the filtrate,
followed by concentration in a vacuum. Recrystallisation of
the solid residue obtained from ethanol gives 2.0 g. of beige
crystals in platelet form, this product being 2-bromo-2-

(2-chlorobenzyl)-~,5,6,7-te-trahydro-thieno(3,2-c)-pyridine;
m.p. with decomposition at about 180C.
A mixture of 1~075 g. of the free base, 0.19 g.
magnesium, 0.57 g. isopropyl bromide and 10 cc. tetrahydro-
furan is heated under reflux for 2 hours under an atmosphere
of nitrogen. After cooling, 1.5 g. tert.-butyl perbenzoate

is added thereto and the reaction mixture then stirred for




15 hours at ambient temperature and subsequently for 1 hour
under reflux. The reaction mixture is poured into an aqueous
solution of sodium citrate and sodium carbonate and then ex-
tracted with benzene. The organic extracts are washed with
water, dried with anhydrous sodium sulphate and concentrated
under reduced pressure. The oily residue obtained is puri-
fied by chromatography on a column of silica, 0.25 g. of a
yellow oil being obtained.
100 mg. of this compound and 100 mg. _-toluene-

sulphonic acid are heated to 150C. for 9 minutes. Afterrapid cooling, the reaction mixture is added to a mixture of
10 cc. 0.15M phosphate buffer (pH 5.5) and 20 cc. butanol.
The organic phase is evaporated under reduced pressure. The
residue obtained is purified by chromatography on a silica
column to give 5-(2-chlorobenzyl)-5,6,7,7a-tetrahydro-4H-
thieno(3,2-c)-py:ridin-2-one; m.p. 73 - 74.5C. (recrystal-
lised from ethanol).
The corresponding oxalate melts at 168 - 170C.,
after recrystallisation from ethanol; IR (KBr): v CO = 1660
cm~l (large).
The corresponding hydrochloride semihydrate, after
precipitation from acetone, melts with decomposition at about
180C
The base melts at 73 - 74.5C., after recrystalli-
sation from ethanol; NMR (CDC13): 7.1-7.6 (m,4H); 6.2 (s,lH);
4.2-4.7 (m,lH); 3.9 (s,2H); 1.5-4.2 (m,6H).
EXAMPLE 2

5-Benzyl-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-p ridin-2-one
Formula (I); R = C6H5; R' = H; _ = l; Derivative No. 2
This is prepared according to the method of E~ample
1, starting from 5-benzyl-4,5,6,7-te-trahydro-thieno(3,2-c)-

.~



pyridine. Maleate: beige crystals; m.p. 132 - 134Cor re-
crysta]lised from isopropanol; IR (KBr): v CO = 1680 cm
Base: NMR (CDC13): 7.25 (m,5H); 5.90 (s,lH); 3.60 (s,2H).
EXAMPLE 3
5 (4-Chlorobenzyl)~5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-
pyridin-2-one. Formula (I); R = 4-Cl.C H ; R' = H; n = l;
_ _ _ 6 4
Derivative No. 3
This is prepared according to the method of Example
1, starting from 5-(4-chlorobenzyl)-4,5,6,7-tetrahydro-
thieno(3,2-c)-pyridine. Maleate: beige crystals; m.p. 158 -
160 C., recrystallised from ethanol; IR (KBr): v CO = 1680
cm 1. Base: NMR (CDC13): 7.30 (m,4H); 6.0 (s,lH); 3.50
(s,2~)
EXAMPLE 4
5-(2-Methylbenzyl)-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-
.
pyridin-2-one. Formula (I); R = 2-H3C.C6H4; R' = H; _ = l;
Derivative No. 4
This is prepared according to the method of Example
1, starting from 5-(2-methylbenzyl)-4,5,6,7-tetrahydro-
thieno(3,2-c)-pyridine. Oxalate: beige crystals, m.p. 195 -
197 C., recrystallised from methanol; IR (KBr): v CO = 1690
cm 1. Base~ NMR (CDC13): 7.10 (s,4H); 5.90 (s,l~l); 3.55
(s,2H); 2.30 (s,3H).
EXAMPLE 5
5~ ~-(2-Chlorophenyl)-ethy ~-5,6,7,7a-tetrahydro-~H-thieno-
(3,2-c)-pyridin-2-one. Formula (I); R = 2-Cl.C6H4; R' = CH3;
. . .
n = l; Derivative No. 5

This is prepared according to the method of Example
1, starting from 5- ~-(2-chlorophenyl ~-4,5,6,7-tetrahydro-
thieno(3,2-c)-pyridine. ~Iydrochloride: yellow crystals;

m.p. 140 - 142 C.; IR (KBr): v CO = 1690 cm . Base: NMR
(CDC13): 7.30 (m,4H); 6.05 and 5.95 (2s,1H); two diastereo-

'7

isomers.
EXA~PLE 6
5- ~-(2-Chloxophenyl)-pro~y ~-5,6,7,7~-tetrahydro(3,2-c)-
. . _ . . _ . ,. . ~
pyridin-2-one. Formula (I); R = 2 Cl-C6H4; R' -- C2H5; n = l;
Derivative No. 6
This is prepared according to the method of Example
1, starting from 5- ~-(2-chlorophenyl ~-4,5,6,7-tetrahydro-
thieno(3,2-c)-pyridine. Hydrochloride: beige crystals; m.p.
124 - 126 C.; IR (KBr): v CO = 1690 cm l Base: NMR (CDC13):
7.30 (m,4H); 6.05 and 5.90 (2s,lH); two diastereoisomers.
EXAMPLE 7
5-(2-Cyanobenzyl)-5,6,7,7a-tetrahydro-4H-thieno(3,2-c)-
. ~
pyridin-?-one. Formula (I); R = 2-CN.C6H4; R' = H; n = l;
Derivative No. 7
This is prepared according to the method of Example
1, starting from 5-(2-cyanobenzyl)-4,5,6,7-tetrahydro-thieno-
(3,2-c)-pyridine. Oxalate: beige crystals; m.p. 176 - 178C.
(recrystallised from acetonitrile); IR (KBr): v CO = 1700
cm ; v CN = 2210 cm l Base: N~R (CDC13): 7.50 (m,4H); 6.00
(s,lH); 3.80 (s,2H).
EXAMPLE 8
5-(2-Nitrobenzyl)-5,6,7,7a--tetrahydro-4H-thieno~3,2-c)-
pyridin-2-one. Formula (I); R = 2-O2N.C6H4; R' = H; _ = l;
Derivative No. 8
This is prepared according to the me-thod of Example
l, starting from 5-(2-nitrobenzyl)-4,5,6,7-tetrahydro-thieno-
(3,2-c)-pyridine. Oxalate: beige crys-tals; m.p. 186 - 188C.,
recrystallised from isopropanol-ethanol. Base: NMR (CDC13):
7.50 (m,4H); 5.95 (s,lH); 3.90 (s,2H).
EXAMPLE 9
5-(2-Bromobenzyl)-5,6,7,7a-tetrahydro-4H~-thieno(3,2-c)-
pyridin-2-one. Formula (I); R - 2-Br.C6H4; R' = H; n = 1;
Derivative No. 9

l l 7

This is prepared according to the method of Example
1, starting from 5-(2-bromobenzyl)-4,5,6,7-tetrahydro thieno-
(3,2-c)-pyridine. Oxalate: beige crystals; m.p. 151 - 153C.,
recrystallised from isopropanol; IR (KBr): v CO = 1690 cm
Base (CDC13): 7.30 (m,4H); 5.95 (s,lH); 3.75 (s,2H).
The proton ~MR spectra were obtained with the use
of a Hitachi-Perkin~Elmer R-24A apparatus, the chemical dis-
placements being expressed in ppm with reference to TMS as
internal reference.