KR800000977B1 - Process for preparing new aminobenzocyclo heptene derivatives - Google Patents

Abstract

The title compds. (I; X=H; Y=H; Z=H; R=H, phenyl, C1-5 alkyl; R1=H, C1-5 alkyl, C2-5 alkenyl; R2=C1-5 alkyl, C2-5 alkenyl), useful as antidepressants, were prepd. by reduction of compd. II in the presence of Pd catalyst, obtained by dehydration of III. Thus, 8 g 7-ethylamino-5-hydroxy-6, 7, 8, 9-tetrahydro[5H benzocycloheptene and 80 cc dioxane were refluxed in the presence of 16 cc 18N-H2SO4 to give 7-ethylamino-6, 7-dihydro[5H benzocycloheptene.

Description

New aminobenzocycloheptene derivatives and preparation method thereof

The present invention relates to a method for preparing new amino benzocycloheptene derivatives and their addition salts with inorganic or organic acids, and these derivatives correspond to the general formula (I) as follows.

Where x is a hydrogen atom or a halogen atom except fluorine, the halogen atom is located at the 2 or 4 position of the phenyl nucleus, Y represents a hydrogen atom or together with Z forms a double bond of carbon carbon, Z Represents a hydrogen atom or together with Y represents a double carbon-carbon bond, R is a hydrogen atom, an alkyl or phenyl group having 1-5 carbon atoms, which may be substituted with a fluorine or chlorine atom or a methyl or methoxy group R ₁ is a hydrogen atom, an alkyl group containing 1-5 carbon atoms or an alkenyl group containing 2-5 carbon atoms, and R ₂ is an alkyl group containing 1-5 carbon atoms or 2-5 carbon atoms the alkenyl group, which, together with the nitrogen atom, R ₁ and R ₂ form a saturated heterocycle having from 4 to 6 carbon atoms, which is another hetero-may consist of atoms, and 1-5 carbon atoms A may be substituted with an alkyl group.

In formula (I), X preferably represents a chlorine or bromine atom, and an alkyl group having 1-5 carbon atoms represents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl atom groups. Alkenyl groups containing carbon atoms represent, for example, vinyl, allyl, buten-2yl or pentene 2-yl groups, and saturated heterocycles containing 4-6 carbon atoms are composed of other heteroatoms or 1-5 Substituted alkyl groups containing carbon atoms include, for example, pyrrolidino, piperidino, morpholino, piperazinyl, N-methyl-piperazinyl, N-ethyl-piperazinyl, N- Propyl-piperazinyl or N-butyl-piperazinyl group.

Examples of addition salts with inorganic or organic acids include, for example, hydrochloric acid, bromic acid, iodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxalic acid and There may be salts formed with aspartic acid, alkanesulfonic acid such as methane or ethane sulfonic acid, benzene or paratoluene sulfonic acid and arylsulfonic acid such as aryl carboxylic acid.

In more detail the addition salts with inorganic or organic acids in addition to the derivatives corresponding to formula (I) in the products obtained according to the invention, in the formula (I), X represents a hydrogen atom or a chlorine atom, and R Is a hydrogen atom or a methyl or phenyl group, R ₁ is a hydrogen atom or methyl, ethyl, propyl or allyl group, R ₂ is a methyl, ethyl, propyl or allyl group, and together with the nitrogen atom, R ₁ and R ₂ are pyrrolidino To form a piperidino, morpholino, piperazinyl or N-methyl piperazinyl group. Also among the derivatives corresponding to formula (I), R represents a hydrogen atom or a phenyl group, R ₁ represents a hydrogen atom or methyl, ethyl, allyl group, R ₂ represents a methyl, ethyl, allyl group, or together with an N atom , R ₁ and R ₂ may form a pyrrolidino or N-methyl piperazinyl group. In addition, in the derivatives corresponding to formula (I), R ₁ may represent a hydrogen atom or a methyl group and R ₂ may represent a methyl, ethyl or alkyl group. On the other hand, in the product corresponding to formula (I), R represents an alkyl group or phenyl group containing 1-5 carbon atoms, which may be substituted by fluorine or chlorine atoms, or methyl or methoxy groups, and Y and Z are Such products, representing hydrogen atoms, can of course be represented in two isomeric forms (A and B).

The present invention relates to the preparation of such new products and these products are described in more detail in the Examples.

Derivatives defined as the formula (I) and a method for preparing the salts thereof is the product of formula (II)

It is characterized by the dehydration to produce a compound of formula (I ')

The above compounds may be isolated or form salts and the product of formula (I ') is reduced to give the product of formula (II').

The product may be isolated or form salts.

Under the conditions of carrying out the present invention, the manufacturing method described above has the following features. In other words,

a) The dehydration reaction of the product of formula (II) is carried out at the boiling point of the reaction mixture, either by strong acids such as hydrochloric acid or sulfuric acid, potassium bisulfate or by heating in hexametapol.

b) Reduction of the product of formula (I ') is carried out with hydrogen gas in the presence of a catalyst such as palladium.

The present invention also aims to produce a derivative defined by the formula (I '') in a different manner from that described above, and such a modified method is obtained by the following formula (II) ,

It is characterized by being reduced by a strong reducing agent to give the product of formula (I '')

The product may be isolated or form salts.

In carrying out this modified process, the reduction of the product of formula (II) is advantageously carried out by sodium in liquid ammonia and in the presence of low molecular weight alkanols such as ethanol.

Derivatives of the formulas (I ') and (II' ') are alkaline. Addition salts of such derivatives can be advantageously prepared by reacting inorganic or organic acids with the derivatives stoichiometrically. Salts can be prepared without isolating the corresponding bases.

Compound of formula (II) is a compound of formula (III)

By reacting with an amine of formula (IV)

The product of formula (V) can be prepared.

Meanwhile, the above product reacts with an organometallic compound of formula MR (IV), wherein M represents a lithium atom or a -Mg-Hal group, Hal is a chlorine or bromine atom, and R is as described above except for hydrogen. The product of formula (II) is obtained, wherein R does not represent a hydrogen atom,

In addition, the product of formula (V) is reduced to obtain the product of formula (II ′) and then isolated.

A good method for preparing the product of formula II is as follows.

a) The reaction of the product of formula (III) with the amine of formula (IV) proceeds at room temperature in a low amount of alkanol such as ethanol.

b) is the reaction of the product of formula (V) with the organometallic compound of formula (IV) is carried out in anhydrous ether such as ethyl ether or tetrahydrofuran.

c) Reduction of the product of formula (V) is carried out by sodium borohydride in the presence of a low molecular weight alkanol such as ethanol or by lithium aluminum hydride in an organic solvent such as tetrahydrofuran.

In the product of formula (I), R ₁ and R ₂ are the same or different and represent an alkyl group containing 1-5 carbon atoms, or an alkenyl group containing 2-5 carbon atoms, and X , R, Y and Z are as described above, the product of formula (I) is also a compound of formula (I '''),

Produced by reacting with a halide of the structure Hal-R ₁ (VII), wherein Hal represents a chlorine, bromine, or iodine atom, and R ₁ is as described above.

In the product of formula (I), R ₁ represents a methyl group, R ₂ represents an alkyl group comprising 1-5 carbons, X, R, Y and Z are as described above, and '') Compound,

(Wherein R ₂ ′ is an alkyl group containing 1-5 carbon atoms, X, R, Y and Z are as described above) and react with formaldehyde and sodium cyanoborohydride to yield the product of formula (I) Obtained.

It goes without saying that the products of formula (I) containing asymmetric carbon atoms can be divided into two according to known methods.

The products obtained by the method of the present invention have very interesting pharmacological properties, which are particularly noteworthy in the test of antipressurant activity.

These properties make it suitable for use as pharmaceuticals with amino benzo cycloheptene derivatives of formula (I) and addition salts with their pharmaceutically usable acids. Such drugs include those consisting of aminobenzocycloheptane corresponding to formula (I) as well as addition salts with their pharmaceutically acceptable acids, wherein X represents a hydrogen atom or a chlorine atom, and R It is and represents a hydrogen atom or a methyl or phenyl group, R ₁ represents a hydrogen atom, or methyl, ethyl, propyl or allyl, R ₂ represents a methyl, ethyl, propyl or allyl, and together with the nitrogen atom, R ₁ R ₂ forms a pyrrolidino, piperidino, morpholino, piperazinyl or N-methyl piperazinyl group.

Among these, as a compound corresponding to Structural Formula (I), R represents a hydrogen atom or a phenyl group, R ₁ represents a hydrogen atom, or methyl, ethyl, or an allyl group, R ₂ represents a methyl, ethyl or allyl group, and nitrogen Together with the atoms, R ₁ and R ₂ include addition salts of compounds forming pyrrolidino or N-methyl piperazinyl groups with their pharmaceutically acceptable acids. Also among these pharmaceuticals are compounds of formula (I) in which R ₁ represents a hydrogen atom or a methyl group and R ₂ forms a methyl, ethyl or allyl group, as well as addition salts with their pharmaceutically acceptable acids. Included. Among these, especially the following products are included.

* 7-dimethylamino 6,7-dihydro [5H] benzocycloheptene,

* A and B isomers of 7-dimethylamino 5-phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene,

* 7-methylamino 6,7-dihydro [5H] benzocycloheptene,

Addition salts with 2-chloro 7-methylamino 6,7-dihydro [5H] benzocycloheptene and their pharmaceutically acceptable acids.

These medicines can be used, for example, to treat depression, depression, depressive psychosis, repulsive depression, depression caused by fatigue, neurodepressants, and also in the treatment of Parkinson's disease.

Typical dosages may vary depending on the product used, the subject of treatment, and the condition involved, for example, from 10 mg to 300 mg per day orally in adult men.

Addition salts with the products of formula (I) and their pharmaceutically acceptable acids are employed to prepare pharmaceutical ingredients comprising at least one of the abovementioned products or at least one of their salts as the active ingredient. Can be. Therefore, as a medicament, new derivatives of aminobenzocycloheptene of formula (I) and their addition salts with pharmaceutically acceptable acids can be combined with pharmaceutical ingredients for digestive or parenteral administration.

These pharmaceutical ingredients can be, for example, solid or liquid, and can be used, for example, in the form of pharmaceutical tablets or dragees, gelatin capsules, granules, suppositories and injections which are usually administered to the human body. These are prepared according to known methods.

These active ingredients include talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous excipients, animal or vegetable fatty substances, paraffin derivatives, glycols, various wetting agents commonly employed in pharmaceutical compositions. , Dispersion and emulsifiers or preservatives.

From the process of the invention, a new industrial product is obtained, in particular the product having the following structure (II) which is useful for the preparation of derivatives corresponding to structure (I).

X, R, R ₁ and R ₂ in the above structure is as described above, in particular 7-dimethylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-ol, 7-dimethylamino 5- Phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-ol, 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-ol, 7-methylamino 5 -Phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-ol, 1 and 3-chloro 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-ol , 7-ethylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-ol hydrochloride, 1- (5-hydroxy 6,7,8,9-tetrahydro [5H] 7-benzo Cycloheptenyl) 4-methylpiperazin and 7- (2-propenyl-amino) 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-ol, and the following structural formula: The product of V) is also obtained.

In the above structure X, R ₁ and R ₂ are as described above, in particular 7-dimethylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one, 7-methylamino 6,7,8 , 9-tetrahydro [5H] benzocycloheptene 5-one, 1 and 3-chloro 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one, 7-ethylamino 6, 7,8,9-tetrahydro [5H] benzocycloheptene 5-one hydrochloride, 1- (5-oxo 6,7,8,9-tetrahydro [5H] 7-benzocycloheptenyl) 4-methylpipe This corresponds to razin, 7- (2-propenylamino) 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-on hydrochloride.

의 구조를 가진 생성물의 할로겐화(플루오르화는 제외) 반응이 수행되어 다음과 같은 구조의 생성물이 얻어지는 특성을 가진 방법에 의해서 제조될 수 있다.The products of the formula (III), in which X does not represent a hydrogen atom, in particular when they are not known,

The halogenation (except for fluorination) reaction of the product having the structure of may be performed by a method having the property of obtaining a product having the structure:

In the above structure, X is a halogen atom excluding fluorine, and these halogen atoms are in positions 1 or 3 on the phenyl nucleus, and these products are bromide salts such as copper bromide, bromine or, for example, pyridinium and bromide in an organic solvent. And the product of the following structural formula is obtained.

X is as described above, and this product is debrominated hydrogenated in the presence of lithium bromide and lithium carbonate to give the product of the following formula (III).

An embodiment of the manufacturing method as described above is as follows.

Example 1

7-diethylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride

8 grams of 7-diethylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene and 80 cm 3 of dioxane were mixed and refluxed, followed by the addition of 16 cm 3 of 18N sulfuric acid. Continue reflux for minutes, add 80 cm 3 dioxane and reflux for another 30 minutes, cool the whole, add ammonia added to pH 10 or more, saturate with sodium chloride and extract with ethyl acetate. The extract is washed with brine and then evaporated to dryness.

The residue was chromatographed on silica and eluted with a mixture of hexanes / ethyl acetate / triethylamine in a 7: 3: 1 cycle to give 3.6 grams of the desired product in base form. It is dissolved in ethyl ether. A solution of saturated hydrochloric acid is added to the ether, and the precipitated hydrochloride is vacuum filtered. It is recrystallized from isopropanol again to give 2.8 grams of the desired product. Melting point = 172 ° C

Assay: C ₁₃ H ₁₈ ClN

Calculated Value: C% 69.78 H% 8.10 N% 6.25 Cl% 15.84

Experimental Value: 70.0 8.2 6.3 15.8

Starting product 7-dimethylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene was obtained by the following method.

Step A: 7-dimethylamino 5-oxo 6,7,8,9-tetrahydro [5H] benzocycloheptene

7 grams of 5-oxo 8,9-dihydro [5H] benzocycloheptene was dissolved in 70 cm 3 of ethanol, and 12.2 grams of a benzene solution of dimethylamine (33% by weight) was added thereto, followed by 3 at room temperature. Stir for time, filter and evaporate to dryness. 8.7 grams of the desired crude product are obtained and used in the next step.

Step B: 7-diethylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene

After dissolving 8.7 grams of the product obtained in step A in 435 cm 3 of ethanol, a solution of 8.7 g of sodium borohydride in 87 cm 3 of water was added thereto, and the whole was stirred at 20 ° C. for 1 hour 30 minutes. It was poured into iced water, saturated with sodium chloride, extracted with ethyl acetate, and the organic layer was washed with brine and evaporated to dryness. Eight grams of the desired crude product is obtained, which is used again in the next step.

Example 2

7-dimethylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride

11.2 grams of 7-dimethylamino 6,7-dihydro [5H] benzocycloheptene (obtained in the same manner as in Example 1) and 800 cm 3 of ethanol and 11.2 grams of palladium on activated carbon (10% Pd (OH ₂ ) are mixed and the whole is kept under hydrogen gas for 30 minutes. When the theoretical amount of hydrogen gas is absorbed, the mixture is filtered and the filtrate is evaporated to dryness. The residue is chromatographed on silica and eluted as a mixture of 8: 2: 1 ethyl acetate / benzene / triethylamine to yield 4.1 grams of the desired product in base form. It is dissolved in ethyl ether and hydrochloric acid solution saturated in ether is added, the whole is filtered and the product is recrystallized from a mixture of ethyl acetate / methylene chloride. Obtain 4.3 grams of the desired product. Melting point = 210 ° C

Assay: C ₁₃ H ₂₀ ClN

Calculated: C% 69.16 H% 8.93 Cl% 15.70 N% 6.20

Experimental value: 68.9 8.9 15.9 6.3

Example 3

7-dimethylamino-9-phenyl 6,7-dihydro [5H] benzocycloheptene hydrochloride.

29.1 grams of 7-dimethylamino 5-phenyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene and 290 cm 3 of dioxane were mixed and 60 cm 3 of 18N sulfuric acid was refluxed under inert gas. The mixture was stirred for 3 minutes, cooled, and ice was added thereto, followed by addition of concentrated ammonia until the pH reached 10 or more, saturated with sodium chloride, which was extracted as ethyl acetate, and the organic layer was washed with brine and evaporated. To dry. The residue is chromatographed on silica and eluted as a mixture of 10: 1 benzene / triethylamine to give 20.2 grams of the desired product in base form.

4 grams of this product is dissolved in 600 cm 3 of ethyl ether, and then a solution of saturated hydrochloric acid is added to the ether, and the hydrochloride formed is vacuum filtered. Recrystallization from isopropanol again yields 3.6 g of the desired product. Melting Point 270 ℃

Analysis: C ₁₉ H ₂₂ ClN

Calculated: C% 76.1 H% 7.39 Cl% 11.82 N% 4.66

Experimental Value: 76.2 7.4 11.6 4.8

7-Dimethylamino 5-phenyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene used as starting material of Example 3 was obtained by the following method.

A solution of 1.2 M lithium phenyl in ethyl ether was cooled to 0 + 5 ° C. under nitrogen and over 1 hour 15 minutes obtained 24.46 grams of 7-dimethylamino 5-oxo as described in Preparation Step A of Example 1 A solution of 6,7,8,9-tetrahydro [5H] benzocycloheptene dissolved in 488 cm 3 of ethyl ether is added. It was stirred for 2 hours at 0. + 5 ° C., and then 120 cm 3 of saturated aqueous solution of ammonium chloride was added thereto, and 100 cm 3 of water was slowly added at 0. + 15 ° C. The whole was decanted to wash the volatile layer with water and then dried to yield 29.4 grams of the desired crude product, which is used in the next step (they consist of a mixture of isomers at position 5).

Example 4

7-dimethylamino-5-phenyl 6,7,8,9-tetrahydro [5H] benzocyclo heptene hydrochloride

5 g of 7-dimethylamino 9-phenyl 6,7-dihydro [5H] benzocycloheptene (obtained as an intermediate in Example 3) are dissolved in 250 cm 3 of ethanol and 5 g of palladium on activated carbon (10 Pd (OH) ₂ ) is added and the whole is stirred under hydrogen gas at 20 ° C. until absorption is complete. After filtration of the whole and evaporation to dryness of the filtrate, the residue was chromatographed on silica, eluting with a 9: 1: 1 cyclohexane / ethylacetate / triethylamine mixture to give 0.52 grams of Isomer A (equation Direction 5H) and 2.9 grams of isomer B (5H in axial direction) are obtained in base form.

Preparation of Hydrochloride of Isomer A:

0.47 grams of Isomer A is dissolved in 50 cm 3 of ethyl ether and thereto is added a solution of saturated hydrochloric acid. The hydrochloride is vacuum filtered and recrystallized from the ethyl acetate / methylene chloride mixture to give 0.44 grams of the desired product. Melting point = 166 ° C

Analysis: C ₁₉ H ₂₄ ClN

Calculated: C% 75.59 H% 8.01 Cl% 11.74 N% 4.63

Experimental value: 75.4 8.1 11.6 4.5

Preparation of Hydrochloride of Isomer B:

2.8 grams of isomer B is prepared in the same manner as the starting material and gives 2.9 grams of product. Melting point = 202 ° C.

Analysis: C ₁₉ H ₂₄ ClN

Experimental Value: C% 75.8 H% 8.1 Cl% 11.9 N% 4.6

Example 5

7-dimethylamino 5-phenyl 6,7,8,9-tetrahydro [5H] benzocyclo heptene hydrochloride

600 cm 3 of ammonia was concentrated, 12.4 cm 3 of ethanol and 12 grams of 7-dimethylamino 5-phenyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene (Preparation of Example 3) A solution of isomers obtained in the above) is added to 600 cm 3 of tetrahydrofuran.

To this was added 12.4 grams of sodium at −40 ° C. and the whole was stirred at this temperature for 20 minutes. Ammonia and tetrahydrofuran are evaporated and the residue is dissolved in ethyl acetate, washed with water and evaporated to dryness. The residue was chromatographed on silica and eluted as a mixture of 9: 1: 1 cyclohexane / ethylacetate / triethylamine to give 3.2 grams of Isomer A (equation direction 5H) and 6.5 grams of Isomer B (axial direction). 5H) is obtained in base form.

Hydrochloride of isomer A is obtained in the same manner as in Example 4, with 3.2 grams of isomer A as starting material to obtain 2.9 grams of the desired product. Melting point = 166 ° C.

Analysis: C ₁₉ H ₂₄ ClN

Calculated: C% 74.25 H% 8.01 Cl% 11.74 N% 4.63

Experimental value: 74.2 8.2 11.4 4.5

Example 6

7-methylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride.

50 grams of 7-methylamino-5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene and a mixture of 500 cm 3 of dioxane were refluxed and then 50 cm 3 over 30 minutes. After 18N sulfuric acid was added, the mixture was refluxed continuously for 1 hour, the whole was cooled, and concentrated ammonia was added until the pH was 10, saturated with ammonia sulfate and extracted with ethyl acetate. The organic phase is washed with brine and evaporated to dryness. The residue is chromatographed on silica and eluted with a mixture of 95: 5: 2 methylene chloride / methanol / triethylamine to give 22.8 grams of the desired product in base form.

The product is dissolved in 50 cm 3 of ethyl acetate and then a solution of saturated hydrochloric acid is added to ethyl acetate, and the crystals formed are vacuumed and recrystallized from ethanol. 18 grams of product are obtained.

Melting point = 215 ° C.

Analysis: C ₁₂ H ₁₈ NCl

Theoretic value: C% 68.72 H% 7.69 Cl% 16.91 N% 6.68

Experimental value: 68.8 7.7 16.8 6.4

Hydrochloride of 7-methylamino 6,7-dihydro [5H] benzocycloheptene can be resolved into its optically active isomers in the following manner:

=+135.5°±2.5° (C=0.9% 메탄올)The hydrochloride is treated with 2N soda and the lecieric dibenzoyl tartaric acid is reacted on the base. It is filtered, treated with soda and again with hydrochloric acid to give the desired preferential hydrochloride. Melting point = 213 ° C,

= + 135.5 ° ± 2.5 ° (C = 0.9% Methanol)

The filtrate obtained from the above filtration is treated with preferential dibenzoyl tartaric acid and then the desired siting hydrochloride is obtained by the method described above. Melting point = 213 ° C.

=-138.5°±2.5° (C=0.9% 메탄올).

= -138.5 ° ± 2.5 ° (C = 0.9% methanol).

7-methylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene as starting material is obtained by the following method.

Step A: 7-methylamino 5-oxo 6,7,8,9-tetrahydro [5H] benzocycloheptene

40 grams of 5-oxo 8,9-dihydro [5H] benzocycloheptene was dissolved in 400 cm 3 of ethanol and a solution of 22.7 grams of monomethylamine in 160 cm 3 of benzene was added thereto for 2 hours 30 minutes. Stirring and concentrated to dryness yield 47.5 grams of the desired product. This is used in the next step.

Step B: 7-Methylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene.

47.5 grams of the crude product obtained in step A was dissolved in 2.4 liters of ethanol, and a solution of 47.5 grams of sodium borohydride dissolved in 475 cm 3 of water was slowly added thereto, stirred for 2 hours 30 minutes, and the whole was 500 cm 3. After concentration, it is poured into 2 liters of brine and extracted with ethyl acetate, and the organic layer is washed with brine and evaporated to dryness. 50 grams of crude product are obtained and used for the next step.

Example 7

7-ethylamino 6,7,8,9-tetrahydro [5H] benzocycloheptanohydrochloride.

3.4 grams of 7-methylamino 6,7-dihydro [5H] benzocycloheptene (obtained as an intermediate product in Example 6), 200 cm 3 ethanol and 3.4 grams of palladium on activated carbon (10% Pd (OH) ₂ ) are mixed, the whole is left under hydrogen gas until absorption is complete, then the whole is filtered and the solvent is removed in vacuo to yield 2.9 grams of the expected product in base form.

It was again dissolved in 300 cm 3 of ether, and thereto was added a solution of saturated hydrochloric acid, and then the crystals formed were vacuum filtered and recrystallized from an 8: 2 ethyl acetate / methanol mixture to give 2.6 grams of the expected product. Obtained. Melting point = 270 ° C.

Analysis: C ₁₂ H ₁₈ ClN

Calculated: C% 68.07 H% 8.57 Cl% 16.74 N% 6.62

Found 67.9 8.5 16.7 6.6

Example 8

7-methylamino 9-phenyl 6,7-dihydro [5H] benzocycloheptene hydrochloride

4.62 grams of 7-methylamino 5-phenyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptane was dissolved in 90 cm 3 of dioxane, and the whole was refluxed to obtain 9.2 cm 3 again. After 18N sulfuric acid was added, the whole was refluxed for 15 minutes, cooled, poured into ice water, extracted with ethyl acetate, and the organic layer was washed with brine and evaporated to dryness. The residue was chromatographed on silica and eluted with a 2: 8: 1 benzene / ethylacetate / triethylamine mixture and then eluted with a 95: 5: 1 mixture of chloroform / methanol / triethylamine. The expected product of is obtained in base form.

This was again dissolved in 500 cm 3 of ether, to which a solution of saturated hydrochloric acid in ether was added, and the crystals formed were vacuum filtered and then recrystallized from isopropanol to yield 2.3 grams of the expected product.

Melting point = 244 ° C.

Analysis: C ₁₈ H ₂₀ ClN

Calculated: C% 75.63 H% 7.05 Cl% 12.40 N% 4.90

Experimental Value: 75.4 7.2 12.2 4.7

The 7-methylamino 5-phenyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene used as the starting material of Example 8 can be obtained by the following method.

10.8 grams of 7-methylamino 5-oxo 6,7,8,9-tetrahydro [5H] benzocycloheptene (obtained in step A of Example 6) was dissolved in 200 cm 3 of toluene and then 440 cm 3 1.35 M magnesium phenylbromide solution of Hydrofuran was substituted), the whole was refluxed under an inert gas for 2 hours and 30 minutes, cooled at a maximum of 15 ° C., 200 cm 3 aqueous solution of ammonium chloride was slowly added, the whole was filtered and extracted as ethyl acetate, and then the organic layer was Wash with water and evaporate to dryness. The residue is chromatographed on silica to give a mixture of 9: 1 benzene / ethyl acetate, 2: 8: 1 mixture of benzene / ethyl acetate / triethylamine, or 95: 5: 10 chloroform / methanol / triethyl. Elution with an amine mixture or the like yields 8.7 grams of the desired product, which is obtained in the form of a mixture of two isomers at the 5 carbon position.

Example 9

7-methylamino-5phenyl 6,7,8,9-tetrahydro [5H] benzocyclo heptene hydrochloride.

2.47 grams of 7-methylamino 9-phenyl 6,7-dihydro [5H] benzocyclo heptene (obtained as an intermediate product in Example 8), 130 cm 3 ethanol and 3.67 grams palladium on activated carbon (10% Pd (OH) ₂ ) is mixed. The whole is kept under hydrogen gas until absorption is complete and the filtrate is concentrated to dryness. The residue is chromatographed on silica and eluted with a 4: 6: 1 benzene / ethylacetate / triethylamine mixture to give 1.82 grams of the desired product in base form.

It is again dissolved in 250 cm 3 of ethyl ether, and then a solution of saturated hydrochloric acid is added to the ether, and the crystals formed are filtered and recrystallized as isopropanol to give the desired product of 1.35 perram. Melting point = 265 ° C .;

Analysis: C ₁₈ H ₂₂ ClN

Calculated: C% 75.10 H% 7.70 Cl% 12.31 N% 4.86

Experimental value: 75.0 7.9 12.5 4.6

Example 10

Hydrochloride of 2 with 4-chloro 7-methylamino 6,7-dihydro [5H] benzocycloheptene

A mixture of 41.5 grams of 1 and 3-chloro 5-hydroxy 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene and 800 cm 2 of 2N hydrochloric acid was refluxed for 24 hours and then cooled Wash with ethyl acetate, make alkaline and extract with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness. The residue is chromatographed on silica and eluted with an 8: 2: 1 ethyl acetate / methanol / triethylamine mixture to give 14.1 grams of the desired product in base form, which is a mixture of 2-chloro and 4-chloro isomers. Consists of These isomers were chromatographed on silica and eluted with a 95: 5: 1 ethylacetate / methanol / triethylamine mixture to yield 8.7 grams of 4-chloro isomers and 2.5 grams of 2-chloro isomers.

Hydrochlorides of these isomers are formed in the ether by adding a solution of saturated hydrochloric acid to the ether, 1.5 grams of 2-chloro isomer hydrochloride (after recrystallization from isopropanol) (melting point = 195 ° C.) and 9.6 grams of 4-chloro isomer. Hydrochloride (melting point = 225 ° C) is obtained.

Assay: (2-Cl isomer) C ₁₂ H ₁₄ ClN

Calculated: C% 59.03 H% 6.19 Cl% 29.04 N% 5.74

Experimental value: 59.1 6.4 29.2 5.7

An initial mixture of 1 and 3-chloro-5-hydroxy 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene is obtained by the following method:

Step A: Mixture of 1 and 3-chloro benzosuberon

400 grams of benzosuberon was dissolved in 1600 cm 3 of 1,1,2,2-tetrachloroethane, to which 797 grams of aluminum chloride was added over 20 minutes at 0 ° C., followed by concentration of 166 cm 3 The prepared chlorine is injected at 20 ° C. over 5 hours 30 minutes and then the whole is left overnight at 20-25 ° C.

The mixture is poured slowly from a mixture of water / ice / hydrochloric acid at 17 ° C., then the organic layer is washed with methylene chloride, hydrochloric acid, evaporated to dryness with water and sodium bicarbonate, and the residue is chromatographed on silica and eluted with benzene. . 217 grams of a mixture of the desired isomers are obtained.

Step B: Mixture of 1 and 3-chloro 6-bromo benzosuberon

A mixture of 656 grams of copper bromide and 3200 cm 3 of ethyl acetate was refluxed for 45 minutes, and then a solution of 328 grams of the isomeric mixture obtained in step A was dissolved in 1600 cm 3 of chloroform while refluxing for 1 hour, and 151 g of The reflux was continued for 3 hours while further adding copper bromide, the whole was cooled and filtered, the filtrate was washed with brine and dried to evaporate the solvent. 464 grams of the desired crude product are obtained and used in the next step.

Step C: Mixture of 1 and 3-chloro 5-oxo 8,9-dihydro [5H] benzocycloheptene

465 grams of the mixture obtained in the previous step was dissolved in 5 liters of dimethylformamide, 459 grams of lithium carbonate and 459 grams of lithium bromide were added thereto, the whole was heated at 110 ° C. for 2 hours and 30 minutes, then cooled and filtered. After diluting methylene chloride, the solution is washed with brine and dried to evaporate the solvent. 397 grams of the desired composition are obtained, which is used in the next step.

Step D: Mixture of 1 and 3-chloro 5-oxo 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene

A mixture of 100 grams of the product obtained in step C, a mixture of 500 cm 3 ethanol and a saturated monomethylamine solution in 200 cm 3 ethanol was stirred for 2 hours, the solvent was evaporated, and the residue was put in 1 liter of ethyl acetate. After extraction with 1 N hydrochloric acid, the acid layer is alkaline with soda and then extracted with ethyl acetate. The organic layer is washed with brine and evaporated to dryness. 67.2 grams of crude product are obtained, which is used in the next step.

Step E: Mixture of 1 and 3-chloro 5-hydroxy 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene

The product obtained in step D is dissolved in 2 liters of ethanol, to which a solution of 67.2 grams of sodium borohydride dissolved in 800 cm 3 of water is added and stirring is continued at 20 ° C. for 4 hours. After adding 2 liters of ethyl acetate, the whole was decanted and the organic layer was concentrated to 1 liter, which was extracted with 2N hydrochloric acid to make the acid layer alkali and again extracted with ethyl acetate. The whole was evaporated to dryness and the residue was chromatographed on silica and eluted with a mixture of 8: 1: 1 ethyl acetate / methanol / triethylamine to afford 41.5 grams of the desired product.

Example 11

4-chloro-7-methylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride

Dissolve in 14 grams 1-chloro 5-hydroxy 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptanol 280 cm 3 hexamethylphosphotriamide and hold the whole at 220 ° C. for 50 minutes The mixture was concentrated to 50 cm 3, cooled, and then added to 500 cm 3 of water and ice. Then, concentrated ammonia was added until the pH was 10, the whole was extracted with ethyl acetate, and the organic layer was washed with water and dried. The whole was concentrated to dryness and the residue was chromatographed on silica, eluting with a mixture of 95: 5: 10 ethyl acetate / methanol / triethylamine to afford 2.2 grams of the desired product in base form.

2.19 grams of base is dissolved in 260 cm 3 of ethyl ether, 2 cm 3 of ether saturated with hydrochloric acid is added, the hydrochloride is vacuum filtered and recrystallized from methanol / ethyl acetate mixture to give 2.1 grams of the desired product. Melting point = 228 ° C

Analysis: C ₁₂ H ₁₅ Cl ₂ N

Theoretic value: C% 59.02 H% 6.19 Cl% 29.04 N% 5.73

Experimental value: 58.9 6.3 28.7 5.7

As starting material 1-chloro 5-hydroxy 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene was obtained in the same manner as in Example 10, and the chlorination process described in step A It is carried out at 0 ° C. and 1-chloro isomers are obtained. The synthesis order is the same.

Example 12

7-ethylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride

2.3 grams of 7-ethylamino 5α-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene are dissolved in 46 cm 3 of dioxane while refluxing and 4.6 cm 3 of 18N sulfuric acid is added thereto. The whole was refluxed again for 30 minutes, concentrated to 15 cm 3, cooled and added to 100 cm 3 of ice water followed by concentrated ammonia. The whole is extracted again with methylene chloride and the organic layer is washed with water and concentrated to dryness. 1.85 grams of the desired product are obtained in base form.

The base was dissolved in a 5 cm 3 solution in which hydrochloric acid was saturated in ethyl acetate, the hydrochloride was vacuum filtered and recrystallized from a mixture of methanol / ethyl acetate to give 1.7 grams of the desired product. Melting point = 180 ° C

Assay: C ₁₃ H ₁₈ ClN

Calculated: C% 69.78 H% 8.11 Cl% 15.85 N% 6.26

Experimental value: 69.8 8.3 15.9 6.2

By heating the 5β-OH isomer under the above conditions, the same product is obtained. Melting point = 180 ° C

As starting materials, 5α-OH and 5β-OH 7-ethylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene are obtained by the following method.

Step A: 7-ethylamino 5-oxo 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride

4.74 grams of 5-oxo 8,9-dihydro [5H] benzocycloheptene in 20 cm 3 of ethanol and 20 cm 3 of solution (13%) in which ethylamine was dissolved in ethanol were dissolved, and then the whole was 30 at 20 ° C. After stirring for evaporation to dryness, the residue is dissolved in methanol and thereto is added a solution of saturated hydrochloric acid in methanol. The solvent is evaporated, the residue is dissolved in acetone and the obtained crystals are vacuum filtered to give 5.2 grams of the desired product. Melting point = 212 ° C

Assay: C ₁₃ H ₁₈ ClNO

Calculated: C% 65.12 H% 7.57 Cl% 14.79 N% 5.84

Experimental value: 65.2 7.8 15.1 5.8

Step B: 7-ethylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene

0.96 grams of the product obtained in step A is dissolved in 10 cm 3 of ethanol and 2 cm 3 of 2N soda mixture, to which 1 gram of sodium borohydride is slowly added and the whole is stirred at 20 ° C. for 30 minutes. Again 30 cm 3 of water was added thereto, the ethanol was evaporated and the whole was cooled and extracted with methylene chloride. The organic layer is washed with water and evaporated to dryness. The residue is dissolved in isopropyl ether and the crystals obtained are vacuum filtered. This gives 0.5 grams of β-OH isomers which are the desired products. Melting point = 131 ° C

Drying the mother liquor of the crystal obtained above yields 0.4 grams of the α-OH isomer as an amorphous form.

Example 13

7- (4-methyl piperazin-1-yl) 6,7-dihydro [5H] benzocycloheptene difumarate

Nine grams of 7- (4-methyl piperazin-1-yl) 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene was dissolved in 180 cm 3 of dioxane and the whole was refluxed to 18 Cm 3 of 18N sulfuric acid is added. The reflux was maintained for 30 minutes, the whole was concentrated and cooled to 20 ° C., and then 100 cm 3 of a mixture of ice and water was added thereto, the whole was washed with ethyl acetate, and the aqueous layer was made of alkali by adding concentrated ammonia, which was then chlorinated. After extraction with methylene, the organic layer is dried and the solvent is evaporated. This gives 6.2 grams of the desired product in base form.

The base is again dissolved in 80 cm 3 of ethanol, 6 grams of fumaric acid is added thereto, the whole is left for several hours to crystallize, and the crystals are vacuum filtered and recrystallized from methanol to obtain 9 grams of the desired product. Melting point = 210 ° C

Assay: C ₂₄ H ₃₀ N ₂ O ₈

Calculation: C% 60.75 H% 6.37 N% 5.90

Experimental Value: 60.6 6.4 5.7

As a starting material, 7- (4-methyl piperazin-1-yl) 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene is obtained by the following method:

Step A: 7- (4-Methylpiperazin-1-yl) 5-oxo 6,7,8,9-tetrahydro [5H] benzocycloheptene

6.32 grams of 5-oxo 8,9-dihydro [5H] benzocycloheptene was dissolved in 40 cm 3 of ethanol and 8 cm of N-methyl piperazine in 80 cm 3 was added over 5 minutes The mixture was stirred at 20 ° C. for 4 hours, evaporated to dryness and dissolved in 0.5N hydrochloric acid. The solution was then washed with ethyl acetate and concentrated to alkaline with concentrated ammonia, extracted with methylene chloride, dried and Is evaporated. 8.8 grams of the desired product are obtained.

Step B: 7- (4-Methylpiperazin-1-yl) 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene

8.8 grams of the product obtained in step A was dissolved in 88 cm 3 ethanol and 8.8 cm 3 water, then 8.8 grams sodium borohydride was added at 22-26 ° C. over 20 minutes and the whole was stirred at 20 ° C. for 1 hour. Ethanol is evaporated, water is added and extracted with methylene chloride, and then the organic layer is washed with water and evaporated to dryness. 9 grams of crude product are obtained, which product is used to continue the synthesis (the product obtained is a mixture of 5α and 5β isomers).

Example 14

7-allylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride

6.2 grams of 7-allylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene was dissolved in reflux with 124 cm 3 of dioxane, 12.4 cm 3 of 18N sulfuric acid was added and continued for 30 minutes. Reflux.

The whole was cooled and concentrated to 40 cm 3, then 100 cm 3 of ice water was added, the aqueous layer was washed with ethyl acetate, made alkaline by addition of concentrated ammonia, extracted with methylene chloride, the organic layer was washed with water and evaporated to dryness. 4.5 grams of the desired product are obtained in base form. This product is dissolved in 5N ethyl acetate and a solution of saturated hydrochloric acid in ethyl acetate is added at 15-20 占 폚. The solvent is then evaporated, the residue is crystallized from isopropanol and recrystallized from methylethylacetone to yield 3.6 grams of the desired product. Melting point = 148 ° C

Assay: C ₁₄ H ₁₈ ClN

Calculated: C% 71.32 H% 7.69 Cl% 15.04 N% 5.94

Experimental value: 71.2 7.9 14.8 5.9

As a starting material, 7-allylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene is obtained by the following method.

Step A: 7-allylamino 5-oxo 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride

6.33 grams of 5-oxo 8,9-dihydro [5H] benzocycloheptene was dissolved in 30 cm 3 of ethanol, followed by the addition of a solution of 4.6 grams of allylamine in 46 cm 3 of ethanol and the whole at 1O < 0 > C for 1 hour. Stir for and evaporate to dryness. The oily product was dissolved in 30 cm 3 of ethyl acetate, a solution of saturated hydrochloric acid was added to ethyl acetate, and the crystals were vacuum filtered to yield 7.3 grams of the desired product.

Melting point = 170 ° C

Step B: 7-allylamino 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene

The 7.3 grams of the product obtained in step A was dissolved in 73 cm 3 of ethanol and 7.3 cm 3 of water and then cooled down to which 7.3 g of sodium borohydride was added at 15 ° C. over 30 minutes. The whole is stirred for 1 hour at 20 ° C. and then neutralized with hydrochloric acid and made alkaline by addition of concentrated soda. Ethanol is evaporated, water is added, extraction is performed with methylene chloride, and the organic layer is washed with water and evaporated to dryness. 6.2 grams of product are obtained and this product is a mixture of 5α and 5β-OH isomers.

Example 15

Di- [7- (pyrrolidin-1-yl) 6,7-dihydro [5H] benzocycloheptene] fumarate:

A mixture of 5 grams of 5-hydroxy 7- (pyrrolidin-1-yl) 6,7,8,9-tetrahydro [5H] benzocycloheptene and 5 grams of anhydrous potassium sulfate at 220 ° C. for 5 minutes Stir. The whole is cooled to 25 ° C., dissolved in water, washed with ether, made alkaline by addition of concentrated ammonia, extracted with methylene chloride and evaporated to dryness.

3.3 grams of crude product are obtained.

3.3 grams of crude product obtained above was dissolved in 25 cm 3 of isopropanol and 870 cm 3 of fumaric acid was added thereto. The whole is dissolved by heating and left for 2 hours at 20 ° C. and vacuum filtered to wash the filtrate with isopropane and then ether.

1.75 grams of the desired product (melting point = 190 ° C., then 200 ° C.) is obtained, which can be recrystallized from methanol. The melting point does not change.

Assay: C ₃₀ H ₃₈ N ₂ , C ₄ H ₄ O ₄

Calculated Value: C% 75.24 H% 7.80 N% 5.16

Experimental Value: 75.0 8.2 5.1

As a starting material, 5-hydroxy 7- (pyrrolidin-1-yl) 6,7,8,9-tetrahadro [5H] benzocycloheptene is obtained by the following method:

Step A: 5-oxo 7- (pyrrolidin-1-yl) 6,7,8,9-tetrahydro [5H] benzocycloheptene

7.5 grams of 5-oxo 6,7-dihydro [5H] benzocycloheptene are dissolved in 30 cm 3 of ethanol and to this is added a solution of 7.1 grams of pyrrolidine in 30 cm 3 of ethanol. The whole was stirred at room temperature for 30 minutes and then evaporated to dryness to yield 11.5 grams of the desired product.

Step B: 5-hydroxy 7- (pyrrolidin-1-yl) 6,7,8,9-tetrahydro [5H] benzocycloheptene

The 11.5 grams of product obtained in step A is dissolved in 11.5 cm 3 of ethanol and 11.5 cm 3 of water, then the whole is cooled to 10 ° C. and 5.75 grams of sodium borohydride is slowly added thereto. The whole is stirred at 20 ° C. for 1 hour, ethanol is evaporated and then 100 cm 3 of water is added. The whole is extracted with methylene chloride, washed with water and evaporated to dryness. 11.35 grams of the desired product are obtained.

Example 16

2-Chloro 7-methylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride

A solution of 3.7 grams of 3-chloro 5-hydroxy 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene dissolved in 37 cm 3 of dioxane was refluxed, followed by 7.4 cm 3 concentrated sulfuric acid. After refluxing is continued for 20 minutes, the whole is cooled to 20 DEG C, 50 cm <3> of water is added thereto, and soda solution is added to make alkaline. The whole is extracted with methylene chloride, washed with water and evaporated to dryness.

3.5 grams of product are obtained, which are dissolved in 5 cm 3 of ethyl acetate. A solution obtained by dissolving the hydrogen chloride gas in ethyl acetate was added at 10 ° C. and the crystals formed were vacuum filtered to give 3.3 grams of the desired product. The melting point is 195 ° C., which is the same as the product described in Example 10.

3-chloro 5-hydroxy 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene as starting material can be obtained by the following method:

Step A: 3-Chloro 5-oxo 8,9-dihydro [5H] benzocycloheptene

7.1 grams of 3-chlorobenzosuberne (as described in J. Chem. Soc. C. 2176-1969) is dissolved in 10.5 cm 3 of dimethylformamide, and then 12 grams of pyridinium perbromide is dissolved in 10 cm 3 of dimethyl. A solution dissolved in formamide was added at 80 ° C. over 10 minutes and the whole was held at 80 ° C. for 15 minutes, then the solution was added at 7 ° C. of dimethylformamide, 12.4 grams of lithium carbonate and 10 at 120 ° C. over 20 minutes. To a mixture of grams of lithium bromide. The whole was stirred at 120 ° C. for 2 hours and 20 minutes, then cooled to 50 ° C. and placed in a mixture consisting of 60 cm 3 of water, 120 grams of ice, and 23 cm 3 of hydrochloric acid, extracted as ether, washed with water and dried Treated with activated carbon, filtered, and the solvent is evaporated. 7 grams of crude product is obtained, which is used in the next step.

The product can be purified purely by chromatographic separation on silica and eluted with a mixture of 8: 2 cyclohexane / ethylacetate to recrystallize from ether. Melting Point = 55 ℃

Step B: 3-Chloro 5-oxo 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride

An ethanol solution of 60 cm 3 of 5N mono-methylamine is added to a solution of 5 grams of the product obtained in step A at 20 ° C. dissolved in 50 cm 3 of ethanol. The whole is stirred for 1 hour and then evaporated to dryness and washed with ether in 1N hydrochloric acid. The whole was cooled to 10 ° C. again, made alkaline by addition of concentrated ammonia, extracted as ether, washed with water, dried, treated with activated carbon, filtered and evaporated to dryness.

7.6 grams of product are obtained, which are dissolved in 5 cm 3 of methanol. The whole was cooled to 10 ° C. again, and the resulting crystals were vacuum filtered through addition of a solution of hydrogen chloride gas dissolved in ethyl acetate to give 4.6 grams of the desired product. Melting point = 218 ° C

Step C: 3-Chloro 5-hydroxy 7-methylamino 6,7,8,9-tetrahydro [5H] benzocycloheptene

The 4.6 grams of product obtained in step B is suspended in 100 cm 3 of water, the whole is cooled to 10 ° C. and soda solution is added. The whole is extracted with methylene chloride and evaporated to dryness. 4 grams of oily product are obtained, which are dissolved in 40 cm 3 of ethanol and 4 cm 3 of water. Then 2 grams of sodium borohydride was added thereto at 20 ° C. and the whole was stirred for 1 hour. The whole is evaporated to dryness, dissolved in methylene chloride, washed with water and evaporated to dryness. Washing it with isopropyl ether yields 3.7 grams of product. Melting point = 90 ° C.

Example 17

2-chloro 7-dimethylamino 6,7-dihydro [5H] benzocycloheptene fumarate

4.7 grams of 2-chloro 7-methylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride (prepared as described in Example 16) is placed in 47 cm 3 of acetonitrile. 7.7 cm 3 of formaldehyde solution in a 40% aqueous solution and 4.5 grams of sodium cyano borohydride are added. The whole was stirred at room temperature for 15 minutes, acetic acid was added until PH was 7, and then stirred at room temperature for 45 minutes to dry in vacuo.

2.6 grams of 2-chloro-7-dimethylamino 6,7-dihydro [5H] benzocycloheptane are obtained in oil form. By adding fumaric acid to methanol, 3.3 grams of 2-chloro 7-dimethylamino 6,7-dihydro [5H] benzocycloheptene fumarate are obtained. Melting point = 160 ° C

Assay: C ₁₃ H ₁₆ ClN, C ₄ H ₄ O ₄ = 337.795

Calculated: C% 60.44 H% 5.97 N% 4.15 Cl% 10.50

Experimental Value: 60.2 6.0 4.1 10.7

Example 18

Tablets of the following compositions are prepared:

-7-dimethylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride… … … 25mg

-Excipient per tablet. … … … … … … … … … … … … … … … … … … … … … 200mg

(Specific excipients: lactose, starch, talc, magnesium stearate)

Example 19

Tablets of the following compositions are prepared:

-7-dimethylamino 5-phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride… … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … 25mg

-Excipient per tablet. … … … … … … … … … … … … … … … … … … … … … 200mg

(Specific excipients: lactose, starch, talc, magnesium stearate)

Example 20

Tablets of the following compositions are prepared:

-7-methylamino 6,7-dihydro [5H] benzocycloheptane hydrochloride… … … … 25mg

-Excipient per tablet. … … … … … … … … … … … … … … … … … … … … … 200mg

(Specific excipients: lactose, starch, talc, magnesium stearate)

Example 21

Tablets of the following compositions are prepared:

2-Chloro 7-methylamino 6,7-dihydro [5H] benzocycloheptene hydrochloride… … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … 25mg

Excipient per tablet… … … … … … … … … … … … … … … … … … … … … … … 200mg

(Specific excipients: lactose, starch, talc, magnesium stearate)

Claims (1)

As detailed herein, the product of formula (II) is dehydrated by heating with a strong acid at the boiling point of the reaction mixture, or by heating with potassium bisulfate or in hexametapol, to give the product of formula (I ′). Process for preparing a new amino benzocycloheptene derivative of formula (I) and its addition salt with inorganic or organic acid, characterized in that the product of formula (II ′) is obtained by reduction with hydrogen gas in the presence of a catalyst such as palladium. .

Where X is a hydrogen atom or a halogen atom excluding fluorine, the halogen atom is at position 2 or 4 of the phenyl nucleus, Y represents a hydrogen atom or together with Z forms a carbon-carbon double bond, Z represents a hydrogen atom or together with Y represents a double carbon-carbon bond, R is a hydrogen atom, an alkyl group having 1-5 carbon atoms or a phenyl group, which may be substituted with fluorine or chlorine atoms or with methyl or methoxy groups R ₁ is a hydrogen atom, an alkyl group containing 1-5 carbon atoms or an alkenyl group containing 2-5 carbon atoms, and R ₂ is an alkyl group containing 1-5 carbon atoms or 2-5 carbon atoms the alkenyl group, which, on the other hand, together with the nitrogen atom, R ₁ and R ₂ form a saturated heterocycle having from 4 to 6 carbon atoms, and which may be composed of different hetero atoms, and also 1 to 5 carbons Which it may be equally substituted with an alkyl group having from.