CS197278B2 - Method of producing derivatives of 1,5,10,10a-tetrahydrothiazolo/3,4-b/isoquinoline - Google Patents

Description

The present invention provides a process for the preparation of 1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline derivatives of the general formula I wherein one of X1 '' and X2 '' is hydrogen and the other nitro group can be obtained by cyclization of 1,2 3,4-isoquinoline of formula II

Χχ χ;

N-CS-NH

(ID where one of the symbols

X 1 'and X 2' 'represent a hydrogen atom and a second amino group in the form of R or S, in a mixture of these forms, in free form or in salt form, characterized in that the corresponding nitro derivative is reduced.

The reaction is preferably carried out in an acidic medium (for example in the presence of hydrochloric acid) in the presence of a metal, for example tin, at a temperature of 10 to 40 ° C.

Compounds of general formula

where one of the symbols

X 1 and X ²¹ represent a hydrogen atom and a second nitro group.

The reaction is usually carried out by heating under acidic conditions. It is particularly preferred to carry out the reaction at a temperature of 65 to 100 ° C in an aqueous solution of an inorganic acid, for example hydrochloric acid.

1,2,3,4-Tetrahydroisoquinoline II can be obtained by treatment with an iso thiocyanatopyridine III

S = C = N and

to 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline of formula IV

where

X 1 * and X 2 ‘are as defined above.

The reaction is usually carried out in an organic solvent such as an alcohol such as ethanol at a temperature of 15 to 70 ° C.

The isothiocyanate-3-pyridine of formula III can be obtained as described in J. C. Jochims, Chem. Ber. 101, 1746 (1968).

The 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline of formula (IV) may be obtained by reducing the 1,2,3,4-tetrahydroisoquinoline of formula (V).

_(In , where

X 1 and X 2 are as defined above and

R is alkyl of 1 to 4 carbon atoms, or by reduction of one of the salts thereof.

The reduction is preferably carried out with an alkali metal borohydride, for example sodium borohydride, in an organic solvent or in a mixture of water and an organic solvent, for example a mixture of ethanol and water, at a temperature between 10 ° C and reflux.

The 1,2,3,4-tetrahydroisoquinoline of formula (V) may be obtained by esterifying a 1,2,3,4-tetrahydroisoquinoline of formula (V) wherein R is hydrogen by methods generally known to convert an acid to an ester without affecting the rest of the molecule.

Compounds of formula V can be obtained by nitration of the corresponding compound of formula V 'in which X ¹ ' and X ²¹ are hydrogen atoms. Nitration may also be carried out on the corresponding compounds of formulas II or IV, in which X 'and X 2 ^L are hydrogen.

This is usually carried out with a mixture of nitric acid and sulfuric acid at a temperature of -20 ° C or a mixture of sodium nitrate and trifluoroacetic acid at a temperature of 20 ° C, with the possible subsequent separation of the isomers thus obtained.

The 1,2,3,4-tetrahydroisoquinoline of formula (V) wherein R, X 1 and X 2 * are hydrogen atoms can be obtained from phenylalanine as described in A. Pictet and Th. Spengler, Chem. Ber., 44, 2030 (1911).

When phenylalanine L is used, the resulting product of formula I is obtained in form (S).

When phenylalanine in form D is used, the resulting product of formula I is obtained in form (R).

When phenylalanine D, L is used, the product of formula I is obtained in the form (RS).

The amine-3-pyridine is treated with a salt of formula VI

where one of the symbols

Xi "and Xz" mean the hydrogen atom and the second nitro group,

R 1 represents a chlorine atom or an alkylthio group having from 1 to 4 carbon atoms or a benzylthio group; and

A 1 is an anion, or R 1 is a chlorine atom and A 1 is a chloride ion, or R 1 is an alkylthio group, preferably a methylthio or benzylthio group, and A 1 is an anion, for example an iodide ion, sulfate ion, tetrafluoroborate ion or fluorosulfonate ion.

In the case where R1 is a chlorine atom and A1 is a chloride ion, the reaction is carried out in an organic solvent such as acetonitrile in the presence of an alkaline condensing agent such as triethylamine at 20 ° C.

When R1 is alkylthio or benzylthio and A1 is iodide ion, sulfate ion, tetrafluoroborate ion or fluorosulfonate ion, the reaction is carried out in a basic organic solvent such as pyridine at 20 ° C.

The salt of formula VI wherein R 1 is chlorine and Al 2 is a chloride ion can be obtained by treating a 1,5,10,10a-tetrahydrothiazole [3,4-b] with a chlorinating agent such as phosgene, phosphorus pentachloride, thionyl chloride or oxalyl chloride. isoquinoline-3-quinone of formula VII

where

X1 'and X2' are as defined above.

The reaction is usually carried out in an organic solvent or in a mixture of organic solvents, for example a mixture of toluene and tetrahydrofuran at 0 to 70 ° C.

A salt of formula VI wherein R 1 is alkylthio or benzylthio and Al 1 is iodide ion, sulfate ion, tetrafluoroborate ion or fluorosulfonate ion can be obtained by treatment with a reactive ester of formula VIII

Ri‘ — Ai (VIII), where

R 1 represents an alkyl radical of 1 to 4 carbon atoms or a benzyl group and

A 1 represents a residue of a reactive ester, for example an iodine atom or an alkoxysulfonyloxy group, or by treating triethyloxonium tetrafluoroborate or methyl fluorosulfonate with a compound of formula VII.

The reaction is usually carried out in the presence or absence of an organic solvent such as methylene chloride at 20 ° C.

The thiazoloisoquinoline derivative of the general formula VII, in which X1 'and X2' are as defined above, can be obtained by treatment of the 1,2,3,4-tetrahydroisoquinoline of the general formula IX by treatment with basic carbon disulfide.

where

X1 'and X2' are as defined above, and

E represents a halogen atom or a hydroxysulfonyloxy group.

The reaction is usually carried out in the presence of sodium or potassium hydroxide at 20 ° C.

Compounds of formula (IX) may be obtained by treatment of a compound of formula (IV) wherein X ¹ 'and X ^21' are defined as X ¹ 'and X 2' by the action of an inorganic acid.

In order to obtain compounds of the formula IX in which E is hydroxysulfonyloxy, the process is usually carried out by treatment with sulfuric acid in an aqueous medium at 100 ° C or in an organic solvent, for example dimethylformaimide, in the presence of dicyclohexylcarbodiimide at 20 ° C.

In order to obtain compounds of formula (IX) in which E is bromine, the process is generally carried out by treatment with a 48% aqueous solution of hydrobromic acid at the reflux temperature of the reaction mixture, whereupon the resulting product is isolated as the hydrobromide.

In order to obtain a compound of the formula (IX) in which R is a chlorine atom, the reaction is usually carried out by treatment with thionyl chloride in an organic solvent such as chloroform saturated with gaseous hydrogen chloride at the reflux temperature of the reaction mixture. hydrochloride.

Compounds of formula (IX) or (VII) may also be obtained by nitration of a compound of formula (IX) or (VII) in which X 1 'and X 2' are hydrogen atoms.

The nitration is generally carried out under the same conditions as the nitration of the compounds of formulas II, IV or V.

The compounds of formula I prepared by the process of the invention are valuable intermediates for the preparation of derivatives of formula X

x X (X) where

X1 is halogen, dimethylamino or cyano, and

X 2 represents a hydrogen atom, or

X1 is hydrogen and

Xž represents a fluorine atom.

In order to obtain compounds of the formula (X) in which X 1 is chlorine, the decomposition is generally carried out by treatment with copper (I) chloride at a temperature of 20 to 70 ° C, decomposing the diazonium salt previously prepared in an aqueous medium at - 5 to + 5 ° C by treatment of the corresponding amine of general formula I with nitrite, sodium in the presence of an acid, for example hydrochloric acid

In order to obtain a compound of formula X in which X 1 or X 2 is fluorine, the process is usually carried out by decomposing the diazonium salt of the corresponding amine of formula I in hexafluorophosphoric acid at -10 ° C.

In order to obtain a compound of formula X in which X 1 is cyano, the process is usually carried out by decomposing the diazonium salt of the corresponding amine of formula I with potassium cyanide and copper sulfate.

The reaction is preferably carried out in a mixture of water and an organic solvent, for example a mixture of water and toluene at a temperature of 0 to 50 ° C.

When a compound of formula X in which X 1 is dimethylamino is to be obtained, the reaction is generally carried out by treatment with formaldehyde in the presence of a reducing agent. Preferably, sodium cyanoborohydride is used in the presence of an acid such as acetic acid at a temperature of 20 ° C in a mixture of water and an organic solvent of the body, such as a mixture of water and acetonitrile.

The compounds of formula (X) and their salts have interesting pharmacological properties. These are analgesics and antipyretics. Their anti-inflammatory activity is less pronounced.

Analgesic efficacy can be demonstrated in rats at doses of 2 to 50 mg / kg when administered orally by the method of L. O. Tandall and J. J. Selitto, Arch. Int. Pharmacodyn., 111, 409 (1957), in the modification described by K. F. Swingle et al., Proc. Soc. Exp. Biol. Med., 137, 536 (1971). Most compounds are also active in mice at a dose of 20 to 200 mg / kg by oral administration, as evidenced by the method of E. Siegmund, Proc. Soc. Exp. Med., 95, 729 (1957).

Antipyretic activity can be demonstrated in rats at a dose of 5-50 mg / kg by oral administration as described by J. J. Loux et al., Toxicol. Appl. Pharmacol., 22,674 (1972).

Anti-inflammatory activity can be demonstrated in rats at doses of 5 to 50 mg / kg by oral administration as described by KF Benitz and L. M. Halí, Arch. Int. Pharmacodyn., 144,185 (1963).

In addition, the compounds of formula X have low toxicity. Their DL 50 is between 300 mg / kg and 3000 mg / kg and above.

The invention will be illustrated by the following examples.

Example 1

To a solution of 3.3 g of 7-nitro-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (S) in 100 ml of 6 N hydrochloric acid is added 6.5 g of tin powder and the mixture was stirred for 15 hours at 20 DEG C. After diluting with 200 ml of water and basifying by adding 65 ml of 10N sodium hydroxide, the mixture was extracted with 3 x 150 ml of methylene chloride. 200 ml of water, freed from magnesium sulphate, filtered and evaporated to dryness and recrystallized from 90 ml of acetonitrile to dryness at 60 DEG C. and 13.3 Pa, yielding 2.2 g of 2-amino- 3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline (m.p. 191 ° C).

[α] ο ^2θ = -245 ± 3 ° (c = 2, chloroform).

7-Nitro-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline (S) can be prepared as follows:

A solution of 0.344 g of 3-hydroxymethyl-7-nitro-N- (3-pyridyl) -1,2,3,4-tetrahydro-2-isoquinolinecarbothioamide (Sj in 4 ml of hydrochloric acid) is heated at 50 DEG C. for 30 minutes. The mixture is poured into 100 ml of distilled water and basified to pH 12 by addition of sodium hydroxide.

The mixture was extracted with methylene chloride (3 x 50 ml), the extracts were dried over potassium carbonate and evaporated to dryness under reduced pressure of 30 Torr at 40 ° C. In this way 0.200 g of 7-nitro-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (S) are obtained in the form of yellow crystals having the same properties as below the product of variant b) described.

3-Hydroxymethyl-7-nitro-N- (3-pyridyl) -1,2,3,4-tetrahydro-2-isoquinolinecarbothioamide (S) can be prepared as follows:

To a suspension of 0.416 g of 3-hydroxymethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline- (Sj in 10 ml of absolute ethanol) was added 0.272 g of 3-isocyanatopyridine. After 3 minutes the mixture became homogeneous and a light yellow formed. The mixture was further stirred at 20 ° C for 1 hour, then the precipitate was collected by filtration to give 0.575 g of crystals after drying, m.p. 175 ° C.

[Α] ²⁰ D = +132.6 ± 2 ° (c = 0.5, methanol).

3-Hydroxymethyl-7-nitro-1,2,3,4-tetrahydroquinoline (S) can be prepared as follows:

While stirring at 20 ° C, 8.4 g of sodium borohydride in solution in 56 ml of ethanol and 56 ml of water (distilled) are added to a suspension of 14 g of 3-ethoxycarbonyl-7-nitro-1,2,3,4-tetrahydroisoquinoline - (S) in 56 ml of ethanol and 56 ml of distilled water. After stirring for 1 hour at 20 ° C, the reaction mixture was allowed to stand, after 30 minutes a precipitate formed. The mixture is then allowed to stand for one hour at 20 DEG C. and the ethanol is then distilled off under reduced pressure. The residue is mixed with 250 ml of distilled water and extracted with 3 x 50 ml of methylene chloride. The organic extracts were dehydrated with potassium carbonate, filtered and evaporated to dryness under reduced pressure (40 psi) at 40 ° C. An orange solid is obtained, which is recrystallized from 100 ml of acetonitrile. After drying, 5 g of pale yellow crystals having a melting point of 184 DEG C. are obtained.

_{[?] D} 20 = _73,4 ± 1.5 ° (c = 0.5,

HC10.1N).

3-Ethoxycarbonyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (S) can be prepared as follows:

While stirring at -20 ° C, 50 g of 3-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride are added in small portions to 325 ml of a 1.83 density sulfuric acid. After 10 minutes an opalescent solution was obtained. The mixture was cooled to -30 ° C and 10 ml of 1.49 nitric acid was added over 15 minutes. The reaction mixture is then allowed to stand with stirring at -40 ° C for 30 minutes, then poured onto 1 kg of ice and basified by the addition of 1000 ml of 1.33 sodium hydroxide, maintaining the temperature between 15 and 20 ° C. . The reaction mixture was extracted with methylene chloride (3 x 500 ml). The organic extracts are combined, dehydrated with potassium carbonate, filtered and evaporated under reduced pressure (40 kPa) at 40 ° C to give a reddish solid which is recrystallized from 300 ml of isopropyl oxide. 17.5 g of pink crystals are obtained, m.p. 94-95 ° C.

[ «] _{D20 =} _ 7 ₁₀ ± 2 ° (c = 0.5, chloroform).

3-Ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride can be obtained as described in S. Yamada et al., Chem. Pharm. Bull. 15, 490 (1967).

b) To a solution of 11 g of 3-aminopyridine in 400 ml of pyridine was added 23 g of 3-methylthio-7-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium iodide (Sj). The reaction mixture is evaporated to dryness under reduced pressure (50 mm Hg) at 20 DEG C. The residue is dissolved in a mixture of 1500 ml of methylene chloride and 500 ml of water. The residue was recrystallized from acetonitrile / ethanol (1: 1 by volume) to give 16.2 g of 7-nitro-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo. [3,4-b] isoquinoline- (S is in the form of yellow crystals, m.p. 234 DEG C. [ _.alpha .] _D @ ²⁰ = -311. + -. 3 DEG (c = 2, chloroform).

3-Methylthio-7-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium iodide (S) can be obtained as follows:

16 g of 7-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthione (S) are dissolved in 800 ml of methyl iodide. After 15 hours at 20 ° C, the formed crystals were collected by filtration, washed with 2 x 30 ml ether and then dried at 20 ° C under reduced pressure of 133Pa. 23.3 g of 3-methylthio-7-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinium iodide (S) are obtained.

7-Nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthione (S) may be obtained by the method of Example 1.

7-Nitro-, 8-nitro- and 9-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinolinthionium (S) can be obtained as follows:

To a solution of 122 g of 3-hydroxysulfonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (with 1000 ml of trifluoroacetic acid) was added 85 g of anhydrous sodium nitrate as a fine powder, and the mixture was stirred at 20 ° C for 5 hours. The residue was washed with ether (3 x 200 mL) to give a bright yellow solid which was crushed and dried at 40 ° C under reduced pressure.

The solid thus obtained was dissolved in 5000 ml of 0.3 N sodium hydroxide solution. With stirring, 35 ml of carbonate was added to the solution thus obtained, and the mixture was further stirred at 20 ° C for 17 hours. The mixture was neutralized by the addition of 4 N hydrochloric acid. The resulting precipitate was collected by filtration, washed with plenty of water and then with ethanol, dried under reduced pressure of 13.3 Pa and then dissolved in 3200 ml of boiling toluene. The insoluble matter was collected by filtration and the filtrate was cooled to 10 ° C. The crystals formed are collected by filtration, washed with 100 ml of ethanol, dried at 80 DEG C. under a reduced pressure of 13.3 Pa and recrystallized from 1000 ml of a 1: 1 mixture of acetonitrile and ethanol. There was thus obtained 7-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolithithione (S) (45 g), m.p. 182 ° C.

[Α] ²⁰ D = - 458 + 5 ° (c = 2, chloroform).

The toluene filtrate is evaporated to dryness and the residue is dissolved in boiling acetonitrile (600 ml). The resulting crystals were collected by filtration and dried at 60 ° C and 13.3 Pa. 29 g of a mixture of 8-nitro and 9-nitro-1,5,10,10a-tetrahydrothlazolo [3,4-b] -3-isoquinolinthione (S) are thus obtained. The two products are separated by chromatography on

2.4 kg of silica gel in a 7 cm diameter column. The column is eluted with a 4: 1 mixture of methylene chloride and cyclohexane and 1000 ml fractions are collected.

Fractions 6 to 15 are combined and evaporated to dryness. The residue is recrystallized from 150 ml of anisole and 150 ml of acetonitrile. After drying at 60 ° C and 13.3 Pa, 6.2 g of 9-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthione- (S) o was obtained. mp 203 ° C.

[α] _D ²⁰ = -654 ± 7 ° (c = 1, chloroform).

Fractions 17 to 26 are combined and evaporated to dryness under reduced pressure. The residue is recrystallized from 170 ml of anisole and then 170 ml of acetonitrile. After drying at 60 DEG C. under a reduced pressure of 13.3 Pa, 3.9 g of 8-anitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] -3-isoquinolinthione- (S) are thus obtained. mp 220 ° C.

[α] _D ²⁰ = -338 ± 3 ° (c = 0.5, chloroform).

Example 2

To a solution of 13 g of 7-amino-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline (Sj) in 25 ml of 4 N hydrochloric acid, cooled to

9 7 27 8 th

A solution of 3.1 g of sodium nitrite in 10 ml of distilled water was added slowly at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes and then added to a suspension of 6 g of cuprous chloride in 25 ml of 1.18 hydrochloric acid. The temperature was allowed to rise to 20 ° C and then heated to 70 ° C for 33 minutes. Decomposed to 20 ° C, 200 ml of distilled water, 250 ml of methylene chloride and 100 ml of 1 N sodium hydroxide are added. After filtration, the organic phase is separated, dried over magnesium sulphate, filtered and evaporated to dryness at 40 ° C. pressure 2.66 kPa.

The residue obtained is purified by chromatography on 200 g of silica gel in a 3 cm diameter column, eluting with 5000 ml of methylene chloride with 1% methanol and collecting 1 liter fractions. Fractions 2-4 are combined and evaporated to dryness. The residue was recrystallized from a mixture of 70 ml of isopropanol and 103 ml of heptane to give 5.5 g of 7-chloro-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline. - (S) with a melting point of 125 ° C.

[α] ²⁰ D = -273 ± 3 ° (c = 1.1, chloroform).

Example 3

To a solution of 11.8 g of 7-amino-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (S) in 8 ml of distilled water, cooled to 5 ° C, was added. 12 ml of 1.18 hydrochloric acid are added. The mixture is cooled to -5 ° C with stirring, slowly adding a solution of 3.35 g of sodium nitrite in 8 ml of distilled water, maintaining the temperature at -3 to -5 ° C. After the addition was complete, the mixture was further vigorously stirred for 10 minutes, then cooled to -10 ° C and 15.4 g of 75% hexafluorophosphoric acid was added with stirring. The mixture was then stirred at -10 ° C for 45 minutes to form a brown precipitate.

The aqueous phase is decanted and the brown solid is washed with 5 x 30 ml of an 8: 2 by volume mixture of ethyl ether and methanol and then dried under reduced pressure of 13.3 Pa at 20 ° C.

The solid was then added in small portions to 150 ml of boiling anhydrous xylene. After the addition was complete, the xylene was boiled for a further 20 minutes and then cooled to 20 ° C, after which 100 ml of a 5% aqueous sodium carbonate solution was added with vigorous stirring. The organic phase is decanted and the brown precipitate formed is dissolved in 110 ml of a 90:10 mixture of methylene chloride and methanol. The methylene chloride solution is washed with 2.times.80 ml of 0.1 N sodium hydroxide solution and 2.times.50 ml of distilled water. is added to the xylene solution. The mixture was dehydrated with magnesium sulfate, filtered and evaporated to dryness under reduced pressure (100 psi) at 70 ° C.

The residue obtained is purified by chromatography on 120 g of silica gel in a diameter column

2.5 cm, eluting with 2500 ml of methylene chloride and 2% methanol, collecting 250 ml fractions. Fractions 5-8 are combined and concentrated, and the residue is recrystallized from ethyl ether to give 5.1 g of 7-fluoro-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiolo [3, m.p. 4-b] isoquinoline (m.p. 99 ° C).

[Α] ²⁰ = -227 ± 3 ° (c = 1, methanol). Example 4

To a solution of 11.4 g of 7-amino-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- (S) in 30 ml of a 30% aqueous solution of formic aldehyde and 150 ml of acetonitrile are added, while stirring at 20 ° C, 7.5 g of sodium cyanoborohydride and 7.5 ml of acetic acid in small portions alternately. The mixture was stirred at 20 ° C for 2 hours and then basified by the addition of 12 ml of 10 N sodium hydroxide solution.

The reaction mixture is concentrated to a volume of 50 ml under reduced pressure at 40 ° C. 250 ml of methylene chloride are added, the mixture is washed with 5 x 109 ml of distilled water, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure.

3.99 kPa at 40 ° C. A brown oil is obtained which is dissolved in 250 ml of 4N hydrochloric acid and refluxed for 6 hours, then cooled to 4 ° C, basified with 10N sodium hydroxide solution and extracted with ethyl acetate. 3 x 100 ml chloroform.

The chloroform extracts are combined, washed with 5 x 100 ml of water, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure at 40 ° C.

The residue thus obtained is purified by chromatography on 200 g of silica gel in a 3 cm diameter column, eluting with 500 ml of methylene chloride and then with 1 liter of methylene chloride with 1% methanol. The fractions corresponding to the second eluate are combined and evaporated to dryness.

The residue obtained is recrystallized from acetonitrile. 1.6 g of 7-dimethylamino-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline (Sj), m.p.

[α] _D 20 ₌ -279 ± 3 ° (c = 1, methanol).

Example 5

To a solution of 15.2 g of copper sulphate as pentahydrate in 30 ml of distilled water, a solution is added gradually at 0 ° C

16.3 g of potassium cyanide in 30 ml of distilled water and then 33.6 g of sodium hydrogen carbonate, 150 ml of toluene and, while maintaining the temperature at 0 ° C, a solution obtained by mixing 14.8 g of 7 at 0 ° C. -amino-3- (3-pyridylimino) -1,11,10,10a-tetrahydrothiazolol-3-yl-isoquinoline-5S, 15 ml of distilled water, 20 ml of 1.18 hydrochloric acid and 3.9 g of sodium nitrite in 20 ml of distilled water. After the addition was complete, the mixture was maintained at 0 ° C for 1 hour while stirring, the temperature was allowed to rise to 20 ° C and then heated to 50 ° C in a water bath for 30 minutes.

The mixture was cooled to 20 ° C, filtered and the precipitate was washed with warm toluene (3 x 100 mL). The toluene phase is decanted, washed with 2 x 200 ml of 1N sodium hydroxide solution and 100 ml of distilled water, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure at 70 ° C.

The residue is purified by chromatography on 180 g of silica gel in a 3 cm diameter column, eluting with 7509 ml of methylene chloride with 0.6% methanol and collecting 250 ml fractions. Fractions 11 to 30 are combined and evaporated to dryness. The residue is recrystallized from ethanol to give 4.8 g of 7-cyano-3- (3-pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline (Sj), m.p. Mp 172 ° C.

[α] _D ²⁰ = -300 ± 3 ° (c = 1, chloroform). Example 6

Following the procedure of Examples 1-3, 8-nitro-1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline-3-thione- (R, S) gave 8-fluoro-3- (3). pyridylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline- [R, S] m.p. 139 ° C.

Claims (1)

A process for the preparation of 1,5,10,10a-tetrahydrothiazolo [3,4-b] isoquinoline derivatives of formula (I) Where one of the symbols X ¹ 'and X 2' ¹ represent an amino group and a second hydrogen atom, in the form (R 1 or (S) or in the form of a mixture of both, in free form or in salt form, characterized in that it is reduced under acidic conditions in the presence a metal, for example tin, at a temperature of 10 to 40 ° C corresponding to the nitro derivative.