IE43084B1 - Improvements in or relating to a process for the preparation of thieno-pyridine derivatives - Google Patents

Description

This invention relates to a new process for the preparation of thiono-pyridine derivatives having the structural formula: (I) in which R^ represents an optionally substituted alkyl, aryl or aralkyl radical, and R2 and R^, which may be the same or different, each represent hydrogen or a 0χ_4 alkyl, aryl or heterocyclic radical. 4,5,6,7-Tetrahydro-thienoii/3,2-c7l>yridine derivatives of this typo have already been described, together with their therapeutic applications and a process for their preparation in French Patent Application N° 73 03 503 filed February 1st, 1973. Said process comprises condensing a compound of the formula: in which A and B represent each at least an atom Or group selected grom hydrogen, halogen, or a hydroxy, lower alkyl, lower alkoxy, nitro or amino group, with a halide of the formula Iial-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: and subsequently hydrogenating the pyridinium salt to give the derivative of the formula (l). - 2 43084 Thia process, however, is expensive and cumbersome bo operate in that it requires numerous difficult operatin'; steps.

The object of the present invention, is to overcome such drawbacks and to provide a simple inexpensive process for the preparation of the aforementioned 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 formulas in which aM I formula IIal-S02-R4 (III) in which Hal represents halogen and R^ represents an optionally substituted alkyl, aryl or aralkyl group, to give a compound having the formula! (b) subsequently reacting the latter compound with an amine of the formula: Rj-NILj (V) in which R^ is as defined for the formula (l), to give a compound having the formula: (VI) and (c) subsequently cyclising compound (VI) with formaldehyde to give the derivative of the formula (ΐ)ί step (a) being effected in* the presence of an organic or inorganic base when a derivative of formula 11 in which X is hydrogen is used. -3-.

The process of this invention may be illustrated by means of tho following reaction schemes (III) β*τι Rj. I3 I2 (b) derivative (IV) + ΖΒ^ΝΠ^Λ-ΟΗ-ΟΗ-ΝΗ-^ + Rj-N^.HSO^ (V) (VI) (c) derivative (VT) + H - CHO—} \B„ The compounds of the formula (Ila) or (lib) 2j-(2-thienyl)~ ethanolic derivatives^/ may be obtained by reacting a thiophene metallation product of the formula (VTI) with an oxiran of the formula (VIII), according to the following reaction scheme: fr (VII) ύBq Bq I3 I2 M + CII - CH · Y (VIII) R, Ro 3 r2 CH - OM · R, Ro s. 3 12 -> z jT~“ CH - CH - 011 (lib) h20 acid * Or Ro B. |3 |2 CH - CH OH (lib) (Ila) In the derivatives of the formula (lib) and (Vll), M represents an alkali metal such as lithium, sodium and potassium, or a Mg-Y radical, 7 being halogen and Rg and R^ having the afore-defined meanings. -443084 Thiophene metallation may generally be effected with any suitable known reagent for that purpose, such as organolithium derivatives RLi in which R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, phenyl, substituted phenyl, etc., preferably methyl lithium, ethyl lithium and n-butyl lithium; organosodium derivatives of the formula RNa in which R has the above defined meaning; or organopotassium derivatives of the formula RK in which R has the above defined meaning. Thiophene metallation may also be effected via a GRIGNARD reaction which leads to the corresponding organomagnesium compound.

The derivative of the formula (Ila) (X = H) may be Obtained by hydrolysis of the derivative of the formula (lib). When derivative (Ila) is used in the reaction of step (a) with the halo-sulfonated derivative Hal-SC^-R^, the reaction is effected in the presence of a base which may be selected from th,e tertiary amines of trialkylamine or aryldialkylamine type, or from the pyridine or quinoline derivatives, or also from inorganic derivatives of weak acids (e.g., alkali metal carbonates, alkali metal or alkali-earth metal hydrides, metal alkoxides).

Examples of useful halo-sulfonyl derivatives include methane sulfonyl chloride, trichloromethane sulfonyl chloride, trifluoromethane sulfonyl chloride, benzene sulfonyl chloride, para-toluene sulfonyl chloride, m.acetyl benzene sulfonyl fluoride or p.bromophenyl sulfonyl chloride.

The amination reaction of step (b) of the process of this invention is advantageously effected using excess amine R1~NH2 which may be readily recovered and recycled for subsequent use.

This reaction is advantageously effected at elevated temperatures, within a polar solvent such as acetonitrile, ethanol or pyridine, for example - 5 According io nil embodiment of tho invention, the cyclisation reaction of step (c) with formaldehyde is effected in a single stop, 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» It is advantageous to operate at the boiling temperature of the solvent and With an equimolar mixture of derivative of the formula (Vi) and formaldehyde.

According to another embodiment, tho desired compounds of the formula (l) may be Obtained in improved yields by effecting the cyclisation in two distinct steps, viz»: (a) reaction of formaldehyde with the derivative of the formula (Vi) in aqueous medium, and isolation of the water-free product, followed by (b) reaction of the compounds obtained in (a) with a solution of dry hydrochloric 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 60%, whereas the yields are about 40% via 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 fully understood and which, purely for indicative purposes, may he represented by the structures of the following types! R-, IL R.

CH (X) (XI) (IX) The compound (IX) in which = Rj = H and R^ = CH^.

Cl 3 0 8 4 was isolated from the mixture and characterized by elemental analysis and NMii spectroscopic analysis.

It is essential that the addition product or products of formaldehyde and the compound of the formula (VI) be isolated and. obtained free from water. However, they may be used in the next step as a. solution in an inert solvent such as benzene, toluene or any other similar solvent compatible with the nature of the products, the essential point being that 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-dimethylacetamide, etc., may also be used. It is useful to select the solvent so that the hydrochloride of the compound of the formula (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 of 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 (l) precipitates as crystals. The yet unconverted portion of the compound of the formula (VI) is then very readily converted in a second operation, as follows: The filtrate from the cyclisation stop (see (b)) is neutralized with an aqueous base solution to release the compounds of the formulae (VI) and (I) which are extracted together with a waterimmiscible solvent. This solution, which contains the compounds of the formulae (Vi) and (I), is stirred with aqueous formaldehyde in a manner analogous to that described under (a) to convert - 7 43084 the compound of the formula (Vi) into one or more product(s) identical with those obtained under (a). The organic phase which contains those products,togethor with the compound of the formula (I) which undergoes no degradation,io then dried. The driod solution may be concentrated or used as ouch 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 motherliquors still contain some hydrochloride of the compound of the formula (l) 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.

) EXAMPLE 1 Preparation of 5-(2-chloro-benzyl)-4,5,6,7-tetrahydrothieno/T,2-c7pyridine (as the hydrochloride) 1. Preparation of 2-(2-thienyl)-ethanol (derivative (Ila); r2 = R3 = II). ί Butyl lithium (100 moles; 6.40 kg) dissolved in hexane (64 litres) is added to thiophene (110 moles; 8.75 litres) mixed with dry tetrahydrofuran (10 litres), under an inert nitrogen atmosphere, The exothermic reaction is effected under refluxing conditions; addition of butyl lithium is effected over 1.5 hours, using suitable ==* 8 “ cooling means) the i*caction medium is then cooled io about 70°C and a solution of ethylene oxide (105 moles; 4.62 kg) in tetrahydrofuran (10 litres) is added, thereto. The reaction is exothermic and the temperature is maintained, below 25°C by cooling. This stop taken about 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, concentrated, and the residue is distilled under reduced pressure, to give 12.47 kg (Yields 790) 2-(2-tliienyl)-ethanol. 2· Properation of 2-(2-tlilnnyl)-ethyl paratolueno 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 litres water. The organic phase is washed with carbonated. water and thon with pure water until neutral, after which it is dried over sodium sulfate. Evaporation of tho solvent gives 16.62 g (Yields 90.600) 2-(2-thienyl)-ethyl paratoluene sulfonate. 3. Preparation of N-(2-chloro-benzyl)- 2-(2-thienyl)-ethylainlnc 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 sulfonate are removed by filtration. The filtrate is concentrated and the residue is taken up into diisopropyl ether and 500 ml 2N sodium hydroxide. The organic phase is separated and is made acidic 3084 with 3N hydrochloric acid. The resulting hydrochloride precipitates out; it is collected by filtration, suction filtered and washed with acetone, to give 684 g (Yield! 78%) N-(2-chloro-benzyl)2-(2-thienyl)-ethylamxne hydrochloride.

This compound may also bo obtained directly, via derivative (Hb), as follows; To a solution of 87.5 ml thiophene (1.1 mole) in 100 ml tetrahydrofuran is added a solution of 64 g butyl lithium (1 mole) in 1 litre hexane, at a temperature of 35-39°C, The mixture is cooled to 10°C and a solution of 48 ml ethylene oxide (1.08 mole) iii 50 ml tetrahydrofurdn is added thereto in such a manner that the temperature does not exceed 25°C.

The reaction medium is then cooled to -20°C and a solution of 19.0.50 g (1 mole) paratoluene sulfonyl chloride in 250 ml tetrahydrofuran is added thereto, while maintaining the temperature at about -20°C. The temperature of the mixture is then raised to 0°C and ortho-ehlorobenzylamine (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 diisopropyl ether add 520 ml 4N hydrochloric acid. The N-(2-chlorobenzyl)- 2-(2~ihxenyl)-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 lithiums 39%), . 4. Preparation of 5-(2-chloro-benzyl)-4,5?6,7—tetrahydrothieno/3,2-c7pyridine g (0.052 mole) of the compound obtained in (3), 100 ml - 10 4 3 0 8 4 water and 5 ml of a 35$ aqueous formaldehyde solution (0.058 mole) arc heated at 90°C during 15 minutes, after which 2N hydrochloric acid (100 ml) is added thereto and the resulting mixture is heated at 90°C during 1.5 hour. After cooling, a slight precipitate is removed by filtration. The aqueous phase is made alkaline with 2N NaOH and is then extracted with 350 ml diisoj^ropyl ether. The organic phase is washed with water, dried over sodium 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 HC1, gives 10 g of a hydrochloride precipitate which is purified by recrystallization from boiling absolute ethanol (Yield! 64$).

EXAMPLE 2 Preparation of 5-(2-chloro~benzyl)-6-methyl-4,5,6,7-tetrahyflrothieno/3,2-c7pyridine (as the hydrochloride) 1. Preparation of l-(2thicnyl)-2-propanqltosylate To a cooled solution (0°C) of 135 g (0.71 mole) tosyl chloride in 360 ml dry pyridine is added dropwise a solution of 98.1 g (0.69 mole) 1-(2-thienyl)-2-propanol in 300 ml dry pyridine.

The mixture is kept in the refrigerator during 65 hours and is then poured over 2.5 litres cold water. The resulting precipitate is filtered off, rinsed with water and dried (Yield! 182.8 g; 89$; M.p. = 68°C) 2· Preparation of N-t>, chlor obenzyl-1 -methyl-2-(2-thienyl) ellylimino A mixture of 18.2 g (0.0615 mole) of the tosylate obtained in (1), 17.4 g (0.123 mole) orthochlorobenzylamine and 50 ml toluene is refluxed during 24 hours. After cooling, wator (50 ml) and 2N sodium hydroxj.de (35 ml) are added thereto and the resulting material is extracted with other. The ether phase is treated with an - 11 4308 4 aqtioous 6N bydroohJoric acid solution, with vigorous «birring.

The precipitate which separates out is filtered, washed with ether and dried to give 11.6 g of material, m.p. = 166°C (Yield: 66%). 3. Preparation of 5-0.»chiorobenzyl-6-mcthyl-4,5,6,7tetraliydro-thienOj/f,2-c.7pyrid.ine (as the hydrochloride) A mixture of 1 g of the amine hydrochloride obtained in (2), 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 hy column chromatography on silica (eluent: benzene-ethyl acetate 7:3).

The resulting 5-t>.chlorobenzyl-6-methyl-4,5,6,7-tetrahydrothieno^,3-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 (Yields 300 mg} 28%} m.p. = 178-182°C).

EXAMPLE 3 Preparation of 5-(2-chlorO-benzyl)-4,5,6,7-tetrahydrotliieno/3,2-c7pyridine via a two-step cyclisation (a) To N-(2-cliloro-benzyl)-2-(2-thienyl)ethylamino (2515 gj 10 moles) is added, with stirring,a 35% formaldehyde aqueous solution 946 g;l^noLe^>T}le reaction is immediate and slightly exothermic. The aqueous phase is decanted, washed with water and the organic phase is dried azeotropically, to give 2780 g intermediate products of step (a). (b) The resulting mixture of intermediate products is poured over 5 litres of 5M HCl solution in dimethylformamide. The reaction is - 12 exothermic and the temperature rises to 45-5O°G, at which level it is maintained by external cooling. 'J'he addition is complete in nbout 30 minutes. Ten minutes after completion of the addition, the '5-(2-chloro-bcnzyl)-4,5,6,7-tctrahydro-thieno/3,S-c/pyridine hydrochloride begins to precipitate out. The reaction mixture is cooled to room 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 desired product and 325 g N-(2~chloro-bonzyl)-2-(2-thienyl)ethylamine. Thus, the conversion rate of this amine is 87.1% and the yield of 5-(2-ehloro-benzyl)~ 4,3,6,7-tetrahydro-thieno^,2-jc7pyridine is 86%, the major portion of which is obtained as a precipitate.

In order to recover the unreactcd starting amino 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 bo removed , or not, for another formalin treatment and another cyclisation according to a procedure similar to that described '20 above. The conversion rates and the yields based on the N-(2chloro-benzyl)-2--(2-thienyl)-ethylamine contained in the filtrate of the primary operation are approximately the same.

The derivatives set forth in following Tables I and 11 were prepared according to the above-described procedures.

TABIJi I li ΪΓ-Rf Compound No. »1 M.p. or b.p. (°C) yio: (% 1 CH3 b.p. 52-54°/0.1 mm Hg 39 2 (CH2)6Cn3 b.p. 118°/0.5 mm Ilg 42 3 -™2-O 240° (hydrochloride) 40 4 208-210° (hydrochloride) 46 οΐξ” 5 -“3-0 215° (hydrochloride) 47 \ί13 6 260° (hydrochloride) 38 7 -^-0 ρ 168° (maleate) 48 8 Ρ 216° (methiodide) 51 9 “CH2O*P 215° (hydrochloride) 50 190° (hydrochloride) 38 212° (maleate) 44 182° (methiodide) 48 Ί'ΛΠΙ.Κ ] (conLdnued) No. H1 M.p. or b.p. (°C) 200° (hydrochloride) ^Cl -c,,i-Qci 240° . (hydrochloride) 200° (hydrochloride) 210° (hydrochloride) 122° 240° (hydrochloride) 86° 90° OCIij -M3 OCIL· -οη2£)-οοπ3 200° (hydrochloride) 215° (hydrochloride) 100° (methiodido) 210° (hydrochloride) 195° (hydrochloride) Yield TABLE T (continued) Yield . J&L· 196-198°(hydrochloride) 43 205° (hydrochloride) 32 195° (mothiodide) 46 230-235° (hydrochloride) 38 180° (hydrochloride) 48 119-121° 46 226° (hydrochloride) 38 176° (hydrochloride) 29 120° 48 200° (hydrochloride) 37 164-166° (hydrochloride) 42 -Cn(CH3 )-CH(0H)-^^ 230® (hydrochloride) 51 co J θ 3 0 8 4 TABLE ΐ (continued) Compound No. 1 M.p. or b.p.(°C) jy 38 -CH2-CH (OH) 210° (hydrochloride) 55 39 -ClI2-CH(0H)-^y-F 124° 47 40 -CH2CH(0H)-^y.Cl 195° (hydrochloride) 41 41 -CH2CH(OH)-^2^-OH 216-218° (hydrochloride) 44 42 -cii2cii(oh)-/A h co' och3 224° (hydrochloride) 37 43 -CH2-Cn(OH)-/ \ 170° (hydrochloride) 38 44 -CH2-CH (oh) -θ-Ο^ /°CH3 206-208° (hydrochloride) 42 45 -0Η2-0Η(0Η)-ΛΛ H3C0Z 106° 41 46 -CH2-CH(0H) 150° (fumarate) 48 TABLE JI -R, Compound No, M.p. or b.p.(°C) -CH. 190-194°(hydrochloride) Yield J&L.

-CH, Cl -ch2-/2 179-180° (hydrochloride) 178-180° (hydrochloride)

Claims (11)

CLAIMS :

1· Process for the preparation of thieno-pyridine derivatives having the formulas (I) in which R^ represents an optionally substituted alkyl, aryl or aralkyl radical and Rg and Rj each represent hydrogen or a alkyl, aryl or. heterocyclic radical, comprising! (a) roacting a derivative having the formulas ΙΟ (II) in which Rg and Rj are as defined for formula (l) and X represents hydrogen, or an alkali metal or a radical MgY in which Γ represents halogen, with a halosulfonyl derivative having the formulas Hal - S0„ - R. (Ill) 2. 4 z·. in which Hal represents halogen and R^ represents an optionally substituted alkyl, aryl or aralkyl radical, to give a compound having the formulas R. R„ , 3 ? CH - CH - OSO. (IV) (b) reacting derivative (IV) with an amine of the formula R r MIg (V) in which R^ is as defined for formula (i), to give a compound having the formulas - 19 J3084 CH - CH - NH - R. '1 (VI) and fc) subsequently cyclising said derivative (VI) with formaldehyde, to give the derivative of the formula (I); step (a) being effected, in the presence of an organic or inorganic base when a derivative of the formula (II) in which X is hydrogen is used.

2. 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).

3. Process as claimed in claim 1 or claim 2, wherein the halo-sulfonyl derivative of the formula (III) is methane sulfonyl chloride, trichloromethane sulfonyl chloride, trifluoromethane sulfonyl chloride,benzene sulfonyl chloride, paratoluene sulfonyl chloride m.acetyl benzene sulfonyl fluoride or p-bromophenyl sulfonyl chloride.

4. Process as claimed in any one of the preceding claims, wherein step (b) is effected with an excess of the amine.

5. Process as claimed in any one of the preceding claims, wherein the cyclisation of step (c) is effected in a single stage in acidic medium, within an inert solvent.

6. Process as claimed in any one of claims 1 to 4, 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.

7. Process as claimed in claim 6, wherein the aprotic polar solvent is dimethylformamide.

8. Process as claimed in claim 6, wherein the aprotic polar solvent is dimethyl sulfoxide, N-methyl pyrrolidone or N,N-dimethylacetamide. 20 4 3084

9. Λ process as claimed in claim 1 substantially as herein disclosed.

10. Λ process as claimed in claim 1 substantially as herein disclosed in any of Examples 1 to 3.

11. Compounds of general formula I as defined in claim 1 whenever prepared by a process as claimed in any of claims 1 to 10.