KR800000304B1 - Preparation of thiazolo [3, 4-b] isoquinoline derivatives - Google Patents

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Description

Preparation of thiazolo [3, 4-b] isoquinoline derivatives

The present invention relates to thiazolo [3,4-b] isoquinoline derivatives represented by the following general formula (I) and useful methods for preparing acid addition salts thereof useful as therapeutic agents.

Food,

A represents a 3-pyridyl group and a 5-isoquinolyl group, and when Ar is a 3-pyridyl group,

X ₁ represents a hydrogen atom or a halogen atom,

X ₂ represents hydrogen or fluorine atom,

X ₃ represents a hydrogen atom or a nitro group,

At least two of X ₁ , X ₂ and X ₃ represent a hydrogen atom, or X ₁ and X ₂ together represent a methylene dioxy group and

X ₃ represents a hydrogen atom.

When A represents 5-isoquinolyl group

X, X ₂ and X ₃ each represent a hydrogen atom.

Compounds of formula (I) may exist in (R) -form and (S) -form and the present invention includes both these types of compounds and mixtures thereof.

According to the present invention, the thiazolo [3,4-b] isoquinoline derivative of the general formula (l) is prepared by cyclizing the 1, 2, 3, 4-tetrahydro isoquinoline derivative represented by the following general formula (II).

Food,

A ₁ represents a 3-pyridyl or 5-isoquinolyl group,

When A ₁ represents a 3-pyridyl group,

X ₄ represents hydrogen or a halogen atom,

X ₅ represents hydrogen or fluorine atom,

X ₆ represents a hydrogen atom or a nitro group,

At least two of X ₄ , X ₅ and X ₆ represent a hydrogen atom, or

X ₄ and X ₅ together represent a methylenedioxy group,

X ₆ represents a hydrogen atom,

When A ₁ represents a 5-isoquinolyl group,

X ₄ , X ₅ and X ₆ represent a hydrogen atom.

The reaction is generally carried out by heating in an acid medium. In particular, the reaction is advantageously carried out in an aqueous inorganic acid solution such as aqueous hydrochloric acid at a temperature in the range of 65-100 ° C.

1, 2, 3, 4-tetrahydro isoquinoline derivatives of the general formula (II) is the following isothiocyanate of the general formula (III) and 3-hydroxy methyl-1, 2, 3 of the general formula (IV) And 4-tetrahydro isoquinoline derivatives.

Food,

A ₁ , X ₄ , X ₅ and X ₆ are as described above.

The reaction is generally carried out in organic solvents such as alcohols such as ethanol at temperatures in the range of 15-70 ° C.

In general formula (III), isothiocyanate of general formula (III) in which A ₁ represents a 5-isoquinolyl group is condensed with carbon disulfide and 5-amino isoquinoline, and then dicyclohexylcarbodiimide is added. Can be prepared. Condensation is generally carried out in the presence of a base such as a tertiary amine such as triethylamine. The reaction is advantageously carried out in an organic solvent such as pyridine at a temperature in the range of −10 ° C. to 25 ° C.

3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline derivatives of the general formula (IV) are 1, 2, 3, 4-tetrahydro isoquinoline derivatives of the following general formula (V) or acid addition salts thereof It can be prepared by reducing.

Food,

R represents a hydrogen atom or an alkyl group of 1-4 carbon atoms,

X ₄ , X ₅ and X ₆ are as described above.

When R represents a hydrogen atom in the general formula (V), the reduction is preferably performed using lithium aluminum hydride in tetrahydrofuran at a temperature in the range of 20-70 ° C.

When R in formula (V) represents an alkyl group of 1-4 carbon atoms, the reduction is sodium borohydride at temperatures ranging from 10 ° C. to the reflux temperature of the reaction mixture in an aqueous solvent such as an organic solvent or an ethanol-water mixture. It is preferable to use an alkali metal borohydride such as a ride.

When a compound of the general formula (IV) in which X ₆ represents a nitro group is required, it is preferable to use an ester of the general formula (V) (R = alkyl). In this case the reduction takes place under conditions which have no effect on the nitro group.

Formula 1, 2, 3, 4-tetrahydro isoquinoline derivatives of general formula (V), wherein R represents an alkyl group having 1-4 carbon atoms, are known in a known method for converting acids to esters without affecting the remaining groups of the molecule. It can be prepared by esterifying 1, 2, 3, 4-tetrahydro isoquinoline derivative of the general formula (V) wherein R is a hydrogen atom.

As used herein and in the claims, the term `` notice method '' means a method that has been used conventionally or described in the chemical literature.

Wherein 1, 2, 3, 4-tetrahydro isoquinoline derivatives of general formula (V) wherein R represents a hydrogen atom, X ₄ and X ₅ are as described above, and X ₆ represents a hydrogen atom, are described in Chem. Ber., 44, 2, 030 (1911) can be prepared from phenylalanine derivatives of the following general formula (VI) using a method published by A. Pictet and Th. Spengler. Can be.

Food,

X ₄ and X ₅ are as described above.

When the (L) -form of the phenylalanine derivative represented by formula (VI) is used, the compound of formula (I) obtained via the compound of formula (V) is (S) -form. When the phenylalanine derivative represented by the general formula (VI) is used in the (D) -form, the compound of the general formula (I) is obtained in the (R) -form. When used as a mixture of the (D) -form and the (L) -form of the phenylalanine derivative represented by the general formula (VI), the compound of the formula (I) is obtained in the (R, S) -form.

The compounds of formulas (II), (IV) and (V) in which X ₆ represents a nitro group are prepared by nitrating the compounds of formulas (II) (IV) and (V) in which X ₆ represents a hydrogen atom. can do.

The nitration reaction is generally carried out using a mixture of nitric acid and sulfuric acid at a temperature of about −20 ° C. or a mixture of sodium nitrate and trifluoroacetic acid at a temperature of about 20 ° C., then separating the isomers obtained as necessary. Let's do it.

The thiazolo [3,4-b] isoquinoline derivatives of the general formula (I) obtained by the above-described methods may be purified by physical methods such as crystallization or chromatography, or salt formation, salt crystallization and salting in alkaline media. It can refine | purify by chemical methods, such as a decomposition method. The anionic nature of the salt is not critical when this chemical method is carried out, and the only prerequisite is that the salt is well formed and easy to crystallize.

The thiazolo [3,4-b] isoquinoline derivatives of formula (I) can be converted to acid addition salts by known methods. Acid addition salts are obtained by reacting an acid with a thiazolo [3,4-b] derivative in a suitable solvent. As the organic solvent, alcohols, ketones, ethers or chlorinated hydrocarbons are used. The salts formed are separated by concentration of the solution, precipitated, filtered or tilted and drained as necessary.

Thiazolo [3,4-b] isoquinoline derivatives of formula (I) and acid addition salts thereof have useful pharmacological properties. In particular, the compound of formula (I) and acid addition salts thereof are effective as analgesics and antipyretics, and have some anti-inflammatory action.

Compounds of formula (I) and acid addition salts thereof are prepared according to Proc. Soc. Exp. Biol. Arch., Improved by K. F. Swingle- et al., In Med., 137, 536 (1971). Int. The techniques of L. O. Randall and J. J. Selitto, published in Pharmacodyn., 111, 409 (1957), have proven effective as analgesics at doses of 2-50 mg / kg when administered orally to rats. In addition, most of the derivatives represented by the general formula (I) are proc. Soc. Exp. Biol. E. Siegmund's technique, published in Med, 95, 729 (1957), has proven effective at doses of 20-200 mg / kg when administered orally to mice.

The antipyretic effect of thiazolo [3,4-b] isoquinoline derivatives represented by formula (I) is shown in Toxicol. Appl. According to the technique of J. J. Loux et al., Published in Pharmacol., 22, 674 (1972), a dose of 5-50 mg / kg was orally administered to mice.

Anti-inflammatory action is Arch. Int. According to KF Benitz and LM Hall and the technique, published in Pharmacodyn., 144, 185 (1963), it was demonstrated in most of the derivatives at doses of 5-50 mg / kg upon oral administration to rats. In addition, thiazolo [3,4-b] isoquinoline derivatives of formula (I) are less toxic and LD ₅₀ ranges from 300 mg / kg to 3,000 mg / kg.

Of particular importance among the compounds of formula (I) are those in which A represents a 3-pyridyl, or 5-isoquinolyl group, and X ₁ , X ₂ and X ₃ represent a hydrogen atom; ) -Type thiazolo [3, 4-b] isoquinoline derivatives and mixtures and acid addition salts thereof, more specifically (S) -3- (pyrid-3-ylimino) -1, 5, 10, 10a -Tetrahydrothiazolo [3,4-b] isoquinoline, (R) -3- (pyrid-3-ylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b Isoquinoline, (R, S) -3- (pyrid-3-ylimino) 1, 5, 10, 10a-tetrahydrothiazolo [3, 4-b] isoquinoline, (S) -3- (Isoquinol-5-ylimino) -thiazolo [3, 4-b] isoquinoline and (R) -3- (isoquinol-5-ylimino) -1, 5, 10, 10a-tetra Hydrothiazolo [3,4-b] isoquinoline and acid addition salts thereof.

Thiazolo [3,4-b] isoquinoline derivatives of formula (I) may be used as such for therapeutic purposes or in the form of nontoxic acid addition salts such that the inherent and beneficial physiological properties of the bases are not countered by adverse effects caused by anions. Salts (hydrochlorides, sulfates, nitrates, phosphates, acetates, propionates, succinates, benzoates, fumarates, maleates, tartarates, theophylline acetates, riceicylates, phenolphthaleins, and methylene-bis-β-hydroxynaphs Toe, etc.), in the form of salts containing anions that are relatively harmless to animal organisms.

Hereinafter, the present invention will be described in detail with reference to the following examples.

Example 1

(S) -3-hydroxymethyl-N-pyrid-3-yl) -1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (13.5 g) was heated at 100 ° C. for 40 minutes After cooling, the resulting solution was concentrated under reduced pressure (25mmHg) to a capacity of 1/5, alkalinized by adding 10N sodium hydroxide solution (200cc), extracted with methylene chloride (3 × 150cc), and the organic extracts were combined with magnesium sulfate. After drying over filtration, the filtrate was concentrated to dryness under reduced pressure (25mmHg) to give a yellow oily substance. Diisopropyl ether (150cc) was added to the oily substance, and the precipitated white precipitate was collected by filtration. Washed with (3 × 10 cc) and dried under reduced pressure (1 mmHg) at 60 ° C. (S) -3- (pyrid-3-ylimino) -1,5,10,10a-tetrahydro thiazolo [3 , 4-b] isoquinoline (9.8 g) was obtained. Melting point 111 ℃

= -258±3°(C=2, 에탄올)

= -258 ± 3 ° (C = 2, ethanol)

The preparation of (S) -3-hydroxymethyl-N- (pyrid-3-yl) -1,2,3,4-tetrahydro isoquinoline-2-carbothioimide used as starting material is as follows. .

To a solution of (S) -3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (8.15 g) dissolved in ethanol (150 cc) was added 3-isothiocyanatopyridine (6.8 g) and After 3 hours at 20 ° C., the solution was cooled to 0 ° C., and the precipitated white precipitate was separated by filtration and recrystallized from propanol (200 cc). The crystals were filtered off, washed with propanol (2 × 10 cc), and then reduced at 60 ° C. (S) -3-hydroxymethyl-N- (pyrid-3-yl) -1,2,3,4-tetrahydro isoquinoline-2-carbothioamide (12.1 g) as a result of drying under (1 mmHg) Got it. Melting point 192 ℃

= +55±1°(C =1, 디메틸포름아미드)

= + 55 ± 1 ° (C = 1, dimethylformamide)

(S) -3-hydroxymethyl-1,2,3,4-tetrahydro isoquinoline is obtained from Chem. Pharm. It may be prepared according to the methods of S. Yamada and T. Kunieda published in Bull., 15, 490 (1967).

3-isothiocyanatopyridine is described in Chem. It may be prepared according to the method of J. C. Jochims published in Ber, 101, 1, 746 (1968).

Example 2

(R) -3-hydroxymethyl-N- (pyrid-3-yl) -1,2,3,4-tetrahydroisoiso dissolved in 6N hydrochloric acid (150 cc) as a starting material according to the method of Example 1 Results from using quinoline-2-carbothioamide (12 g) (R) -3- (pyrid-3-ylimino) -1,5,10,10a-tetrahydrothiazolo [3,4-b] iso Quinoline (6.8 g) was obtained.

Melting point 112 ℃

=+260±3°(C =2, 에탄올)

= +260 ± 3 ° (C = 2, ethanol)

=-55±1°(C=2, 디메틸포름아미드)]는 실시예 1에 기술된 조건으로 처리하여 (R)-3-하이드록시메틸-1, 2, 3, 4-테트라하이드로 이소퀴놀린으로부터 제조할 수 있다.(R) -3-hydroxymethyl-N- (pyrid-3-yl) -1,2,3,4-tetrahydro isoquinoline-2-carbothioamide (melting point 196 ° C) used as starting material

= -55 ± 1 ° (C = 2, dimethylformamide)] was treated from (R) -3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline by treatment under the conditions described in Example 1. It can manufacture.

=+94±1°(C =2, 에탄올)]은 Chem. Pharm. Bull. 15, 490(1967)에서 L-페닐아라닌에 대해 발표된 S. Yamada 및 T. Kunieda의 방법에 따라 L-페닐아라닌으로부터 제조할 수 있다.(R) -3-hydroxymethyl-1,2,3,4-tetrahydro isoquinoline [melting point 116 ° C

= + 94 ± 1 ° (C = 2, ethanol)]. Pharm. Bull. 15, 490 (1967) can be prepared from L-phenylalanine according to the methods of S. Yamada and T. Kunieda published for L-phenylalanine.

Example 3

(R, S) -3-hydroxymethyl-N- (pyrid-3-yl) -1, 2, 3, 4- dissolved in 6N hydrochloric acid (1.4 L) as a starting material according to the method of Example 1 As a result of using tetrahydro isoquinoline-2-carbothioamide (115 g) (R, S) -3- (pyrid-3-ylimino) -1, 5, 10, 10a-tetrahydro thiazolo [3, 4-b] isoquinoline (76 g) was obtained. Melting point 110 ℃

(R, S) -3-hydroxymethyl-N- (pyrid-3-yl) -1, 2, 3, 4-tetrahydro isoquinoline-2-carbothioamide (immediate melting point) used as starting material; 180 ° C.) is Example 1 for the preparation of (S) -3-hydroxymethyl-N- (pyrid-3-yl) -1,2,3,4-tetrahydro isoquinoline-2-carbothioamide It can be prepared from (R, S) -3-hydroxymethyl-1, 2, 3, 4-detrahydro isoquinoline by treatment under the conditions described in.

(R, S) -3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline is Med. Pharm. Chem. 4, 79 (1961), can be prepared from DL-phenylalanine according to the method of E. Schipper et al.

Example 4

(R, S) -6-fluoro-3-hydroxymethyl-N- (pyrid-3-yl) -1, 2, 3, 4-tetrahydro isoquinoline-2-carbothioamide (19 g) and After 6N hydrochloric acid (240cc) was heated at 65 ° C for 1 hour, the reaction mixture was cooled to 0 ° C and alkalinized by the addition of 10N sodium hydroxide solution. The mixture was extracted three times with methylene chloride (450cc in total), and the organic layer was sodium sulfate. After drying over, filtered and concentrated to dryness under reduced pressure (25mmHg) at 40 ° C, the residue was recrystallized from acetonitrile (R, S) -8-fluoro-3- (pyrid-3-ylimino)- 1, 5, 10, 10a-tetrahydro thiazolo [3, 4-b] isoquinoline (14 g) was obtained. Melting point 139 ℃

(R, S) -6-fluoro-3-hydroxymethyl-N- (pyrid-3-yl) -1, 2, 3, 4-tetrahydro isoquinoline-2-carbothio used as starting material The manufacturing method of an amide is as follows.

3-isothiocyanatopyridine (20 g) in a solution of (R, S) -6-fluoro-3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline (20 g) dissolved in ethanol (250 cc) 15 g) was added at about 15 ° C. over 5 minutes, the temperature gradually increased and white precipitate was formed. The mixture was stirred at 20 ° C. for 20 hours, and the precipitate was filtered off and washed with diethyl ether (40 cc). Drying results in (R, S) -6-fluoro-3-hydroxymethyl-N- (pyrid-3-yl) -1, 2, 3, 4-tetrahydro isoquinoline-2-carbothioamide (34 g ) Is obtained in the form of white crystals. Melting point 190 ℃

The preparation method of (R, S) -3-fluoro-3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline is as follows.

Sodium borohydride (46 g) dissolved in water (280 cc) and ethanol (280 cc) was dissolved in water (280 cc) and ethanol (280 cc) (R, S) -3-ethoxycarbonyl-6-fluoro- 1, 2, 3, 4-tetrahydro isoquinoline hydrochloride (79 g) was added, the reaction mixture was stirred at about 20 ° C. for 20 hours, the mixture was concentrated to dryness at 40 ° C. under reduced pressure (25 mmHg), and the residue was water (500 cc). ), Extracted three times with methylene chloride (500 cc total), and then a small amount of insoluble material was filtered off, and the organic layer was dried over sodium sulfate, filtered and concentrated to dryness at 40 ° C. under reduced pressure (25 mmHg), and then the residue was purified from acetonitrile. Recrystallization gives (R, S) -6-fluoro-3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline (27 g) in the form of white crystals. Melting point 121 ℃

Hydrochlorides of (R, S) -3-ethoxycarbonyl-6-fluoro-1, 2, 3, 4-tetrahydro isoquinoline are prepared according to the method disclosed in Japanese Patent Publication No. 73/07, 115 can do.

Example 5

(R, S) -6, 7-methylenedioxy-3-hydroxymethyl-N- (pyrid-3-yl) -1, 2, 3, 4-tetrahydro isoquinoline-2-carbothioamide ( 33.6 g) and 6N hydrochloric acid (336 cc) were heated at 100 ° C. for 90 minutes, the reaction mixture was cooled to 0 ° C., alkalized with calcium carbonate, and extracted with methylene chloride (5 × 500 cc). The yellow insoluble matter was separated by filtration, and the combined organic extracts were dried over anhydrous calcium carbonate, concentrated to dryness at 40 ° C. under reduced pressure (25 mmHg), and the obtained crystals (melting point 191 ° C.) were acetonitrile and dimethylformamide (7: 1). Recrystallization twice from a mixture of (R, S) -7, 8-methylenedioxy-3- (pyrid-3-ylimino) -1,5, 10, 10a-tetrahydro thiazolo [3, 4-b] Isoquinoline (4.5 g) is obtained in the form of light yellow crystals. Melting point 201 ℃

(R, S) -6, 7-methylenedioxy-3-hydroxymethyl-N- (pyrid-3-yl) -1, 2, 3, 4-tetrahydro isoquinoline-2- used as starting material The manufacturing method of carbothioamide is as follows.

3-isothiocyanatopyridine (15 g) dissolved in ethanol (400 cc) (R, S) -6, 7-methylenedioxy-3-hydroxymethyl-N- (pyrid-3-yl) -l To a solution of 2, 3, 4-detrahydro isoquinoline (20.7 g) was added at 27 ° C. over several minutes. At this time, the temperature rises to 37 ° C and white precipitates are formed rapidly. The reaction mixture was stirred at a temperature of about 20 ° C. for 20 hours, and then the precipitate was separated by filtration. ) -1, 2, 3, 4-tetrahydro isoquinoline (34 g) is isolated in the form of pale yellow crystals. Melting point 212 ℃

The preparation method of (R, S) -6, 7-methylenedioxy-3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline is as follows.

(R, S) -6, 7-methylenedioxy-3-ethoxycarbonyl-1, 2, 3, 4-tetrahydro isoquinoline hydrochloride (115 g) dissolved in water (550 cc) and ethanol (550 cc) It was added to sodium borohydride (71.5 g) dissolved in ethanol (550 cc) and water (550 cc) while maintaining the temperature at 10-20 DEG C. The mixture was stirred at 20 DEG C for 30 minutes and then heated under reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure (25 mmHg), and the residue was dissolved in water (1,000 cc) and methylene chloride (500 cc). The insoluble substance was filtered off, dried, the filtrate was raced, and the aqueous layer was methylene chloride. The combined organic extract was extracted three times (total 600 cc) and dried over kalium carbonate, and then concentrated to dryness under reduced pressure (25 mmHg) to obtain a product (melting point of 144 ° C). Then, the solid and the insoluble material separated by filtration were recrystallized from ethyl acetate to give (R, S) -6, 7-methylenedioxy-3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline ( 49.9 g) is isolated in the form of white crystals. Melting point 144 ℃

The hydrochloride salt of (R, S) -6,7-methylenedioxy-3-ethoxycarbonyl-1, 2, 3, 4-tetrahydro isoquinoline is described in Chem. Pharm. Bun. 21, 2, 043 (1973), can be prepared according to the method of H. Kato et al.

Example 6

(S) -3-hydroxymethyl-N- (isoquinolin-5-yl) -1, 2, 3, 4-tetrahydro isoquinoline-2-carbothioamide (1.3 g) dissolved in 6N hydrochloric acid (20 cc) ) Was cooled by heating at 100 DEG C for 1 hour, and then concentrated under a reduced pressure (40 mmHg) to a volume of 1/3, alkalinized by adding 10 N aqueous sodium hydroxide solution (5 cc), followed by methylene chloride (3 x 25cc), and the organic extracts were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure (25mmHg) at 40 ° C. (S) -3- (isoquinol-5-ylimino) -1, 5, 10, 10a-tetrahydro thiazolo [3,4-b] isoquinoline (0.8 g) is obtained in the form of weak beige crystals. Melting point 164 ℃

=-197±2.5 (C =2, 클로로포름)

= -197 ± 2.5 (C = 2, Chloroform)

The preparation of (S) -3-hydroxymethyl-N- (isoquinol-5-yl-)-1, 2, 3, 4-tetrahydro isoquinoline-2-carbothioamide used as starting material is as follows. same.

5-isothiocyanato isoquinoline (0.93 g) was added to a solution of (S) -3-hydroxymethyl-1, 2, 3, 4-tetrahydro isoquinoline (0.82 g) dissolved in ethanol (10 cc). After the mixture was left at about 20 ° C. for 15 hours, the formed crystals were separated by filtration, washed with ethanol, and dried under reduced pressure (0.1 mmHg) at 60 ° C. (S) -3-hydroxymethyl-N- (isoquinol-5). -Yl) -1, 2, 3, 4-xp trihydro isoquinoline-2-carbothioamide (1.3 g) is obtained. Melting point 190 ℃

The preparation method of 5-isothiocyanatoquinoline is as follows.

A solution of 5-amino isoquinol (14.4 g) dissolved in pyridine (40 cc) was added dropwise to a solution of triethylamine (10.1 g) and carbon disulfide (40 cc) in pyridine (20 cc) while maintaining the temperature at about -10 ° C. After 1 hour at this temperature, a solution of N, N'-dicyclohexylcarbodiimide (20.6 g) dissolved in pyridine (20 cc) was added dropwise, followed by 3 hours at -10 ° C to 20 ° C for about 20 ° C. After 20 hours of continuous stirring at N, N'-dicyclohexylthiourea was formed by filtration and washed with methylene chloride (50cc) and the filtrate was evaporated to dryness at 40 ℃ under reduced pressure (20mmHg), and then the solid residue was methylene chloride Dissolved in (100 cc), the new insoluble material was filtered off, washed with methylene chloride (30 cc), the filtrate was evaporated to dryness under reduced pressure (20 mmHg) at 40 ° C., dissolved in acetonitrile (100 cc) and boiled, and then cooled. Formed crystals were separated by filtration Suspend in isopropyl ether (180cc), stir at about 20 ° C for 30 minutes, remove insoluble material and evaporate the filtrate at 50 ° C under reduced pressure (20mmHg) to recrystallize the residue from acetonitrile (40cc) to give 5-isothio Cyanatoquinoline (5.9 g) is obtained as a beige crystalline solid (melting point 99 ° C.), and sublimation at 70 ° C. under reduced pressure (1 mmHg) affords the desired compound at melting point 102 ° C.

By properly selecting the starting material in the above-described embodiments, a compound of formula (I) can be obtained.

(S) -9-nitro-3- (pyrid-3-ylimino) -1, 5, 10, 10a-tetrahydro thiazolo- [3, 4-b] isoquinoline melting point 44 ° C

(R) -3- (isoquinol-5-ylimino) -1, 5, 10, 10a-tetrahydro thiazolo- [3, 4-b] isoquinoline melting point 164 ° C

(S) -7- (chloro-3- (pyrid-3-ylimino) -1,5,10,10a-tetrahydro thiazolo- [3,4-b] isoquinoline melting point 125 ° C

(S) -7-fluoro-3- (pyrid-3-ylimino) -1, 5, 10, 10a-tetrahydrothiazolo- [3, 4-b] isoquinoline melting point 99 ° C.

Claims (1)

Preparation of thiazolo [3,4-b] isoquinoline derivatives of formula (I) and acid addition salts thereof, characterized by cyclization of 1, 2, 3, 4-tetrahydro isoquinoline derivatives of formula (II) Way.

Wherein A or A ₁ represents a 3-pyridyl or 5-isoquinolyl group; When A or A ₁ represents a 3-pyridyl group, X ₁ or X ₄ represents a hydrogen or halogen atom, X ₂ or X ₅ represents a hydrogen or fluorine atom, and X ₃ or X ₆ represents a hydrogen atom Or a nitro group, at least two of X ₁ and X ₂ and X ₃ , or X ₄ and X ₅ and X ₆ represent a hydrogen atom, or X ₁ and X ₂ , X ₄ or X ₅ together A methylenedioxy group is represented, X ₃ or X ₆ represents a hydrogen atom; When A or A ₁ represents a 5-isoquinolyl group, X ₁ , X ₂ and X ₃ or X ₄ , X ₅ and X ₆ each represent a hydrogen atom.