CA1071630A - Process for the preparation of thienopyridine derivatives - Google Patents

Abstract

PROCESS FOR THE PREPARATION OF THIENO-PYRIDINE DERIVATIVES.

ABSTRACT OF THE DISCLOSURE.

This invention relates to a process for the preparation of thieno-pyridine derivatives having the structural formula :

(I) in which R1 represents an optionally subsituted alkyl, aryl or aralkyl radical, and R2 and R3 represent each hydrogen or a lower alkyl, aryl or heterocyclic radical, comprising :
(a) reacting a derivative of the formula (II) in which R2 and R3 are as defined for formula (I) and X represents hydrogen, or an alkali metal, or a radical Mg-Y in which Y
represents halogen, with a halo-sulfonyl derivative having the formula :
Hal-SO2-R4 (III) in which Hal represents halogen and R4 represents an optionally substituted alkyl, aryl or aralkyl group, to give a compound having the formula :

(IV) (b) subsequently reacting the latter compound with an amine of the formula :
R1-NH2 (V) in which R1 is as defined for the formula (I), to give a compound having the ormula :

Description

~7~63~

This invention relates to a neW proCess ~or the preparation of thieno-pyridine deri va ti Ves havi ng the s-tructural formul a:

~S~R2 IL~ /N~R~
in which Rl represents a) a Cl to C8 alkyl, b) (CH)m ( )n ~ wherein m is 1 or 2;
R5 is hydrogen or a Cl to C4 alkyl, n is 0 or 1; :
R is hydrogen, a Cl to C4 alkyl, a Cl to C4 al koxy, halogen, a Cl to C4 acyl, nitro, phenyl, or the chain -CH=CH-CH-CH- attached to the phenyl ring thereby to form a fused benzene ring or the group ~;

X is 1, 2 or 3;

c) -CH2-CH=CH ~ where R and X are as defined previously; or d) -CH2 ~ Cl, and R2 and R3, Which may be the same or different, represent each hydrogen or a lower alkyl, aryl or heterocyclic radical.

~ 2 1~37~630 4,5,6,7-Tetrahydro-thieno ~ ,2- ~pyridine derivatives of this type have already been described, together with their therapeutic applications and a process for their preparation in Canadian Patent 1,0389871. Said process comprises con-densing a compound of the formula:

B~-~N

in which A and B represent each at least an atom or group selected from hydrogen, halogen, or a hydroxy, lower alkyl, lower alkoxy, nitro or amino group, with a halide of the formula Hal-R in which Hal represents a halogen atom and R is an optionally substituted alkyl, aryl or aralkyl radical, to give a pyridinium salt having the formula:
A

N-Rl, HalC) and subsequently hydrogenating the pyridinium salt to give the derivative of the formula (I).
.:- .

_ 2A -.... .

~1~)7~ 3(~
This process, ~lowever, is expensive and cumberso~e to operate in that it requires ~urnerous difficult operating steps.
The object of the present i~vention is to overcome such drawbacks and ~o provide a simple inexpensive process for the preparation of the aforernentioned pyridine derivatives.
Thus,the invention relates to a process for the preparation of compounds of the aforementioned formula (I), comprising (a) reacting a derivative of the formula : ~

C ~ OX (II) in which R2 and R3 are as defined for formula (I) and X represents hydrogen, or an alkali metal, or a radical Mg-Y in which Y repre-sents halogen, with a halo-sulfonyl derivative having the formula Hal-S02'R4 (III) in which Hal represents halogen and R4 represents an optionally substituted alkyl, aryl or aralkyl group, to give a compound having the formula :

~ CH - C~ - OS02 - P~4 (IV) (b) subse,quently reacting the latter compound with an amine O r the formula :
~ R - NH2 (V) in which Rl is as defined for the formula (I), to give a compound having the formula :

¢~3 CH -- C:H --Na -- R~

and (c) subsequently cyclising compound (VI) with formaldehyde to give the derivative of the formula (I).

,, . .
- :. .. '. .,:

The process of this inven-tion may be .illustra-ted by means of the following xeaction sch~me :

~ ~ CH - CH - OH ( X = H ) -~ Hal - SO2 - R4 + base ~ (IIa) (III) ~a) ~ - CH - CH - OM ( X ~ H ) + Elal - SO2 - R4 ¦ (IIb) (III) ~ ~ _CH - CH - OSO2 - R4 (IV) R,3 ,R2 (b) derivative (IV) ~ 2Rl - NH2 ~ cH-~I-Rl + 21 ~I2~S 3 4 (V) (VI) (c) derivative (VI) + H - CHO ~

, . .

The compounds of the formula (IIa) or (IIb) ~2-(2-thienyl)-ethanolic derivatives7may be obtained by reacting a thiophene metallation product of the formula (VII) with an oxiran of the formula (VIII), according to the following reaction scheme ~ ~ M + CH - CH ~ CH - CH - OM

hqI) ~qII) (IIb) R2 ~ H2O _ ~ ,2 , acid > ~ CH - ~1- OH

(IIb) (IIa) In the derivatives of the formula (IIb) and ~VII),M represents an alkali metal such as lithium, sodium and~potassium, or a Mg-Y
radical, Y being halogen and R2 and R3 having the aEore-defined meanings.

,~ _ ., .' ' ' ' ', ' ~ .
, 7~63~

Thiophene metallation may ~enerall~ be effected wi-th any suitable known reayent for that purpose, such as organolithium derivatives RLi in which R is methyl, ethyl, prop~l, isopropyl, butyl, isobutyl, amyl, phenyl, substituted phenyl, etc.,preferably methyl li~hium, ethyl lithiu~ and n-butyl lithium, organosodium derivatives of the formula RNa in which R has the above defined meaning; or organopotassium deriv~tives of the formula RX in whic~.
R has the above defined meaning. Thiophene metallation may also be effected via a GRIGN~RD reaction which leads to the correspon-ding organoma~nesium compound.
The derivative of the formula (IIa) (X = ~1) may be obta ned by hydrolysis of the derivative of the formula tIIb). When derivative (IIa) is used in the reaction of step (a) with the halo-sulfonated derivative Hal-SO2-R4, the reaction is effected in the presence of a base which may be selected from the tertiar~
amines of trialkylamine or aryldialkylamine type, or from the pyridine or quinoline derivatives, or also from inorganic deri-vatives of weak acids (e.g.,'alkali metal carbonates, alkali metal or alkali-earth metal hydrides, metal alkoxidès).
Examples of useul halo-sulfonyl derivatives include methane sulfonyl chloride, trichloromethane sulfonyl chloride, trifluoro-methane sulfonyl chloride, benzene sulfonyl chloride, para-toluene sulfonyl chloride, m.acetyl benzene sulfonyl fluoride or p.bromo-phenyl sulfonyl chloride.
The amination reac~ion of step (b) of the process of this invention is advantageously effected using excess amine Rl-NH2 which may be readily recovered and recycled for subsequent use.
This reac~ion is advantageousl~ effected in the hot, within a polar solvent such as acetonitrile, ethanol or py~idine, ~or example.

. . . .

:

~.~7~3~

l~ccording to an embodimerlt of -the in~entiorl, the cyclisa-tion reaction of step (c) with fo~maldehyde is effected in a single stepl advantageously in acidic medium within an inert solvent such as water or ethanol or a mixture of both, or within any solvent which is stable in acidic medium. I-t is advantageous to operate at the boiliny ternperature of the solvent and with an equimolar mixture o~ derivative of the formula (VI) and formaldehyde.
According to another embodiment, the desired compounds of the formula (I) may be obtained in improved yields by effecting the cyclisation in two distinct steps, viz.: (a) reaction of formal-dehyde with the derivative of the formula (VI) in aqueous medium, and isoiation of the water-free product, followed by ~b) reaction of the compounds obtained in (a) with a solution of dry hydrochlorlc acid in an aprotic polar solvent.
Preparation of compounds of the formula (I) according to the above-described procedure makes it possible to attain yields of the order of about 80%, whereas the yields are about 40% vla direct cyclisation., The compounds obtained on completion of step (a) of reaction of formaldehyde with the compound of the formula (VI) have a structure which is not yet fu~ly understood ad-~hich, purely for ; indicative purposes, may be represented by the structures of the following types :

,3 ,2 ,1 ~~ ~ ~ ,1 S ~ ,2 ,1 ~ ~ ~I-CH-N ~2' ~ CH-C~-N~12 0; ~ --C~-CH-N-C~20H

(IX) (X) (XI) The compound (IX) in ~hich R3 = R2 = H and R1 = CH2 --Cl ~ `` .

~7~3(;1 was isolate~ from tne mi~ ure and characteri%ed b'7 elementa analysis and NMR ~pectroscop:ic analysis.
It is essential that the addition product or products of formaldehyde and the compound oE the formula (VI) be isolated and obtained free from water. However, they may be used in the next step as a solution i.n an inert solvent such as benzene, toluene or any other similar solvent compatible with the natu:e of the products, thè essential point being ~hat such a solution be anhydrous.
The product or products obtained in step (a) are added to a solution of dry hydrochloric acid in an aprotic polar solvent, preferably dimethyl formamide. Other solvents of similar nature, such as dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethyl-acetamide, etc.. may also be used. It is useful to select the solvent so that the hydrochloride of the compound o~ the fo~mula (I) will be as sparingly soluble therein as possible, in order to facilitate the isolation of the final product.
It is very frequently found that the conversion of the compound o~ the formula (VI)` is not complete and that this amine remains frequently dissolved., whereas the major portion of the hydrochloride of the compound of the formula-(I) precipitates as crystals. The yet unconverted portion of the compound of the formula (VI) is then ve~7readily co~7erted in a second operation, as foll~s :
The filtrate from the cyclisation step (see (b~ is neu-tralized with an aqueous base solution to release the compounds ; of the formulae (VI) and (I) which are extracted ~ogether with a waier-immiscible solvent. This.~olution, W~lich contains the com~ounls of the - formulae (Vl) and (I), is sti.rred with aqueous formaldehvde in a manner analogous to that describe~ under (a) to convert _ 7 _ . - .... . . , : .
., , . . : . .
.. ..
.. : .:

~197~ 3~

the compound of the formula (VI) into one or more produc-t(s) identical with those obtained under (a). The organic phase which contains those products, together with ~he compound of the ~ormu~a (I) which undergoes no degradation, is then dried. The dried solution may be concentrated or used as such to undergo the cyclisation reaction effected under the conditions described under (b). Thus, the hydrochloride of the compound of the formula (VI) is found to precipitate in the form of crystals.~ The mother-liquors still contain some hydrochloride of the compound of the formula (I) and a very small amount of the hydrochloride of the compound of the formula (VI). When considered necessary, this filtrate may be recycled once more.
In cyclisation step (b), the reagents may also be added in the reverse order, i.e., the solution of hydrochloric acid in the polar solvent may be added to the mixed amines (of type IX, X, XI). It is then noted, however, that the yields are generally less satisfactory and vary as a function of the conditions used.
The following non limiting examples are given to illustrate ` the invention.

Pre~ara ion of 5-(2-chloro-benzy')-4 ! 5,6,7-tetrahydro-thieno~3,2-c/pyridine (as the hydrochloride) 1. Pre~ar_tlon of 2-(2~thienyl)-ethanol (derivative ~IIa);
R2 = R3 = H)-Butyl lithium (100 moles; 6.40 kg) dissolved in hexane (64 litres) is added ~o thiophene (llO moles; 8.75 litres) mixed with dry tetrahydrofuran (10 litres), under an inert nitrogen atmospnere.
The exothermic reaction is effected under refluxing conditions;
addition of butyl lithium is effected over 1.5 hours,using suitable :

.
.:

~L~7~6~1~

cooling means; the reaction mediurn is then cooled to about 10C
and a solution of ethylene oxide ( 105 mol~s; ~.62 k~) in tetra-hydrofuran (10 litres) is added thereto. The reaction is exothe~C
and the temperature is maintained below 25C by cooling. This step takes a~out 1 hour. The lithium thienyl alkoxide precipitates out.
6N hydrochloric acid is then added to neutralise the reaction medium. The organic layer is then separated, concen-trated, and the residue is distilled under red~ced pressure, to give 12.47 ~g ~Yield : 79%) 2-(2-thienyl)-ethanol.

2. Preparation of 2-(2-thienyl)-e~hyl paratoluene sulfonate 8.32 kg (65 moles) of the 2-(2-thienyl)-ethanol obtained in 1 above are mixed with 12.68 kg (66.6 moles) paratoluene sulfonyl chloride and 6.8 kg (67.2 moles) triethylamine and with 63 litres diisopropyl ether at room temperature. After stirring during 70 hours, the reaction mixture is poured over 40 li~res water. The organic phase ls washed with carbonated water and then with pure water until neutral, after which it is dried over sodium sulfate. Evaporation of the solvent gives 16.62 g( Yield;90.60%) 2-(2-thienyl)-ethyl paratoluene sulfonate.

3. Preparation of N-(2-chloro-benzyl)- 2-(2-thienyl)~ethYlamine hydrochloride.
850 g (3 moles) 2-(2-thienyl)-ethyl paratoluene sulfonate and 850 g (6 moles) ortho-chlorobenzylamine are dissolved in 5.2 litres acetonitrile and the mixture is refluxed during 6.5 hours.
After filtration, 630 g ortho-chlorobenzylamine paratoluene sul-fonate are removed by filtration. The filtra~e is concentrated and the residue is taken up into diisopropyl ~ther and 500 ml 2N
sodium hydr~xide. The organic phase is separated and is made acidic g ~(37~3~

with 3N hydrochloric acid. The resultir~cJ hydrochloride precipitates out; it is c~llected by fil-tration, suc-tion filtered and washed with acetone, to give 684 g (Yield: 78%) N-(2-chloro-benzyl)-2-(2-thienyl)-ethylamine hydrochloride.
This compound may also be obtained directly, via derivative (IIb), as follows :
To a solution of 87.5 ml thiophene (1.1 mole) in 100 ml tetrahydrofur~n is added a solution of 64 g,butyl lithium (1 mole) in 1 litre hexane, at a temperature of 35-39C. The mixture is cooled to 10C and a solution of 48 ml ethylene oxide (1.08 mole) in 50 ml tetrahydrofuran is added thereto in such a manner that the temperature does not exceed 25C.
The reaction medium is then cooled to -20C and a solution of 190O50 g (1 mole) paratoluene sulfonyl chloride in 250 ml tetra-hydrofuran is added thereto, while main-taining the temperature a-t about -20C. The temperature of the mixture is then raised to 0C
and ortho-chlorobenzylamine (282 g; 2 moles) is added thereto.
The resulting mixture is then refluxed during 18 hours, after which it is cooled and water (600 ml) is added thereto. The aqueous phase is extracted with diisopropyl ether and the combined organic phases are concentrated. The oily residue is taken up into diiso-propyl ether and 520 ml 4N hydrochloric acid. The ~-(2-chloro-benzyl)-~2-(2-~hienyl)-ethylamine hydrochloride precipitates out;
it is then suction filtered and washed with acetone, to give 112 g of product (overall yield calculated on the basis of the butyl lithium : 39~).

4. Preparation of 5-(2-chloro-benzyl)-4,5,6,7-tetrah~dro-thieno~ 3/2-c7~yridine 15 g ~0.052 mole) of the compound obtained in (3), 100 ml ' 3L~7 lLf~30 water and 5 ml of a 35% aqueous formaldehyde solution (0.058 mole) are heated at 90C during 15 minutes, after which 2N hydrochloriC
acid (100 ml) is added there-to and the resulting mixture is heated at 90C during 1.5 hour. After cooling, a slight precipitate is removed by filtration. The aqueous phase is n,ade alkaline with 2N NaOH and is then extracted with 350 ml diisopropyl ether. The organic phase is washed witn water, dried over sodlum sulfate and concentrated, to give 11.32 g of a light orange oil.
This oil is then dissolved in isopropyl ether and, after addition of dry ~Cl, gives 10 g of a hydrochloride precipitate which is purified by recrystallization from boi]ing absolute ethanol (Yield: 64%).

Preparation of' 5-(2-chloro-benzyl)-6-methyl-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine (as the hydrochlor'ide) 1. Preparation of 1-(2-thienyl)-2-~opanoltosylate To a cooled solution (0C)'of 135 g (0.71 mole) tosyl chlo-ride in 360 mI dry pyridine is added dropwise a solution of 9~.1 g (0.6~ mole) 1-(2-thienyl)-2-propanol in 300 ml dry pyridine. ~
The mixture is kept in the refrigerator ~uring 65 hours and is then poured over 2.5 litres cold water. The resulting precipi-tate is filtered off, rinsed with water and dried (yield: 182.8 g;
89%; M.p. = 68C) 2. Preparation of ~-o.chlorobenzyl-l-methyl-2-(2-thienyl~thylamine A mixture of 18.2 g (0.0615 mole) of the tosylate obtained in (1), 17.4 g (0.123 mole) orthochlorobenzylamine and 50 mltoluene is' refluxed during 24 hours. After cooling, water (50 ml) and 2N
sodium hydroxide (35 ml) are added ~hereto ~nd the resulting mate-- rial is extracted with ether. ~rhe ~ether phase is treated wi~h an ~ ~ 7 ~

aqueous 6N hydrochloric acid solution, with vigorous stirring.
The precipitate which separates out is filtered, washed ~7ith ether and dried to give 11.6 g of material, m.p. = 166C
(Yield : 66%).
3. Preparation of 5-~.chlorobenz~l-6-methyl-4,5,6,7-tetrahydro-thieno/3,2-c7p~ridine ~as the hydrochloride) A mixture of 1 g of the amine hydrochloride obtained in (2~, 20 ml water, 3 ml formalin ~35% aqueous solution) and 0.5 ml concentrated hydrochloric acid is refluxed during 2.5 hours. After cooling, the mixture is made alkaline with a 2N sodium hydroxide solution and is then extracted with ether. The ether phase is dried and evaporated to dryness. The residue is purified by column chromatography on silica (eluent: benzene-ethyl acetate 7:3).
The resulting 5-o.chlorobenzyl-6-methyl-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine is dissolved in ether and treated with one equivalent hydrochloric acid dissolved in ether. The resulting hydrochloride is recrystallized from a diisopropyl ether-isopropyl alcohol mixture (Yield : 300 mg; 28%; m.p. = 178-182C)~.

Preparation of 5-(2-chloro=benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c7p~ridine v ~ a two-step cvclisation (a) To N-(2-chloro-benzyl)-2-~2-~hienyl)ethylamine (2515 g; 10 moles) is added, with stirring, a 35~ formaldehyde aqueous solution (946 g; 11 moles). The reaction is ~mediate ~nl slightly exothermic. The a~ueous phase is decanted, washed with water and the organic phase is dried azeo-tropically, to give 2780 g intermediat products of step (a).
- (b) The resulting mixture of intermediate products s poured over

5 litres of 5N HC1 solution in dimethylformamide. The reaction is 1~7~L63~) exothermic and the temperature rises to 45-50C, at which level it is maintained by external cooling. The addition is complete in about 30 minutes. Ten minutes after completion of the addition, the 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno/3,2-c/pyridine hydrochloride begins to precipitate out. The reaction mixture is cooled to ro~om temperature and is filtered on completion of the precipitation. The precipitate (1920 g) is washed with acetone.
The filtrate still contains 330 g of the desirea product and 325 g N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine. Thus, the conversion rate of this amine is 87.1% and the yield of 5-(2-chloro-benzyl)-4,5,6,~-tetrafiydro-thieno/3,2-c7pyridine is 86%, -the major portion of which is obtained as a precipitate.
In order to recover the unreacted starting amine and the unprecipitated portion of the desired product, the filtrate is treated in the following manner :
The filtrate is poured over water containing sodium hydroxide; the amines thus released are extracted with methylene chloride which may be removed, or nok, for another formalln treatment and another cyclisation according to a procedure similar to that described a~ove. The conversion rates and the yields based on the N-(2-chlorQ-benzyl)-2-(2-thienyl)-ethylamine contained in the filtrate of the primary operation are approximately the same.
The dérivatives set forth in following Tables I and II
were prepared according to the above-described procedures.

~ , . .

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: . .. : , 16:97~3~

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N~ R, Yield Compo~ d ~ R1 1 C~I3 b~po 52~5~/0~1 mm Hg 39 2 (CII2)6 3 b.p~ 118/005 mrn Hg 42 3 ~CE2 ~ \~ 240 (hydrochloride) 40 .

4 ~CH2 ~ 208.210(hydrochloride) ~6 -CH2 ~ 215 (hydrochloride) 47 C~I3

6 -C~2 4 ~ C 3 260 (hydrochloride) 38

- 7 -CH2 ~ 168" (maleate) 48 p~

8 ~H2 ~ . 216 (methiodid~) 51 F ~
.

9 -Cll2 ~ F 215 ~hydroc~loride~ 50 -CE2 ~ 190 (hydrochloride~ 38 . Gl 11 _CN~ ~ 212 (maleate) 44 CI

12 -C~2 ~ 182 (~lethiodide) 48 , .
.. ' , 7~

T ~UT,I, :r ( c on t:Lml~d ) - . Yi,eld C~ ou~d. No ~ .æ~ .~~.~.~ ~
13 ~C}I;~J~(~ 200 (hydl ochlc-ride ) 46 \Cl 14 -CE ~C:L 240 (hydrcJchlo.. ide) 52 `
~1 .
-CH2~ 200 (hydrocbloride ~ ~9 Cl -16 -CE~2~Cl 210 (hydroc}lloride) 32 Cl 17 -CH2~ 122 3~3 OH
18 -C~I2~0H 240 (hydrochloride ~ 49 19 -CH2~0~COCH3 86 43 -C~2~ 90 34 - OC~I3 ' , 21 ~CE2~ 200 (hydrochloride~ 46 22 -C:EI2~0CH3 215 (hydrochloride) 52 -.

23 C~l2~-~oc~I3 100 (methiodide ) 48 - 24 (:~H2~ocH3 210 (hydrochlnride) 35 C~I24~ 195 (hydrochloride ) 41 .
_ 15 .... . . ... .. . . . ..
.-, ,.. : .. . . . , , . ,., .. , . :, ., . . -.. , ... .. . . . ... .

~7~3~) rr~;Br~ ( c ~n^li i nued.) Y; eld C o r~ o~ d ~o ., ~ o~ ~ C.L~
26 ~ ~ ~ 3 1 g~ 8 (hyclroch:Lorida ~ ~3 H3 C'O OC713 OC~I3 ~(~ocH3 205~ (hyæl~och]oxid~) 32 c~3 OC~3 28 ~CH~OCH3 195 (methiodid~3 ) 46 C~I3 29 -CH2~ocII3 230--23 5 (hydr ochlor ide ) 3 8 OC~I3 -CH2~ - 180 (hydrochlorid~) 48 31 -CH2~No2 1 1 9~1 21 46 32 -CH2-C~I2~ 226(hydroch:loricle) 38 ., , 33 -CH2-CH~CE~ ?76C (hydrochLorid~) 29 : C~

34 -CH2 4~ J20 4 8 ~` ~ ~ ' .
. . . .

~ CH2~-Cl 2û0 (hydroohlorid~) 37 .~ - .
36 -CN2 CH(O~)~ 164-166 (hydrochloricl2) 42 37 ~S,~I(CH3)~CII(OII~ 230(hydrochloride) 51 - 16 _ :

:- ,. . . : , , .
-., . : : :
- .
,.
. . .

~7163~
TJI,PIJI~ on~i.nued) ~i ~lid C~n;~ltnd No 0 ~ ~ M~p~ C)I' bo~ ~L.. ~ ~
38 -c'EI2~cEl(o~ 3 210 (hyd~oc11:1 ol~ide) S~j 39 -C~2-CI~(OH)~ 124 47 ~CII2C~I(OH~-Cl 195 (Lyd~ochloride~ 41 41 ~CII2CM(OH)~OH 216-218~ (hydrochlorid~ 4~

~2 -CH2CH(OH)~ 224 (hydrc)chloxid~ 37 pC~3 :-43 _CH2-CH(OH)~ 170~ (hydrochloride) 38 44 -CH2-CH~Ol[)~ocE3 206-~08 (hydxochloride) 42 , OC~ ' ~CH2-C~(OH)~ 106 41 .

46 -CH2-OH(0~ 3 150 (fu-ar~te) A8 .
, ..

. . . -: ., ~ . , . : ;, '.. , , ' ' ', ' ' '~' " ' ' ' ;''' ,, ' ~' ' . ' ' ' " . ' ' ~ ' ' :' ' ' .

~7~6;~

rL~

ielcl Çwo~r~ n~d, ~\T~ O ".~ M ~ bæ5~ C ~

47 ~ CE2 ~ 19()-1~4 (hydrochloridc) 39 F .

.
48 -CH2~3 179~1$00 ~hydrochloride) 32 ~- Cl - 49 -CH2~ 178--180 (hyd.rochloride~ 44 `; N02 - ..

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.

.. ' '' .

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. . ' ' .

, , - . : : . . , .: :.... . . . ..

:. :
~. , . -

Claims (9)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. Process for the preparation of thieno-pyridine derivatives having the formula:

(I) in which R1 represents a) a C1 to C8 alkyl, b) wherein m is 1 or 2;
R5 is hydrogen or a C1 to C4 alkyl n is 0 or 1;
R is hydrogen, a C1 to C4 alkyl, a C1 to C4 alkoxy, halogen, a C1 to C4 acyl, nitro, phenyl, or the chain -CH=CH-CH=CH- attached to the phenyl ring thereby to form a fused benzene ring or the group ;
x is 1, 2 or 3;

c) -CH2-CH=CH where R and x are as defined previously; or d) -CH2 , and R2 and R3 are each selected from the group consisting of hydrogen and alkyl containing 1 to 8 carbon atoms, comprising:

(a) reacting a derivative having the formula;

(II) in which R2 and R3 are as defined for formula (I) and X is selected from the group consisting of hydrogen, an alkali metal and a radical MgY in which Y represents halogen, with a halosulfonyl derivative having the formula:
Hal - SO2 - R4 (III) in which Hal represents halogen and R4 is selected from the group consisting of the alkyl, substituted alkyl, aryl, substituted aryl, aralkyl and substituted aralkyl groups, to give a compound having the formula:

(IV) (b) reacting said derivative (IV) with an amine of the formula R1 - NH2 (V) in which R1 is as defined for formula (I), to give a compound having the formula:

(VI) and (c) subsequently cyclising said derivative (VI) with formaldehyde to give the derivative of the formula (I).

2. Process as claimed in claim 1, wherein the reaction of step (a) is effected in the presence of a base selected from the group consisting of the organic and inorganic bases when a derivative of the formula (II) in which X is hydrogen is used.

3. Process as claimed in claim 1, wherein a derivative of the formula (II) in which X represents a lithium atom is used in step (a).

4. Process as claimed in claim 1, wherein the halo-sulfonyl derivative of the formula (III) is selected from the group consis-ting of methane sulfonyl chloride, trichloromethane sulfonyl chloride, trifluoromethane sulfonyl chloride, benzene sulfonyl chloride, paratoluene sulfonyl chloride, m.acetyl benzene sulfonyl fluoride and p.bromophenyl sulfonyl chloride.

5. Process as claimed in claim 1, wherein step (b) is effected with an excess of the amine.

6. Process as claimed in claim 1, wherein the cyclisation of step (c) is effected in a single stage in acidic medium, within an inert solvent.

7. Process as claimed in claim 1, wherein the cyclisation is effected in two successive stages comprising (a) reacting formaldehyde with the compound of the formula (VI) in aqueous medium and isolating the water-free product, and subsequently (b) reacting the compounds obtained in (a) with a solution of dry hydrochloric acid in an aprotic polar solvent.

8. Process as claimed in claim 7, wherein the aprotic polar solvent is dimethylformamide.

9. Process as claimed in claim 7, wherein the aprotic polar solvent is selected from the group consisting of dimethyl sulfoxide, N-methyl pyrrolidone and N,N-dimethylacetamide.