KR790001982B1 - Process for preparing 1,2,3,4-tetra hydro benzo isoquinolins - Google Patents

Abstract

1,2,3,4-Tertrahydrobenz(g) isoquinoline derivs. (I; R1 = H, halogen, C1-4 alkoxy or alkyl, R2 = H, C1-4 alkyl, C3-6 alkenyl or alkynyl, C2-5 hydroxyalkyl, C3-5 alkanoylalkyl, C7-10 phenylalkyl, R3 = H, C1-4 alkyl, C7-10 phenylalkyl, R4 = H), useful as central nervous system depressants, were prepd. by treating Ia, Ib, Ic. Ia was prepd. by alkylating Ib, Ic was prepd. by reducing compd. II pd. II.

Description

Method for producing 1,2,3,4-tetrahydrobenzo isoquinoline

The present invention relates to a method for preparing the compound of formula (I).

In the above structural formula

R ₁ is hydrogen, halogen of atomic number 9 to 35, alkoxy or alkyl group of 1 to 4 carbon atoms,

R ₂ is hydrogen, alkyl of 1 to 4 carbon atoms,

Alkenyl or alkynyl having 3 to 6 carbon atoms,

(Where the multiple bonds are at positions other than α, β), 2 to 5 'hydroxyalkyl'

Wherein the hydroxy group is separated from the tricyclic nitrogen atom by at least 2 carbon atoms, alkanoylalkyl having 3 to 5 carbon atoms, or phenylalkyl having 7 to 10 carbon atoms,

Wherein the phenyl ring is unsubstituted or mono-substituted by halogen having 1 to 35 carbon atoms or by alkyl or alkoxy groups having 1 to 4 carbon atoms,

R ₃ is hydrogen, alkyl having 1 to 4 carbons, or phenylalkyl having 7 to 10 carbon atoms, wherein the phenyl ring is unsubstituted or monosubstituted by halogen having 1 to 35 carbon atoms or by alkoxy, or alkoxy. ego

R ₄ is hydrogen

R ₃ and R ₄ together with the nitrogen atom form a 1-pyrrolyl ring.

Unless R ₂ is alkyl, alkyl and alkoxy moieties are preferably 1 to 2 carbon atoms, particularly preferably one.

R ₁ is preferably hydrogen and is located at position 7 or 8.

R ₂ is preferably 1 to 3 carbon atoms when hydrogen or alkyl is preferred and alkyl, especially methyl or isopropyl.

When R ₂ is alkenyl or alkynyl, it is preferably 3 or 4 carbon atoms, and when R ₂ is hydroxyalkyl, 2 or 3 carbon atoms are preferable. When R ₂ is alkanoylalkyl, it contains an acetyl group and means acetonyl.

Benzyl is preferred when R ₂ is phenylalkyl, and preferably substituted with halogen, in particular chlorine, when the phenyl ring is substituted.

R ₃ is preferably hydrogen or methyl, and a preferred _trivalent alternative is when R ₃ and R ₄ and the nitrogen atom bonded thereto form a 1-pyrrolyl ring.

When R ₃ is phenylalkyl, optionally substituted benzyl or phenylethyl group is preferred.

According to the present invention, a method for preparing the compound of formula (I) is as follows.

a) alkylating a compound of formula (Ib) to produce a compound of formula (Ia)

b) reducing the compound of formula (II) to prepare a compound of formula (Ic)

을 분리시켜 상기에서 언급한 구조식(Ib)의 화합물을 만든다.c) in the compound of formula

To form a compound of formula (Ib) mentioned above.

In the above structural formula

R ₁ , R ₃ , R ₄ are as mentioned above,

은 상기에서 언급한 R₂와 같으나 수소인 경우는 제외되며,

Is the same as R ₂ mentioned above except for hydrogen.

는 탄소수 1내지 4개의 1급알킬 그룹이거나, 상기에서 언급한 R₂와 같이 단일 치환되거나 또는 치환되지 않은 1급 페닐알킬이며,

Is a primary alkyl group having 1 to 4 carbon atoms, or a monosubstituted or unsubstituted primary phenylalkyl such as R ₂ mentioned above,

R ₅ is (i) alkanoyl having 2 to 4 carbon atoms

(ii) benzoyl or phenylalkanoyl having from 8 to 10 carbon atoms, wherein the phenyl ring is unsubstituted or monosubstituted by halogen or alkyl or alkoxy having 1 to 4 carbon atoms.

(iii) lower alkoxycarbonyl, aryloxycarbonyl,

은 가용매 분해에 의해서 분리될 수 있는 그룹이다.

Is a group that can be separated by solvolysis.

기의 도입은 테트라하이드로 벤조 [g] 이소인돌린 잔기의 2위치에 모노알킬화를 말하며, 유사한 환상화합물을 다른 기에 유의하며 알킬화시키는 기지의 방법으로 알킬화시킬 수 있다. 예를들면 구조식 (Ib)의 화합물을 하기 구조식(Ⅳ)의 화합물과 반응시킨다.According to preparation method a)

The introduction of groups refers to monoalkylation at the 2-position of the tetrahydro benzo [g] isoindolin residues, and similar cyclic compounds can be alkylated in a known manner to note and alkylate other groups. For example, a compound of formula (Ib) is reacted with a compound of formula (IV).

In the above structural formula

은 이미 언급한 바와 같고,

Is already mentioned,

X represents chlorine, bromine or iodine.

Inert organic solvents are used. Preferred examples include a moderate basic condensing agent and an excess of compound (Ib). As the condensing agent, organic bases such as triethyl amine, pyridine, and even higher organic bases and alkali metal carbonates are used. However, when R ₃ is hydrogen and avoids simultaneous alkylation of 5-amino groups, approximately equal amounts of weakly basic condensing agent and / or alkylating agent and compound (Ib) are used. As mentioned above, when R ₂ is alkanoyl alkyl and the carbonyl group is separated by at least two carbon atoms from the nitrogen atom of the tricyclic moiety, the compounds of formula (Ia) are α, β-unsaturated as alkylating agents. It is prepared using ketones.

The reduction reaction in preparation method b) is carried out using a complex metal hydride in an inert organic solvent. Suitable hydrides include complex aluminum hydrides such as lithium and aluminum hydride.

로서는 아실기, 바람직하기로는 알콕시카보닐 또는 아릴옥시카보닐기, 또는 알카노일 또는 아로일기 등이 있고 예로는 R₅와 관련 언급된 것들이 있다. 사용되는

기의 종류에 따라서 반응은 산매체 예를들면 강한 무기산의 존재하에서 또는 염기성매체 예를들면 적당한 무기염기의 존재하에서 행해진다.Production process c) is carried out by separating an amino protecting group from a heterocyclic amine by solvolysis, in particular hydrolysis, such as, for example, urethane or amide separation. Suitable protector

Examples thereof include acyl groups, preferably alkoxycarbonyl or aryloxycarbonyl groups, or alkanoyl or aroyl groups, and examples thereof include those mentioned for R ₅ . Used

Depending on the type of group, the reaction is carried out in the presence of an acid medium such as a strong inorganic acid or in the presence of a basic medium such as a suitable inorganic base.

The preparation of starting material is as follows.

a ') The compound of formula (II) is obtained by substituting the amino group of the compound of formula (IIa) when R ₃ is not hydrogen.

In the above structural formula

R ₁ , R ₅ have already been mentioned.

For example, suitable alkyl or phenylalkyl halides can be used in the presence of potassium tert-butoxide and optionally dimethylsulfate / pyridine when R ₃ is methyl.

The compound of formula (II), which forms a 1-pyrrolyl ring together with the nitrogen atom to which R ₃ and R ₄ are bonded, reacts the compound of formula (IIa) with 2,5-dimethoxytetrahydrofuran and separates methanol from the product. Get it done.

b ') Compounds of formula (IIa) can be prepared from the 3-benzyl-4-piperidone derivatives of the corresponding formula (V) by

(i) a conventional method of cyanohydrin production, preferably reacting with acetone cyanohydrin to introduce hydrogen cyanide;

(ii) separating water from the resulting 3-benzyl-4-hydroxy-4-piperidine nitrile using thionyl chloride / pyridine

(iii) the resulting 5-benzyl-4-cyano-1,2,3,6-tetrahydropyridine derivative of formula VI, the corresponding 3-benzyl- as a byproduct in the presence of 90% sulfuric acid- Ring closure with 4-cyano-1,2,3,6-tetrahydropyridine derivative.

In the above structural formula

R ₁ and R ₅ are as mentioned.

Those not specifically mentioned for the preparation of starting materials may be known compounds or prepared and purified analogously to the processes mentioned in the known preparations or examples.

The free base form of the compound of formula (I) may be prepared in the form of acid addition salts in the usual manner and vice versa. Suitable acids for salt formation include hydrochloric acid or fumaric acid.

In the examples below, the temperature is in degrees Celsius and does not change.

The following abbreviations from the table

Z = decomposition

HCl = hydrochloride

HBr = hydrobromide.

R _f is an R _f value obtained on silica gel used by mixing benzene / ethanol concentrated ammonia as 84: 15: 1 as an eluent.

Example 1

5-amino-2-isopropyl-1,2,3,4-tetrahydrotrobenzo [g] isoquinoline (method a)

A solution of 5.2 g isopropyl bromide in 10 ml ethanol was mixed with 8.0 g of 5-amino-1,2,3,4-tetrahydrobenzo [g] isoquinotin (see Example 4) and 4.5 g in 30 ml of ethanol at room temperature. Is added dropwise to a mixed solution containing anhydrous sodium carbonate. The mixture is boiled for 6 hours, the solvent is evaporated off and the residue is treated with water. The reaction mixture is extracted with methylene chloride and the organic layer is washed with water and evaporated to dryness with potassium carbonate. Recrystallization of the resulting residue with hexane / isopropanol affords the title compound (melting point: 112 to 113 °).

Example 2

2-allyl-5-amino-1,2,3,4-tetrahydrobenzo [g] isoquinoline (method a)

A mixture of 50 ml of anhydrous chloroform containing 7.9 g of 5-amino-1,2,3,4-tetrahydrobenzo [g] isoquinoline, 5.3 g of allyl bromide and 2.6 g of triethylamine was stirred for 4.5 hours. After boiling and cooling to room temperature, 100 ml of water are added. 40% caustic soda solution is added to make it alkaline and the organic layer is separated.

The separated organic layer was washed with water until neutral, dehydrated with sodium sulfate and concentrated by evaporation. Recrystallisation of the residue twice with methanol gives the melting point 74 ° to 76 ° title compound.

In a similar manner as in Examples 1 or 2, the following compounds of formula (Ia) can be obtained by alkylating the corresponding compounds of formula (Ib) as appropriate compounds of formula (IV).

Example 3

5-amino-2-methyl-1,2,3,4-tetrahydrobenzo [g] isoquinoline (method b)

A solution of 50.0 g of 5-amino-1,2,3,4-tetrahydrobenzo [g) isoquinolin-2-yl carboxylic acid ethyl ester (see Example 4a-c) was dissolved in 1.2 L of anhydrous tetrahydrofuran. Stir at 15 ° to 30 ° and add dropwise to a suspension containing 23.0 g of lithium aluminum hydride in 500 ml of anhydrous tetrahydrofuran. The mixture is stirred for 5 hours at boiling point, cooled to 0 ° and then decomposed by dropwise addition of 90 ml of saturated sodium sulfate solution at 0 ° to 5 °. The precipitated inorganics are filtered off, washed with tetrahydrofuran and concentrated by evaporation. The residue is crystallized by adding ethanol and recrystallized with ethanol to give the title compound having a melting point of 97 ° to 99 °.

In a similar manner as in Example 3, the corresponding compound of formula II is reduced to give a compound of formula Ic below.

Example 4

5-amino-1,2,3,4-tetrahydrobenzo [g] isoquinoline (Manufacturing C)

At room temperature, 80 ml of 48% hydrobromic acid was added dropwise to a solution of 9.6 g of 5-amino-1,2,3,4-tetrahydrobenzo [g] isoquinolin-2-yl-carboxylic acid ethyl ester in 80 ml of glacial acetic acid. Boil for 3.5 hours. After cooling, pour into ice and add 40% caustic soda solution to adjust pH to 12-13 and extract with methylene chloride. The organic solution was washed with neutrality, dehydrated with sodium sulfate, concentrated by evaporation and the solid residue was recrystallized twice with benzene. The title compound thus obtained has a melting point of 150 ° to 152 °.

The preparation method of starting material is as follows.

a) 15.6 g of acetone cyanohydrin is added to 47.5 g of 3-benzyl-4-oxopiperidin-1-yl carboxylic acid ethyl ester and a small amount of potassium carbonate moistened with methanol is added for 5 to 8 hours at room temperature. Stir. After 5 to 10 hours at room temperature, 20 ml of ether and 20 ml of petroleum ether are added to the paste mixture, the solid product is suction filtered, washed again and dried at 50 °. The melting point of the resulting 3-benzyl-4-cyano-4-hydroxy piperidin-1-yl carboxylic acid ethyl ester is 120 ° to 121 °. (Ether / petroleum ether)

b) 6.5 ml of thionyl chloride was added dropwise at 5 ° to a mixed solution in which 16.0 g of the product obtained in step a) was dissolved in 20 ml of anhydrous pyridine and 14 ml of anhydrous benzene. The reaction mixture is left for 5 hours at 0 ° to 5 ° and 12 hours at room temperature. Subsequently, poured into 100 ml of ice water, the organic layer was separated, washed with water, dehydrated with magnesium sulfate and concentrated by evaporation to give an oily 5-benzyl-4-cyano-1,2,3,4-tetrahydropyridin-1-yl- Carboxylic acid ethyl ester (CN band appears in IR: 2230cm <^1> ) is obtained in a rough state.

c) 70 ml of 90% sulfuric acid is added to 9.8 g of the material produced in the process b) with vigorous stirring so that the temperature does not exceed 5 °. Allow to stand at 5 ° for 1 hour, occasionally shaking for 3 to 4 hours at room temperature. It is poured onto 500 g of ice, extracted with methylene chloride, and the aqueous solution is adjusted to pH 9-10 with 40% caustic soda solution and extracted again with methylene chloride. The combined extracts are washed with water, dehydrated with magnesium sulfate and concentrated by evaporation under nitrogen atmosphere. The resulting 5-amino-1,2,3,4-tetrahydrobenzo [g] isoquinolin-2-yl-carboxylic acid ethyl ester as a residue is recrystallized from ethyl acetate (melting point: 198 ° (decomposition)). )

Example 5

5- (1-pyrrolyl) -1,2,3,4-tetrahydrobenzo [g] isoquinoline (Manufacturing C)

20 ml of n-butanol was dissolved 2.0 g of 5- (1-pyrrolyl) -1,2,3,4-tetrahydrobenzo [g] isoquinolin-2-yl-carboxylic acid ethyl ester and 4.0 g of potassium hydroxide. The mixture is boiled for 2 hours. After cooling to room temperature, diluted with benzene, washed with water to neutrality and extracted three times with 10% aqueous tartaric acid solution. The acid solution is washed with ether, 40% caustic soda solution is made alkaline and extracted with benzene. The benzene extract was washed with water, dehydrated with magnesium sulfate, and the benzene solvent was evaporated to give a hydrochloride having a melting point of 240 ° (decomposition).

Starting materials are prepared as follows.

a) 150 ml of ethyl acetate, 30 g of 5-amino-1,2,3,4-tetrahydrobenzo [g] isoquinolin-2-yl-carboxylic acid ethyl ester and 14.7 g of 2,5-dimethoxytetrahydrofuran The mixture is boiled for 30 minutes, cooled to room temperature, and then 11.1 g of potassium hydroxide solution contained in 75 ml of methanol and 75 ml of water is added dropwise and boiled again for 5 hours with stirring. After cooling to 20 °, it is poured on ice and adjusted to pH 2 to 3 by adding concentrated hydrochloric acid and extracted with ether. The ether extract is washed with water and saturated function, dehydrated with sodium sulfate and evaporated. The residue 5- (1-pyrrolyl) -1,2,3,4-tetrahydrobenzo [g] isoquinolin-2-yl-carboxylic acid ethyl ester is crystallized twice with ether / petroleum ether. Melting Point: 109 ° to 111 °

기를 분리시켜 얻는다.In a manner analogous to Example 4 or 5, the compound of formula (Ib)

Obtained by separating groups.

The starting material of Example 5B was prepared as follows.

a) 3 ml of pyridine is added to a mixture containing 27.0 g of 5-amino-1,2,3,4-tetrahydrobenzo [g] isoquinolin-2-yl-carboxylic acid ethyl ester in 50 ml water. 50.4 g of dimethyl sulfate is added dropwise within 10 minutes and stirred for 8 hours at 55 ° to 60 °. The resulting clear solution is diluted with 100 ml of water and extracted several times with chloroform. The extract was washed with water to be neutral, dehydrated with sodium sulfate and concentrated by evaporation. The oily residue is dissolved in ether, acidified with etheric hydrochloric acid solution and the precipitate is filtered off and recrystallized from ethanol / ether. The melting point of the 5-methylamino-1,2,3,4-tetrahydrobenzo [g] isoquinolin-2-yl carboxylic acid ethyl ester hydrochloride thus obtained is 214 ° to 215 °. Structural formula (I) compounds exhibit pharmacological activity. In particular, these compounds were found to be H.C.Y. Airborne activity by inhibition of isolated-induced aggression in mice is shown according to the method of En et al. [J. Pharmacol. exp. Ther. 122, 85A (1958)].

Interesting compounds are those in which R ₁ , R ₂ and R ₄ are all hydrogen and also form a 1-pyrroline ring with the nitrogen atom to which R ₃ and R ₄ are bonded and R ₂ is not hydrogen. The compound of Example 4 shows a particularly interesting activity.

Therefore, these compounds are used as aerosols and additionally exhibit central nervous system inhibitory activity (climbing test on mice).

Compounds in which R ₂ is optionally substituted phenylalkyl are interesting compounds and Example 3B compounds exhibit notable activity.

Therefore, the compound is also used as a central nerve inhibitor.

The daily dose depends on the compound used and the degree of activity and the intended use. For the above-mentioned uses, 20 to 200 mg per day are divided into two to four doses of 50 to 100 mg each for convenience.

The compound of formula (I) is administered in the form of pharmaceutically harmless acid addition salts. This form exhibits the same degree of activity as the free base form and is prepared by conventional methods.

The present invention also provides a pharmaceutical composition which makes the compound of formula (I) together with a carrier or diluent in the form of an organic base or in the form of an acid addition salt. It is made into a liquid or tablet.

And which compound the R ₃ is hydrogen, alkyl, substituted pyenil alkyl or unsubstituted phenylalkyl, and R ₂ is hydrogen, and which compound the R ₂ is hydrogen, alkyl, substituted or unsubstituted phenylalkyl, and R ₃ R ₄ is both hydrogen.

Claims (1)

From the compound of formula

To separate a group to prepare a compound of formula (Ib) or alkylate a compound of formula (Ib) to form a compound of formula (Ia) or to reduce a compound of formula (II) to form a compound of formula (Ic) Preparation method of the compound of formula (I)

In the above structural formula R ₁ is hydrogen, an alkoxy or alkyl group having 1 to 4 halogen carbon atoms of 9 to 35 carbon atoms, R ₂ is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms, wherein the multiple bonds are present at positions other than α, β, wherein 2 to 5 hydroxylalkyl, The hydroxy group is separated from the tricyclic nitrogen atom by at least 2 carbon atoms), alkanoylalkyl of 3 to 5 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms, wherein the phenyl ring is unsubstituted or halogen of atomic number 9 to 35 Mono-substituted by 1 to 4 alkyl or alkoxy groups), R ₃ is hydrogen, carbohydrate 1 to 4 alkyl or 7 to 10 phenylalkyl, wherein the phenyl ring is unsubstituted or monosubstituted by halogen of from 9 to 35 atoms or by 1 to 4 alkyl or alkoxy R ₄ is hydrogen R ₃ and R ₄ together with the nitrogen atom form a 1-pyrrolyl ring,

Is the same as R ₂ mentioned above except for hydrogen,

Is a primary alkyl group having 1 to 4 carbon atoms or a monosubstituted or unsubstituted primary phenylalkyl such as R ₂ mentioned above. R ₅ is (i) alkanoyl having 2 to 4 carbon atoms, (ii) benzoyl or phenylalkanoyl having 8 to 10 carbon atoms, wherein the phenyl ring is monosubstituted or unsubstituted by halogen or alkyl or alkoxy having 1 to 4 carbon atoms (iii) lower alkoxy carbonyl, aryloxycarbonyl,

Is a group that can be separated by solvolysis.