Note: Descriptions are shown in the official language in which they were submitted.
Il 1~f~8539
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Subject of this in~ention i8 a new process for the
preparation of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno-
¦ fi, 2- ~ pyridine, of the fo~mula (I)
I /\, /=\
Q ~ ~2 ~ (I)
This compound involves a great pharmacological and clinical
interest due to it8 anti-inflammatory, ~asodilatatory and pla-
telet aggregation inhibiting activity. See, to this purpose~
Eur.J.Med. Chem.-Chimica Therapeutica, September-October 1974,
9 , n5, pag. 487-490.
Compound (I) can be prepared in different ways either by
reduction of 5-(2-chlorobenzyl)-thieno r,2-~ -pyridinium
chloride (DOS 2404308)~ or by preliminary synthesis of the
N-un~ub~tituted tetrahydro-4,5,6,7-thieno ~?-~ pyridine ring
~ollowed by the reaction with 2-chlorobenzyl chloride (Eur.J. ~ ; -
~ed. Chem-Chimica ~herapeutica, September-October 1974, 9 ,
n5, pag. 483-486). Alte~natively, the latter paper also de-
scribes the acylation of tetrahydro-4,5,6,7-thieno~3,?-c~-p~
ridine with 2-chlorobenzyl ahloride, and the following reduc- -
tion of th8 CO to CH2 group by ~iAlH4.
None of the proce~s described is satisfactory in practise~
both be¢au6e of the poor yields and the cost of the reagents -
used in the steps nece~sary for each synthetic pathway.
It has been fou~d now that compound (I) can be obtained in
a completely sa~isfying way, eYen on an industrial scale, by
cyclization of N-(2-thienylethyl)-N-(2-chlorobenzyl)-amine
lV~8539
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¦(II) with formaldehyde, accordingly to the schema:
Cll2-C~I~-N~1-C~i2 ~ ~ (I)
l (II) -
¦ The ~tarting product of this reaction (which is characteriz d
¦with high yields) can be obtained in turn through two differen
¦ways of synthesi~, which offer no ~pecial di~ficulty.According
¦to the fir~t method, 2-chlorobenæylamine i~ acylated with 2-
¦thienyl-acetic acid chloride~ and amide (III) 80 obtained is
¦reduced to amine (II~ by PC15 and NaBH4:
-COCl + H2N-CH2~ ~.
1) PC15
¦ ~ ~ 2) NaBH
CH2-CO-NH-CH2 ~ ~ (II)
Cl
Alternatively a derivative of 2-thienylacetic acid (e.g.
either the ester according to the method of Bouveault-Blanc~
or the chloride with ~iAlH4, or the ester with NaBH4/ A1~13
too) can ~e reduced to 2-thienyl-ethanol. ~his latter compound
is reaoted a9 the tosylate~ directly affording the amine (II)
together with 2-chlorobenzylamine
1 10~8539
1) To~ylchloride
¦ ~ 2~ 2-chlorobenzylamine
¦ ~ ~ CH2-CH20H ~ (II3
The reaction of the amine (II), whenever obtained~ with
formaldehyde, in the pre~ence of anhydrou~ HCl, preferably in ~.
dimethylformamide solution~ yields the final product (I)
withou~ difficulty It i~ not necessary to isolate the N-
hydro~ymethyl intermediate, the product from cyclization being
directly reached :
_ ,~
HCH0 CH2H HCl
(I
L~S~--CH2 aH2 ~ C 12
(III)
, ' , " '
~he invention i9 illuetrated by the following example~
which are not intended ae a limitation thereof. : ;
E~A}1~E 1 . ,.
~:: ~:
a) N-(2-thien~la¢etyl)-N-(2-chlorobenzyl)amine - ..
o-ehlorobenzylamine (141 g) and triethylamine (101 g) were
dis~olved in 600 ml of anhydrou~ benzene. ~nder ~tirring, 160
: ~g o~ 2-thienylacetic acid chloride were~ adde~, the temperature .
. ~ being mantained at 35-40C. A precipitate developed immediatel~ .
After comFletion of the addition the ~olution wae heated for ~ -
~,: :,
`67 ~
:~ . '
;.. . . , . ~
1088539
30' to 60-65C, the precipitate dissolving again. After cooling,
1 liter of CH2C12 was added and the mixture washed with S00 ml
of H2O. The organic layer was dried on MgSO4, then filtered
and concentrated to approx. 500 ml "in vacuo". After dllution
with 400 ml of n-pentane, the reaction was left for one
hour at 0, and the crystalline product was subsequently
filtered: yield 200 g, m.p. 104-105C. The analytical data
agreed with the values calculated; the compound was shown
to be unitary by thin-layer chromatography.
b) N-~2-thienylethyl)-N-(2-chlorobenxyl)amine ~ ~ `~
106 g (0.4 mole) of the amide as previously described,
dissolved in 500 ml of CHC13, were treated wlth 104 g (0.5
mole) of PC15 and refluxed for 5'. The mixture was cooled to
QC, 46 g (1.2 mole) of NaBH4, suspended in 500 ml of absolute
ethanol, were added during 15' with stirring, keeping the
temperature between 0C and 5C. After heating to 60 for 10'
and cooling to 0-5C a solution of 100 g of Na2CO3 in a liter
of water was slowly added under stirring and external cooling
with an ice bath. The reacting mixture was repeatedly extracted
with CH2C12 and the combined extracts were evaporated. The
residue was taken up with 300 ml of conc. HCl and 300 ml of
water, then 300 ml of diisopropyl ether were added and the
mixture stirred for 10'.
~ he crystalline precipitate (the amine hydrochloride)
was suspended in water and treated with excess Na2CO3; the free
base was extracted with diisopropyl ether and distilled "in
10~8539
vacuo". B.~.o 3 135-140C. 74 g of the product, unitary by thin
¦layer chromatography, were obtained.
¦The ~nalytical and ~pectro~copic data were in ag~eement with
¦the expected structure.
c) N-(2-thienylethyl)-N-(2-chlorobenzyl)-N-hydroxvmethyl-amine.
18.3 g of N-(2-thienylethyl)-N-chlorobenzylamine were dissolved
¦in 100 ml of toluene and 10 ml o~ 40~0 HCH0 were added to the
¦solution. After ~tirring for 5'~ the organic pha~e was sepa-
¦rated and dried on MgS04; the solvent was removed and the
/0 ¦residue distilled "in vacuo"0 The yield of the N-hydroxymethyl
¦derivative, b.p.o 1 1~5-165a, was 6.7 g.
¦d) 5-(2-chlorobenzyl)-4~5~6~7-tetrahydrothie ~ ,2-~ -pyridine
.
5 g of N-(2-thienylmethyl)-N-(2-chlorobenzyl)-N-hydroxy-
methyl amine were dissolved in 10 ml of a 5N HCl solution in
anhydrou~ dimethylformamide. After standing at room temperatur~
o~ernight~ the reacting mixture was ¢ooled to -5C. The crysta~
line precipitate was filtered at the pump~ then washed with
I anhydrous acetone and dr~ed: 4.3 g of 5-(2-chlorobenzyl)-4~5~6
¦ 7-tetrahydrothieno~ ~2-~ pyridine hydrochloride, m.p. 201-203
0 C~ were obtained.
~ he analytical and spectroscopic data were in perfect agree-
ment with the compound ~tructure, which was found unitary~by
~thin-layer chromatography.
EXAMP~E 2
a) N-(2-thienylethyl)-N-(2-chlorobenzyl)amine
In a round bottomed flask, fitted with a ~tirrer~ a ther-
mometer~ a dropping funnel and a reflux condenser, 6 g of a
~7 78~ solution of ~odium hydride in paraffin oil and 100 ml of
~, . . .
~0~8539
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¦ anhydrous tetrahydrofuu~dn were added under anhydrous nitrogen
l Then 24 g of 2-thienylethanol (produced by reducing ethyl
¦ 2-thienylacetate with ~aBH4/AlC13) dissolved in 30 ml of
¦ tetrahydrofuran were quickly added. The mixture obtained was
¦ heated to 50C ~der ~tirring, until a clear solution was
¦ obtained. This solution was cooled to -2C and 33.2 g of
¦ 4-toluene-sulphonyl chloride in 50 ml of anhydrous tetrahy-
¦ furan were dropned over approx. 30'. At the end of the additic n
¦ the cooling bath wa~ removed and a solution of 50 g of
¦ 2-chlorobenzylamine in 50 ml of tetrahydrofuran was dropped.
l ~he mixture was then heated to 70C and kept`at this tempe~
¦ ature for 10'. By cooling to 10C~ 20g of 2-chlorobenzylamine
¦ toluensulphonate precipitated~ which were recovered by
¦ filtration "in vacuo". ~he filtrate was evaporated at reduced
¦ pressure~ taken up with 140 ml of water Qnd basified with
¦ Na2C03 and the base was extracted with CH2C12. ~he solution
in CH2C12was dried on E2C03 and evaporated to dryness. By
¦ distilling the re~idue "in vacuo" the a~ine~ identical to that
I prepared according to example 1b)~ was obtained in a yield of
c2~ 1 33 g~
l b~ 5-(2-chlorobenzyl)-4~5~6~7-tetrahydrothieno 6~2- ~ pyridine
~; I .................................................................... .,-
17.5 g of N-~2-thienylethyl)-N-(2-chlorobenzyl~a-nine~
dissolved in 65 ml of toluene~ were treated with 20 ml o~ 40
aqueous CH20. A~ter stirring for 10' at room temperature the
aqueous layer was separated and discarded and the toluene laye
~,
-
~088539
was dried on Na2S04. This solution was treated with 22.5 ml of
a 5N HCl solutionin dimethylformamide, and processed as in
example ld); 15 g of product ~I), pure on the basis of thin-
layer chromatography, were obtained.
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