KR810000538B1 - Process for preparing new amino-methylbenzocy-cloheptene derivatives - Google Patents

Abstract

Aminomethyl benzocyclophentene derivs. (I; X = H, CL, I; R = H, C1-3 alkyl, phenyl methoxy, benzyl; Y = H, benzylidene; Z = H, able to forming double bond with Y; R1R2 = H, methyl), useful for treatment of melancholia, were prepd. by dehydration of compd. (II) in the presence of H2SO4, HCl, calcium disulfate or hexametapol in org. solvent at boiling point.

Description

Process for preparing new amino methylbenzocycloheptene derivatives

The present invention relates to a method for producing a new derivative of amino methylbenzocycloheptene represented by the following general formula (I).

In this formula, X represents a halogen atom excluding a hydrogen atom or fluorine, these halogen atoms are located at the 2 or 4 position of the phenyl nucleus, R represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, and a phenyl group, if necessary Or a chlorine atom, a methyl or methoxy group, or a benzyl group, or R represents a benzylidene group together with Y, Y represents a benzylidene group together with a hydrogen atom or R, or Y represents a carbon- together with Z Taking the form of a carbon double bond, Z represents a hydrogen atom or together with Y becomes a carbon-carbon double bond, and R ₁ and R ₂ are the same or different and they represent a hydrogen atom or a methyl group, and R ₁ and When R ₂ is a hydrogen atom, R may also be a hydrogen atom.

In formula (I) and the following description, X preferentially represents a chlorine or bromine atom, and the alkyl group containing 1-3 carbon atoms represents a methyl, ethyl, propyl or isopropyl group.

Examples of acid addition salts include hydrochloric acid, bromic acid, iodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, and methanesulfonic acid. Salts formed as aryl sulfonic acids such as alkanesulfonic acid and benzene sulfonic acid.

Among the compounds obtained by the method of the present invention, X represents a hydrogen atom or a chlorine atom, R represents a hydrogen atom, a methyl group, a phenyl group or a benzyl group, and R represents a benzylidene group together with Y, Y, Z, R ₁ And R ₂ may be mentioned sub-infections with inorganic or organic acids as well as derivatives corresponding to formula (I) as defined above. X represents a hydrogen atom or a chlorine atom R represents a hydrogen atom, Y represents a hydrogen atom or together with Z forms a carbon-carbon double bond, Z represents a hydrogen atom or together with Y forms a carbon-carbon double bond , R ₁ and R ₂ may be mentioned derivatives corresponding to formula (I) as well as addition salts thereof with inorganic or organic acids, as defined above.

In the product corresponding to formula (I), R is an alkyl group phenyl group or benzyl group having 1 to 3 carbon atoms, Y represents a hydrogen atom or R represents a benzylidene group together with Y, and the product isomers A and B described below. It can be represented by two isomers.

The present invention, of course, relates to racemic forms that can be cleaved by known methods and to A and B isomers of new products.

In more detail with respect to the compounds obtained in the present invention,

7-aminomethyl 6,7-dihydro [5H] benzocycloheptene,

7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene,

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

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

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

4-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene, as well as addition salts thereof with inorganic or organic acids are included.

Method for preparing a derivative and salts thereof defined by the formula (I) by dehydrating the following formula (II)

(Where X, R, R ₁ and R ₂ are as described above)

The product of formula (I) can be obtained.

The product of formula (I ') can be isolated or salted and reduced to give the product of formula (II').

X, R, R ₁ and R ₂ are the same as described above, and these compounds may be separated or salted.

The characteristics of the production method under suitable conditions in carrying out the present invention are as follows.

a) The dehydration reaction of the formula (II) is carried out at the boiling point of the reaction mixture and the reaction is carried out in an organic solvent such as dioxane by a strong acid such as hydrochloric acid or sulfuric acid or by potassium bisulfate or hexametapol.

b) The reduction reaction of formula (I ') is carried out by hydrogen gas in the presence of a catalyst such as palladium.

It is an object of the present invention to prepare aminomethylcycloheptene derivatives and salts thereof defined by the above structural formula (I). In the above structural formula (I), R represents a hydrogen atom, R ₂ represents a metal atom group, and X, Y, Z and R ₁ are as described above, and the derivative of the following formula is first obtained according to the above method.

R, R ₁ and R ₂ are H)

Where X, Y and Z are the same as before. Such a product of the structure (I),

Reaction with formic acid in the presence of 1) -dicyclohexylcarbonimide yields the product of formula

Where X, Y and Z are the same as above). This product may be a salt if desired.

Where X, Y and Z are the same as before

2) Reaction with formaldehyde and sodium cyanoborohydride yields the product of the following formula. It may also become a salt again.

Where X, Y and Z are the same as before

Under the conditions of carrying out the present invention, the manufacturing process as described above has the following characteristics.

a) The reaction of the product of formula (I) with formic acid is carried out in an organic solvent such as ethyl acetate in the presence of dicyclohexyl carbodiimide.

b) Reduction of the product of formula II is carried out by a reducing agent such as lithium aluminum hydride in an organic solvent such as tetrahydrofuran.

c) The reaction of the product of formula (I) with formaldehyde and sodium cyanoborohydride is carried out at room temperature in the presence of acetonitrile in an organic solvent such as tetrahydrofuran.

The present invention deals with a process for preparing derivatives and salts thereof defined by formula (I), wherein in formula (I) R ₁ represents a hydrogen atom, R ₂ represents a methyl atom group and R, X, Y and Z are described above. As shown.

In the process of the present invention, in the first order according to the method described above, R ₁ and R ₂ represent a methyl atom group and R, X, Y and Z obtain the product of formula (I) as described above and are produced as above. The product of formula (I ') to react with an alkylchloroformate salt as in structure (IV) to obtain a product as structure (V),

(W is an alkyl atom group having 1 to 3 carbon atoms)

(X, R, Y and W are the same as before)

The product (V) is hydrolyzed in an alkaline medium to obtain the product of formula (I). In structure (I), R ₁ represents a hydrogen atom, R ₂ represents a methyl atom group, R, X, Y and Z are as described above, and such a product may be a salt.

The product of formula (I) (R ₁ and R ₂ are methyl atom groups and X, R, Y and Z are as described above) can be prepared by the following method, which is characterized by the following formula (1a) The product of is in the reaction as follows.

Where X, R, X, and Z are as described above

In other words, the desired product is obtained by reacting with the halide of the structural formula of the above product or by reacting with formaldehyde and sodium cyanoborohydride.

(Hal represents a chlorine, bromine or iodine atom)

Derivatives of formula (I) have the property of base. Addition salts of these derivatives are advantageously prepared by reacting inorganic or organic acids with the derivatives.

These salts can be prepared without separating the corresponding bases.

The products obtained in the present invention have very interesting pharmaceutical properties, especially in anti-inhibitory activity tests.

These properties have excellent properties of the derivatives of aminoylbenzocycloheptene of formula (I) and their pharmaceutically acceptable acids.

It is preferable that these properties consist of new derivatives of aminoylbenzocycloheptene corresponding to the formula (I), wherein X represents a hydrogen atom or a chlorine atom, and R represents a hydrogen atom, a methyl atom group, or phenyl. Represents an atomic group or a benzyl atom group, R represents a benzylidene atomic group together with Y, Y, Z, R ₁ and R ₂ are as described above, and also their addition salts with pharmacologically acceptable acids Preferred for use as

Among these drugs, in particular, X represents a hydrogen atom or a chlorine atom, R represents a hydrogen atom, Y represents a hydrogen atom or together with Z forms a carbon-carbon double bond, Z represents a hydrogen atom or Y Together with carbon-carbon double bonds and R ₁ and R ₂ include products corresponding to formula (I) as defined above as well as addition salts with their pharmacologically acceptable acids. Among these include addition salts of the following products with their pharmacologically acceptable acids.

7-aminomethyl 6,7-dihydro [5H] benzocycloheptene,

7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene,

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

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

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

4-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene.

These medicines are used, for example, for depression, depression, mood swings, repulsive and wasting depression, and neurological depression.

Typical dosages may vary depending on the drug used, the subject administered and the disease involved, for example, from 10 mg to 300 mg per day orally.

Addition salts with novel derivatives of formula (I) and their pharmacologically acceptable acids are used to prepare pharmaceutical ingredients containing at least one derivative or at least one derivative or at least one salt thereof as the active substance. Can be used.

Novel derivatives of aminomethylbenzocycloheptenes of formula (I) as pharmaceuticals and their pharmacologically acceptable acids can be used in combination with contract components for digestive or parenteral administration. .

These pharmacological ingredients may be administered, for example, in solid or liquid form, or as a form commonly administered to humans, for example, as tablets or dragees, gelatin capsules, granules, suppositories, or injections as they are. do. These are manufactured by a well-known method.

The active ingredients can be combined with excipients conventionally employed in such pharmaceutical ingredients, and examples of the excipients include talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous excipients, animal or vegetable fatty substances, pyrazine derivatives. , Glycols, various wetting, dispersing or emulsifying agents and preservatives are used.

The product of formula (II) (X and R are as described above, R ₁ represents a hydrogen atom or a methyl atom group, R ₂ represents a methyl atom group) can be prepared by a method having the following characteristics: .

1)-The product of the formula

Where X, R ₁ and R ₂ are as previously mentioned)

To obtain the product of

Wherein X, R ₁ and R ₂ are as defined above and the product is the same as the product of formula (II) wherein R represents a hydrogen atom.

2) -or the product of formula (VI) (X, R ₁ and R ₂ are as described above)

React with the organometallic compound of

(Wherein R ′ represents an alkyl atom group or a phenyl atom group having 1 to 3 carbon atoms, and if necessary, a fluorine or chlorine atom is substituted, and a methyl or methoxy atom group or a phenyl atom group, and M represents a lithium atom or -Mg- Hal 'atom group and Hal' represents chlorine or bromine atom). The product of the following structural formula is obtained.

Wherein X, R ', R ₁ and R ₂ are as described above.

(The above product is the same as the product of formula (II) wherein R does not represent hydrogen).

The product of formula (II), wherein R, R ₁ and R ₂ are hydrogen atoms, is obtained by reducing the following formula.

Where X is as described above.

The products of formula VI can be prepared as described in application Nos. 75-25397 filed in France on August 14, 1975.

The process for preparing these products was carried out using acetone cyanhydrin

It is characterized by the reaction with the product of the following formula.

Where X is as described above.

The above reaction gives the product of the following structural formula.

Where X is as described above.

The above product is a glycol of the formula

(Where n is an integer of 2 or 3). Reaction in the presence of lower alkyl ortho formate and arylsulfonic acid gives a product of the formula

Where X is as described above. This is reduced to give a product of the structure

Where X and n are as described above

The above product is reacted with formaldehyde and sodium cyanoborohydride to give the product of the following formula.

Where X and n are as described above.

On the other hand, the product of the formula (VII) is reacted with formic acid in the presence of dicyclohexylcarbodiimide to obtain the product of the following formula,

Where X and n are as described above. The product of formula (VV) is again heated and reduced to give the product of the following formula.

Where X and n are as described above. The product of formula (XIV) or product of formula (XIV) is hydrolyzed to yield the product of formula (VI), where X is as described above. The product of formula (X), wherein X represents a halogen atom except for fluorine, may be produced by a method having the following characteristics when it is not known.

That is, the halogenating agent reacts with the product of structural formula (XVII)

The product of the following structural formula is obtained.

(Where X is a halogen atom excluding fluorine). The product of formula (VII) is debrominated hydrogenated to give the product of desired structure (VII).

The process of the present invention makes it possible to produce the following products which are useful for the preparation of derivatives corresponding to formula (I) as new industrial products.

As a product of the structural formula

Wherein X, R, R ₁ and R ₂ are as described above. Especially the A and B isomers of 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene, 5-hydroxy 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene, 5-hydroxy 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene A and B isomers, 7-dimethylaminomethyl 5-hydroxy 5-phenyl A and B isomers of 6,7,8,9-tetrahydro [5H] benzocycloheptene, 5-benzyl 7-dimethylaminomethyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene , 3-chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene, 1-chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene and 1-chloro 5-hydroxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

Also as a product of the following structural formula:

Where X, Y and Z are as described above. In particular 7-formylaminomethyl 6,7-dihydro [5H] benzocycloheptene and 2-chloro 7-formylaminomethyl 6,7-dihydro [5H] benzocycloheptene-as a product of the formula ,

(Where X, Y, Z, R and W are as described above), in particular 7-methylaminomethyl N-ethoxycarbonyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene

In the following, embodiments of carrying out the present invention are described, but the present invention is not limited thereto.

Example 1

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

10 grams of 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are added to 100 cm ³ of dioxane and 20 cm ³ of 18N sulfuric acid. Making the whole was heated at 100 ℃ to 1 hour, then 20 ℃ Add the reaction mixture was poured into ether of 400cm ³ of water and ice and the mixture was 200cm ^3.

The whole is extracted with ether, the neutral layer is made of alkali by adding soda solution, and the base portion is extracted with ether again.

The whole is washed with brine, dried over magnesium sulfate and filtered to remove the solvents in vacuo.

Ten grams of 7-aminomethyl 6,7-dihydro [5H] benzocycloheptene are recovered in the form of a chestnut oil.

Preparation of Hydrochloride

10 grams of 7-aminomethyl 6,7-dihydro [5H] benzocycloheptene is dissolved in 500 cm ³ of ether, and then a solution of saturated hydrochloric acid is added to the ether.

The whole is filtered off, washed with ether and dried under vacuum. 8.6 grams of 7-aminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride white was recovered in crystalline form. Melting point = 235 ° C

5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene used as a starting material can be prepared by the following method.

Step A: 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one

84 grams of 8,9-dihydro [5H] benzocycloheptene 5-one are placed in 1.7 liters of methanol, 170 cm ³ of tetrahydrofuran and 74 cm ³ of acetone cyanhydrin, followed by 148 cm ³ of 10% potassium carbonate. Add an aqueous solution. The solution thus obtained is heated to reflux and maintained for 3 hours. Cool the whole and add 1.5 times the volume of ethyl acetate, wash the whole with water saturated with sodium chloride and neutralize by addition of the required minimum acetic acid. The washed mother liquor is again extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and distilled off under vacuum at 35-40 ° C.

107 grams of 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one in the form of brown oil are obtained.

This was eluted with a 6: 4 cyclohexane / ethylacetate mixture and chromatographed on silica to separate 738 grams of crude product, crystallized from 30 cm ³ of 2,2-dimethoxypropane mixed with 60 cm ³ of isopropyl ether. Let's do it. The whole was cooled in ice and vacuum filtered and washed with a mixture of 1: 2 dimethoxypropane and isopropyl ether to give 34.8 grams of 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5- The on is recovered in the form of white crystals that melt at 50 ° C.

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

Three grams of 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one are added to 42 cm ³ of anhydrous tetrahydrofuran, followed by about 1.235 grams of lithium aluminum hydride over 20 minutes. Add again.

The whole is stirred for 2 hours and then cooled with ice and 10 cm ³ of water saturated with ammonium chloride and then 10 cm ³ of distilled water are added at a temperature below 20 ° C.

After filtration and extraction with ethyl acetate, the organic layer was washed with water, dried over sodium sulfate and dried under vacuum. 2.186 grams of 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are obtained in the form of an orange colored resin.

Example 2

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

Step C: 6,7-formylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride

20 grams of 7-aminomethyl 6,7-dihydro [5H] benzocycloheptene (obtained in Example 1) are added to 600 cm ³ of ethyl acetate and 48 grams of dicyclohexylcarbodiimide.

After cooling the whole to 0-5 degreeC, 9 cm <^3> of formic acid is added over 15 minutes. It is left at 0-5 ° C. for 1 hour, filtered, washed with ethyl acetate and the solvent is removed in vacuo.

31 grams of 7-formylaminomethyl 6,7-dihydro [5H] benzocycloheptene are obtained in the form of brown oil and used in this state in the next step.

Step D: 7-formylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride

13.3 grams of lithium aluminum hydride is added to 300 grams of tetrahydrofuran. The whole was cooled to 0-5 ° C. and to this was added a solution of 14 grams of 7-formylaminomethyl 6,7-dihydro [5H] benzocycloheptene in 300 cm ³ of tetrahydrofuram.

The whole was heated to reflux for 3 hours and then cooled to 0-5 ° C. and excess hydride was removed by addition of tetrahydrofuran containing 50% water.

The whole was decanted, extracted with ethyl acetate, washed with water then brine, dried over magnesium sulfate and the solvents removed in vacuo.

This yields 11.7 grams of brown oil in the form of 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene.

[Production of Hydrochloride]

Hydrochloride is prepared by adding a solution of saturated hydrochloric acid in ethyl ether to a solution of 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene in ether.

7.5 grams of product (melting point = 224 ° C.) was recovered and recrystallized from isopropanol.

6.3 grams of 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride are obtained in beige crystalline form. Melting point = 228 ° C

Example 3

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

3.68 grams of 5-hydroxy 7-dimethylaminomethyl 6,7,8,9-dihydro [5H] benzocycloheptene are added to 74 cm ³ of dioxane. The whole was heated to reflux and 18.4 cm ³ of 18N sulfuric acid was added thereto to continue refluxing for 15 minutes. The whole was cooled with ice and slowly added ammonia to pH = 10.

The whole is extracted with ethyl acetate, washed with water and then with brine. The washed liquid is extracted again with ethyl acetate, and the organic layer is collected, dried over sodium sulfate, concentrated to dryness. To obtain 2.93 grams of 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene in oil form, which is chromatographed on silica and purified, and a 4: 6: 1 benzene / ethylacetate / triethylamine mixture. Elute as. 1.94 grams of product are separated in oil form.

[Production of Hydrochloride]

1.94 grams of 7-dimethylaminomethyl 6,7-dihydro [5H]

Benzocycloheptene is dissolved in 250 cm ³ of ethyl ether. To the ether is added dropwise a solution of saturated hydrochloric acid until the precipitation is complete. After vacuum filtration and washing with ether and vacuum drying, 2.113 grams of 7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptenhydrocycloheptene hydrochloride was recovered in the form of beige crystals. Melting point = 234 ° C

5-hydroxy 7-dimethylaminomethyl 6,7,8,9-tetradihydro [5H] benzocycloheptene used as starting material can be prepared by the following method.

3.77 grams of 5-hydroxy 7-aminomethyl 6,7,8,9-tetride [5H] benzocycloheptene (obtained in Example 1) was added to 19.7 grams of formaldehyde and 75 cm ³ of aceto in 30% aqueous solution. Add to nitrile. Again 2 grams of sodium cyanoborohydride were added and the whole was stirred at 20-23 ° C., and 20 cm ³ of acetonitrile was further added thereto, followed by heating the whole to 60 ° C., followed by 10 cm ³ of tetrahydro Add furan. The solution is brought to 20 ° C. and stirred for 30 minutes. 50 cm ³ of water, then 50 cm ³ of ethyl acetate, are added and the whole is decanted, the organic layer is washed with water, dried over sodium sulfate and distilled off under reduced pressure. Five grams of crude organisms are separated and purified by chromatographic separation on silica and eluted as a mixture of benzene / ethylacetate / triethylamine of 4: 6: 1. 3.68 grams of colorless oil in the form of 5-hydroxy 7-dimethylaminomethyl 6,7,8,9-dihydro [5H] benzocycloheptene was recovered.

Example 4

7-dimethylaminomethyl 6,7,8,9-dihydro [5H] benzocycloheptene hydrochloride

3.3 grams of 7-dimethylaminomethyl 6,7,8,9-dihydro [5H] benzocycloheptene (prepared as in Example 3) is added to 165 cm ³ of ethanol. Add 10% palladium on 3.3 grams of activated carbon and hydrogen (the volume of 580 cm ³ is absorbed over 1 hour 45 minutes). After stirring for 45 minutes under hydrogen gas, the catalyst is removed by filtration under vacuum and the filtrate is recovered. Distillation under vacuum recovers 3 grams of crude product which is purified by chromatographic separation on silica and eluted with a 95: 5 petroleum ether / triethylamine mixture.

2.87 grams of 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene was recovered (melting point = 44 ° C.).

[Production of Hydrochloride]

2.48 grams of 7-dimethyl aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are dissolved in 300 cm ³ of ethyl ether, and dropwise addition of hydrochloric acid solution in ether is added thereto.

The obtained crystals were vacuum filtered, washed with ether and dried to recover 3.15 grams of 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride. (Melting point = 250 ° C.).

Example 5

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

1) Preparation of Base

3.9 grams of 5-hydroxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are added to 39 cm ³ of dioxane. The whole is about 110 ° C, and 7.8m ³ of 1 / 2N sulfuric acid is added.

The whole was stirred for 15 minutes while refluxing under inert gas, cooled rapidly and 11N ammonia was added to bring the pH of the solution to 10 or more.

The whole is extracted with ethyl acetate and the organic layer is washed with water and then with water saturated with sodium chloride. The washings are extracted with ethyl acetate and the organic layers are combined, dried over sodium sulfate and dried in vacuo.

3.64 grams of orange oil are isolated and purified by chromatography on silica and eluted with a mixture of 8: 2: 1 ethyl acetate / benzene / triethylamine.

3.27 grams of 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene is finally recovered in the form of a yellow oil.

(2) Preparation of Hydrochloride

2.44 grams of 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene is dissolved in 300 cm ³ of ether ether, and ethyl ether saturated with hydrochloric acid is added dropwise with stirring. The product is filtered under reduced pressure, washed with ether, dried under vacuum and recrystallized from isopropanol. 2.60 grams of 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride is recovered in the form of white crystals.

(Melting point = 228 ° C.). (Same as the product obtained in Example 2).

5-hydroxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzobenzoheptene can be prepared as follows.

Step A: 5,5-ethylenedioxy 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene

15 grams of 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one (prepared as in Example 1) was charged with 150 cm ³ of ethylene glycol and 15 cm ³ of ethylorzoform. Add to acid salt. The whole is heated under stirring at 75 ° C. and then 750 mg of paratoluene sulfonic (monohydrate) acid is added.

After 1 hour, 7.5 cm ³ of ethyl orzo formate is added rapidly. The whole is stirred at 75 ° ± 75 ° for 2 hours and then cooled. 5 cm ³ of triethylamine and then 500 cm ³ of water are added and extracted with ethyl acetate. The organic layer obtained is recovered, washed with water, dried over sodium sulfate and again under vacuum. 19 grams of 5,5-ethylenedioxy 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene are recovered in the form of brown oil.

Step B: 5,5-ethylenedioxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

17.25 grams of 5,5-ethylenedioxy 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene were added to 172 cm ³ of tetrahydrofuran and the whole was cooled to about 0 ° C. Over 40 minutes, 4.3 grams of lithium aluminum hydride is added under nitrogen gas with stirring. After stirring for 2 hours, the temperature was maintained at 20-25 ° C., and then cooled to 0 ° -5 ° C., and 70 cm ³ of water saturated with ammonia chloride and distilled water at 15 ° C. were added dropwise not to exceed + 40 ° C. do.

The whole was filtered, the filtrate was recovered, extracted with ethyl acetate, the aqueous layer was decanted and the organic layer was washed with saturated sodium chloride. The washed solution was re-extracted with ethyl acetate, and then the collected organic layer was dried over sodium sulfate and distilled off under vacuum at 40 ° C.

16.7 grams of 5,5-ethylenedioxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are isolated in the form of a yellow oil.

Step C: 5,5-ethylenedioxy 7-formylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

18.65 grams of 5,5-ethylenedioxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are added to 615 cm ³ of ethyl acetate. Again 33.1 grams of dicyclohexylcarbodiimide was added thereto and the whole was cooled to 0 ° -5 ° C. A solution of 7.38 grams of pure formic acid dissolved in 40 cm ³ of ethyl acetate was added dropwise over about 20 minutes while stirring under inert gas at this temperature.

The whole was washed with ³ cm ³ of ethyl acetate and stirred for 45 minutes at 0 ° -5 ° C. under nitrogen gas.

The residue is filtered and the filtrate is recovered, washed with water, dried over sodium sulphate and distilled under vacuum.

28.1 grams of crude product are isolated which is chromatographed on silica and eluted with an 8: 2: 1 ethylacetate / benzene / triethylamine mixture.

19.6 grams of 5,5-ethylenedioxy 7-formylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are finally isolated and recrystallized from ethyl acetate.

D step: 5,5-ethylenedioxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

14.2 grams of lithium aluminum hydride is added to 425 cm ³ of tetrahydrofuran and the suspension is stirred under an inert gas to cool to a temperature of up to + 15 ° C., which is then added to 19.6 grams of 5,5- over 15 minutes. A solution in which ethylenedioxy 7-formylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene was dissolved in 196 cm ³ of tetrahydrofuran is added.

The whole was heated to reflux for 3 hours 30 minutes.

The whole is slowly added by cooling with ice + saturated aqueous solution of ammonium chloride at a temperature of 5-20 ℃ 40cm ³⁾ and distilled water (40cm ^3.

The whole is filtered off and the filtrate is recovered, washed with water saturated with sodium chloride, dried over sodium sulfate and concentrated to dryness in vacuo.

18.42 grams of 5,5-ethylenedioxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are isolated in the form of an orange resin.

E step: 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one

18.42 grams of 5,5-ethylenedioxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene were added to 184 cm ³ of 70% acetic acid and the whole was stirred under inert gas 80 Heat to &lt; 0 &gt; C and hold for 4 hours in this state. Cool the whole with ice and add dropwise 250 cm ³ of 22 ° B ammonia at + 5 ° -15 °.

The whole was extracted with ethyl acetate, the organic layer was collected, washed with water, dried over sodium sulfate and evaporated to dryness in a vacuum.

15.4 grams of crude product is isolated which is purified in a silica cylinder and eluted as an 8: 2: 1 ethyl acetate / benzene / triethylamine mixture.

Finally, 13.4 grams of 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one in the form of a colorless resin was recovered.

Step F: 5-hydroxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

6.2 grams of 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one are added to 88 cm ³ of tetrahydrofuran and over about 45 minutes at a temperature near + 5 ° C. Add 2.59 grams of lithium aluminum hydride. The whole is stirred for 2 hours while it is brought to room temperature. The whole was cooled with ice and hydrolyzed at 0 ° C., while a saturated aqueous solution of 20 cm ³ ammonia chloride was added over about 45 minutes, followed by 20 cm ³ of water.

After filtration of the whole, the filter was washed with 1000 cm ³ of ethyl acetate, washed with half-saturated water with sodium chloride, and then the organic layer was recovered, dried over sodium sulfate and further distilled to dryness. 5.35 g of crude product are obtained, which are dissolved in 30 cm ³ of isopropyl ether.

The whole was made into a paste, cooled with ice, vacuum filtered and washed with isopropyl ether. 3.13 grams of 5-hydroxy 7-methylaminomethyl 6,7,8,9- in white crystallized solid at melting point 145 ° C. Tetrahydro [5H] benzobenzoheptene is obtained.

Example 6

7-methylaminomethyl 6,7,8,9-dihydro [5H] benzocycloheptene hydrochloride

2.51 grams of 7-methylaminomethyl 6,7-tetrahydro [5H] benzocycloheptene (prepared as indicated in Examples 2 and 5) are added to 125 cm ³ of ethanol.

2.51 grams of 10% palladium on activated carbon and hydrogen (absorbed 345 cm ³ over 26 minutes) are added. The whole is stirred for 45 minutes under hydrogen gas, the crystals are filtered off and the filtrate is recovered.

Concentrate it under vacuum to recover 2.40 grams of crude product which is purified by chromatography. It is separated into a 9: 1 chloroform / triethylamine mixture.

2.30 grams of 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are obtained in the form of white crystals. (Melting point = 56 ° C).

[Production of Hydrochloride]

2.30 grams of 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene is dissolved in 275 cm ³ of ethyl ether, and dropwise addition of hydrochloric acid solution in ether is added thereto.

The crystals obtained are filtered under reduced pressure, washed with ether and dried to recover 2.68 grams of 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride white crystals. (Melting point = 250 ° C)

Example 7

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

5.20 grams of 7-dimethylaminomethyl 5-hydroxy 5-phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene (mixture of isomers A and B) is added to 52 cm ³ of dioxane. The whole is heated to 120 ° C., and 10.4 cm ³ of 18N sulfuric acid is added while refluxing. The reflux was maintained for 15 minutes, then cooled and 20 cm ³ of 11N ammonia was added thereto.

The whole is extracted with ethyl acetate and the organic layer is washed with water saturated with sodium chloride and then again with completely saturated water.

The washings are extracted again with ethyl acetate and the organic layers are collected, dried over sodium sulfate and concentrated in vacuo. 4.71 grams of crude product are obtained, which are purified by chromatography on silica and coagulated with a mixture of 8: 2: 1 cyclohexane / acetate / triethylamine.

4.2 grams of 7-dimethylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene is recovered in the form of a pale yellow resin, which crystallizes.

[Production of Hydrochloride]

4.2 grams of 7-dimethylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene is dissolved in 500 cm ³ of ethyl ether, and 3.5 cm ³ of hydrochloric acid solution dissolved in ethyl ether is added dropwise.

The whole is vacuum filtered, washed with ether ether and dried under vacuum.

4.52 grams of hydrochloride are recovered and recrystallized from a mixture of ethyl acetate (100 cm ³ ) / methanol (10 cm ³ ).

3.26 grams of 7-dimethylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene hydrochloride are obtained in the form of white crystals. (Melting point = 254 ° C).

7-dimethylaminomethyl 5-hydroxy 5-phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene used as starting material can be prepared as follows.

Step A: 5,5-ethyleneoxy 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

14 grams of 5,5-ethyleneoxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene (prepared as directed in step B of Example 5) were prepared with 280 cm ³ of aceto. It is added to nitrile and 70 cm ³ of tetrahydrofuran.

Add 60.5 g of formaldehyde in a 30% aqueous solution with stirring under inert gas and then quickly add 11.35 grams of sodium cyanoborohydride.

The whole is stirred while maintaining at 20 ° -23 ° C. After 35 minutes, water is added, followed by extraction with ethyl acetate. It is dried over sodium sulfate and evaporated to dryness at 40 ° C.

17.25 grams of 5,5-ethylenedioxy 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are recovered in the form of brown oil.

Step B: 7-Dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one

11.1 grams of 5,5-ethylenedioxy 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene is added to 110 cm ³ of 70% acetic acid.

The whole is heated to 75 ° ± 5 ° over 40 minutes and held for 4 hours 30 minutes with stirring under inert gas.

The whole is cooled with ice and the resulting solution is slowly precipitated in 500 cm ³ of water saturated in sodium bicarbonate.

At this time, the pH is adjusted to 8 by adding sodium bicarbonate, which is extracted as ethyl acetate. The organic layer is washed with water, then saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness.

8.95 grams of 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one in yellow oil form are isolated.

Step C: 7-dimethylaminomethyl 5-hydroxy 5-phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

An ethereal solution of lithium phenyl is prepared from 190 cm ³ of ethyl ether, 43 grams of bromo benzene and 4.01 grams of lithium.

Cool 55 cm ³ of this solution to 0 °-+ 5 ° and 15 cm of 1.49 grams of 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one over about 20 minutes. ^A solution dissolved in ³ ethyl ethers is added.

Which was stirred for 6 hours, while the entire thereby after a 20-25 ℃ cooled with ice was added to the distilled water of a saturated aqueous solution of ammonium chloride and then 30cm 30cm ^{3 3} gradually.

The ether layer was decanted and the aqueous layer was extracted with ether and the collected organic layers were washed with water and then with water saturated with sodium chloride. Drying over sodium sulfate and concentrated to dryness separate 3.14 grams of crude product which is purified on silica. It is eluted with a mixture of benzene / ethylacetate of 95: 5 and then eluted with a benzene / ethylacetate / triethylamine mixture of 95: 5: 10.

412 mg of 7-dimethylaminomethyl 5-hydroxy 5-phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene isomer A (maximum mobile isomer Rf = 0.2) is isolated in pale yellow resin form Then, 1.44 grams of 7-dimethylaminomethyl 5-hydroxy 5-phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene isomer B (minimum mobile isomer Rf = 0.13) in crystallized form It is obtained (melting point = 122 ° C).

Example 8

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

Step A: 7- (N-methyl N-ethoxycarbonyl) aminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene

7-dimethyl-amino-methyl 9-phenyl-6,7-dihydro-of 7.74 g [5H] -benzo cycloheptene (example of the one prepared as indicated in 7) was added to a 77cm ³ of benzene and 7.7cm ³ of ethyl chloroform Acid salt is added.

After the whole was heated to reflux for 6 hours, 2.5 cm ³ of ethylchloroformate salt was added and maintained under reflux for 1 hour and 30 minutes.

After the reaction, the whole is cooled and dried under vacuum. 10.47 grams of 7- (N-methyl N-ethoxycarbonyl) aminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene are obtained in the form of a yellow resin.

Step B: 7-methylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene

10.47 grams of 7- (N-methyl N-ethoxycarbonyl) aminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene is placed in 104 cm ³ of n-butanol.

To this was added 10.4 grams of potassium hydroxide and the whole was heated to reflux under an inert gas. After about 4 hours 5 grams of potassium hydroxide is added and reflux is continued for 3 hours. The whole is cooled, dried over sodium sulphate and dried under vacuum.

8.69 grams of crude product is isolated and purified by chromatography on silica. It is separated into a mixture of benzene / ethylacetate / triethylamine of 95: 5: 10. 7.4 grams of 7-methylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene is obtained in the form of a yellow oil.

Step C: 7-methylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene hydrochloride

5 grams of 7-methylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene is dissolved in 500 cm ³ of ethyl ether, followed by dropwise addition of hydrochloric acid solution dissolved in ter.

The whole was vacuum filtered, washed with ether and dried to give 5.5 grams of 7-methylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene hydrochloride which was recrystallized from isopropanol to give 4.9 grams of white crystals. It is recovered in the form of (melting point = 246 ° C).

Example 9

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

1.14 grams of 7-methylaminomethyl 9-phenyl 6,7-dihydro [5H] benzocycloheptene (obtained in Example 8) is added to 60 cm ³ of ethanol and again 1.14 grams of 10% palladium on activated carbon is added.

The whole is hydrogenated until about 132 cm ³ of hydrogen is absorbed over about 50 minutes. It is left under stirring for 1 hour and then the catalyst is removed. Recovering and drying the filtrate yields 1.23 grams of crude product, which is added prior to 2.26 grams of the same product prepared under the same conditions as in Example.

3.6 grams of the total material was purified by chromatography on silica, eluting as a mixture of 7: 3: 1 benzene / ethylacet / triethylamine, yielding 2.8 grams of 7-methylaminomethyl 9-phenyl 6, 7,8,9-tetrahydro [5H] benzocycloheptene is isolated.

[Production of Hydrochloride]

2.8 grams of the above product was dissolved in 500 cm ³ of ethyl ether and a dropwise addition of a saturated ethyl ether solution was added dropwise. Vacuum filtration of the whole and washing with ether yields 2.75 grams of unpurified hydrochloride, which is recrystallized from methanol.

2.11 grams of 7-methylaminomethyl 9-phenyl 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride is obtained in the form of white crystals (melting point = 315 ° C.).

Example 10

9-benzyl-7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride

Step A: of 9-benzyl 7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene and 9-benzylidene 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene A and B isomers.

5.99 grams of 5-benzyl 7-dimethylaminomethyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene are dissolved in 60 cm ³ of dioxane. The whole is heated to 120 ° C., and 12 cm ³ of 18N sulfuric acid is added thereto. The whole was stirred at reflux for 10 minutes, cooled, and then frozen until 11N ammonia was added until the pH was above 10.

The whole is extracted with ethyl acetate, washed with water and washed again with water saturated with sodium chloride. The washings are extracted with ethyl acetate and the organic layer is collected and dried over sodium sulfate.

6.2 grams of crude product is isolated, which is purified by chromatography on silica, eluted with a mixture of 95: 5 petroleum ether / triethylamine, and the following substances are separated in the following order.

a) A isomer of 592 mg 9-benzylidene 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene.

I.R.Spectrum: Chloroform

C at C = 1632 cm ^-1

Direction side 1600cm ^-1, 1574cm ^-1, 1462cm ^-1 and 1484cm ^-1

Tertiary aromatic band -1500cm ^-1

U.V.Spectrum: Ethanol

b) B isomer of 283 mg 9-benzylidene 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene.

I.R.Spectrum: Chloroform

C at C = 1634 cm ^-1

Direction Side 1603cm ^-1 , 1578cm ^-1 , 1498cm ^-1 , 1487cm ^-1

U.V.Spectrum: Ethanol

C) 2.7 grams 9-benzyl 7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene.

I.R.Spectrum: Chloroform

C at C = 1634 cm ^-1

Direction Side 1606cm ^-1 , 1498cm ^-1 , 1489cm ^-1

U.V.Spectrum: Ethanol

Step B: 9-benzyl 7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride

2.7 grams of 9-benzyl-7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene are dissolved in 320 cm ³ of ethyl ether, and dropwise addition of a saturated hydrochloric acid solution in ether is added dropwise. The whole is vacuum filtered, washed with ether and dried under vacuum.

2.82 grams of hydrochloride are obtained, which are recrystallized from a mixture of ethyl acetate / methanol, followed by isopropanol.

2.54 grams of 9-benzyl 7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride are finally recovered in the form of white crystals (melting point = 221 ° C.).

5-Benzyl 7-dimethylaminomethyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene used as starting material can be prepared as follows.

A solution of benzylmagnesium chloride (quantitatively 1.1 mol / 1 liter) in 196 cm ³ of tetrahydrofuran was cooled in a freezing water bath and 4.68 grams of 7-dimethylaminomethyl 6,7,8,9-dihydro [5H Benzocycloheptene 5-one (prepared as directed in step B of Example 7) and 94 cm ³ of tetrahydrofuran are added dropwise over about 3 hours 15 minutes.

The whole is washed with 10 cm ³ of tetrahydrofuran and stirred for 1 hour between 0 °-+ 5 ° C. and brought back to room temperature. It is stirred for 18 hours, cooled with ice, and slowly added to a saturated aqueous solution of 50 cm ³ ammonia chloride. The whole was filtered and extracted as ethyl acetate, which was washed with saturated sodium chloride water, dried over sodium sulfate and dried again under vacuum.

17 grams of crude product was recovered, which was purified by chromatography on silica and eluted with a mixture of 5: 1: cyclohexane / ethylacetate / triethylamine.

5.99 grams of 5-benzyl 7-dimethylaminomethyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene are obtained in resin form.

Example 11

9-benzylidene 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] hydrochloride of the A isomer of benzocycloheptene 557 mg 9-benzylidene 7-dimethylaminomethyl 6,7,8,9-tetra Hydro [5H] benzocycloheptene (obtained in step A of Example 10) is dissolved in 67 cm ³ of ethyl ether, and then a solution of saturated hydrochloric acid is added dropwise to ethyl ether. The whole is vacuum filtered, washed with ether and dried under vacuum. 596 mg of hydrochloride are obtained, which is recrystallized from a mixture of ethyl acetate and methylene chloride. The methylene chloride is distilled off and the remainder is cooled to freezing, vacuum filtered, washed with ethyl acetate and dried.

529 mg of 5-benzylidene 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzoate hydrochloride of the A isomer of benzocycloheptene is recovered in the form of white crystals (melting point = 208 ° C.).

Example 12

Hydrochloride of the B isomer of 9-benzylidene 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

An isomer of 220 mg 9-benzylidene 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene (obtained in step A of Example 10) was dissolved in 26 cm ³ of ethyl ether and ethyl Add dropwise a solution of saturated hydrochloric acid to ether.

The whole is vacuum filtered, washed with ether and dried under vacuum. 229 milligrams of hydrochloride are obtained, which are recrystallized from a mixture of ethyl acetate and methylene chloride. Methylene chloride is distilled off, the remainder is cooled with ice, vacuum filtered, washed with ethyl acetate and dried.

195 mg of 9-bentiidene 7-dimethylaminomethyl 6,7,8,9-tetrahydro [5H] benzoic acid hydrochloride of the B isomer of benzocycloheptene is obtained in the form of white crystals.

Example 13

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

24.8 grams of 3-chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene was added to 500 cm ³ of dioxane and the whole was heated to 120 ° C. and 50 cm ³ 18 N sulfuric acid is added.

The whole was refluxed for 2 hours, cooled, 200 grams of ice was added, and 11N of ammonia was added until the pH was above 10.

The whole was extracted with ethyl acetate, washed with water, dried over sodium sulfate and again under vacuum. 22.1 grams of crude product are obtained, which are chromatographed on silica. Elution of this as a mixture of 9: 1: 1 benzene / methanol / triethylamine gave 9.1 grams of 7-aminomethyl 2-chloro 6,7-dihydro [5H] benzocycloheptene in the form of a yellow oil.

3-Chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene used as starting material can be prepared as follows.

Step A: Mixture of 1 and 3-chlorobenzosuberon

400 grams of benzosuberon was dissolved in 1600 cm ³ of 1,1,2,3-tetrachloroethane, 797 grams of aluminum chloride was added again over 20 minutes at 0 ° C, and then 5 hours and 30 minutes at 20 ° C. Over 166 cm ³ of concentrated chlorine is added to keep the whole at 20-25 ° C. overnight.

The mixture is slowly poured into a mixture of water / ice / hydrochloric acid at 17 ° C. and extracted with methylene chloride, the organic layer is washed with hydrochloric acid, washed with water and sodium bicarbonate, dried and evaporated to dryness, and the residue is silica. Chromatographic separation in phase elutes with benzene.

217 grams of the expected isomeric mixture 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 refluxed again, and then 328 g of the isomeric mixture obtained in step A was dissolved in 1600 cm ³ of chloroform over 1 hour while refluxing again. The solution is added and refluxing is continued for 3 hours while 151 grams of copper bromide is added to cool the whole and filtered, the filtrate is washed with brine and dried and the solvent is evaporated. 465 grams of crude product is obtained, which is used in the next step.

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

465 g of the mixture obtained in the previous step was added to 5 liters of dimethylformamide, 459 grams of lithium carbonate and 459 grams of lithium bromide, the whole was heated at 110 ° C. for 2 hours and 30 minutes, cooled, filtered and diluted with methylene chloride. The solution is washed with brine and dried to evaporate the solvent.

397 grams of the desired crude product are obtained and used in the next step.

Step D: 1 and 3-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one

54.6 grams of the mixture obtained in the previous step are added to an aqueous solution of 1100 cm ³ of methanol and 110 cm ³ of tetrahydrofuran, 55 cm ³ of acetone cyanhydrin, and 110 cm ³ of potassium carbonate at a rate of 10 g per 100 cm ³ . Cooling the whole to 20 ℃ mixture was refluxed for 1.5 hours and was added to acetic acid of 9.1cm ³ here then concentrated under reduced pressure to 400cm ^3.

500 cm ³ of ethyl acetate was added and the whole was decanted, washed with water, washed with water saturated with sodium chloride, dried over sodium sulfate, concentrated and dried. A mixture of 68 g of 1 and 3-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one is obtained, which is purified by chromatography on silica. It is separated into a mixture of 8: 2 chlorohexane and ethyl acetate under a pressure of 2.5 kg.

First 20.28 grams of 1-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one are separated and then 15.74 grams of 3-chloro 7-cyano 6,7, 8,9-tetrahydro [5H] benzobenzohepten 5-one is isolated.

a) Crystallization of 1-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one.

20.28 grams of 1-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one obtained above was absorbed into 40 cm ³ of isopropyl ether, cooled on ice and then vacuum filtered. Wash with isopropyl ether.

Drying gives 15.1 grams of 1-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one as white crystals (melting point = 75 ° C.).

b) Crystallization of 3-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one.

15.74 grams of 3-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one obtained above was dissolved in 30 cm ³ of isopropyl ether, which was then vacuum filtered and then with isopropyl ether. Wash.

Drying it separates 10.91 grams of 3-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one in the form of white crystals (melting point = 77 ° C).

Step E: 3-Chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene.

21.9 grams of 3-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one are dissolved in 330 cm ³ of tetrahydrofuran and the whole is cooled to + 5- + 10 ° C. Add 7.6 grams of lithium aluminum hydride over 45 minutes.

The whole is stirred for 2 hours while the temperature is raised and again cooled to + 5- + 10 °, followed by the addition of 40 cm ³ of saturated ammonia chloride water.

The whole was filtered and extracted with ethyl acetate, washed with water and water saturated with sodium chloride, dried over sodium sulfate and concentrated to dryness. 15.7 grams of 3-chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are obtained in the form of a yellow resin and used as such.

Example 14

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

Step A: 5.21 grams of 2-chloro 7-formylaminomethyl 6,7-dihydro [5H] benzocycloheptene 7-aminomethyl-2-chloro 6,7-dihydro (5H) benzocycloheptene (Example 13) is added to 78 cm ³ of ethyl acetate. The whole was cooled to 0 ° C. + 5 ° C. and 10.4 grams of dicyclohexylcarbodiimide was added thereto, followed by a solution of 2.32 grams of formic acid dissolved in 11.5 cm ³ of ethyl acetate over 25 minutes.

The whole was stirred for 45 minutes, then filtered and the filtrate was recovered and washed with water and saturated with sodium chloride and dried over sodium sulfate.

Eight grams of crude product is recovered which is chromatographed on silica and separated as a mixture of benzene / ethylacetate / triethylamine of 3: 7: 1.

5.5 grams of 2-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene are isolated in crystallized form (melting point = 80 ° C.).

Step B: 2-Chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene

Cool 210 cm ³ of tetrahydrofuran to 0 °-+ 10 ° C. and add 7 grams of lithium aluminum hydride in small portions, followed by 8.67 grams of 2-chloro 7-formylaminomethyl over about 20 minutes at the same temperature. A solution of 6,7-dihydro [5H] benzocycloheptene dissolved in 87 cm ³ of tetrahydrofuran is added.

The whole was heated to reflux for 3 hours and 30 minutes, cooled in an ice bath, and then slowly added to a saturated solution of ammonia chloride of 60 cm ³ . The whole was filtered and the filtrate was concentrated with 100 cm ³ and extracted with ethyl acetate, washed with half saturated sodium chloride, dried over sodium sulfate, concentrated to dryness.

Eight grams of yellow oil was obtained, which was chromatographed on silica and eluted with a mixture of 7: 3: 1 ethyl acetate / benzene / triethylamine to give 2.07 grams of 2-chloro 7-methylaminomethyl 6, Two portions of 7,8,9-tetrahydro [5H] benzocycloheptene and 2-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene in 2.08 grams of resin form are separated.

Step C: 2-Chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride.

2.08 grams of 2-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene are dissolved in ethyl ether saturated with 240 cm ³ of hydrochloric acid. The whole was vacuum filtered, washed with ether, dissolved in a minimum amount of ethanol again, filtered, and then 100 cm ³ of ethyl acetate was added at high temperature. The whole is concentrated, cooled with ice, vacuum filtered and washed with ethyl acetate.

Drying afforded 1.62 grams of 2-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride (melting point = 240 ° C.).

Example 15

2-Chloro 7-methylaminomethyl 6,7.8.9-tetrahydro [5H] benzocycloheptene hydrochloride.

Dissolve 1.23 grams of 2-chloro 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene (prepared as directed in step B of Example 14) in 150 cm ³ of ethyl ether. To this was added dropwise a solution of ethyl ether saturated with hydrochloric acid. The whole was vacuum filtered, washed with ether, dissolved in a minimum amount of methylene chloride, and then 40 cm ³ of ethyl acetate was added thereto, concentrated to 10 cm ³ , cooled with ice, vacuum filtered, and washed with ethyl acetate.

Recrystallization from isopropanol afforded 1.04 grams of 2-chloro 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride in the form of white crystals (melting point = 224 ° C.).

Example 16

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

12.5 grams 1-chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are added to 250 cm ³ of dioxane.

The whole is heated to 120 ° C. and 25 cm ³ of 18N sulfuric acid is added thereto. The mixture was stirred for 2 hours with reflux, cooled, and ammonia was added to bring the pH to 10 or more.

The aqueous layer is saturated with sodium chloride and extracted with ethyl acetate. The organic layer is washed with water saturated with sodium chloride and then again with water saturated with sodium chloride and dried over sodium sulfate.

10.8 grams of crude product is isolated and purified by chromatography on silica, eluted with a mixture of 95: 5: 10 benzene / methanol / triethylamine to give 5.93 grams of 4-chloro 7-methylaminomethyl 6,7 -Dihydro [5H] benzocycloheptene is obtained in the form of a yellow oil.

1-Chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene used as starting material can be prepared as follows.

18.35 grams 1-chloro 7-cyano 6,7,8,9-tetrahydro [5H] benzocycloheptene 5-one (prepared as directed in step D of Example 13) was added 275 cm ³ of tetrahydro After addition to furan, the whole is placed in an ice bath and 6.32 grams of lithium aluminum hydride is added over about 30 minutes.

The whole was stirred for 2 hours while the temperature was again brought to room temperature, and once again cooled, 30 cm ³ of water saturated with ammonium chloride was added to distilled water.

The whole is filtered and the filtrate is washed with water saturated with sodium chloride, dried over sodium sulfate, concentrated and dried under vacuum. 17.6 grams of 1-chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene are obtained in crystallized form (melting point = 175 ° C.).

Example 17

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

5.9 grams of 4-chloro 7-aminomethyl 6,7-dihydro [5H] benzocycloheptene (prepared as directed in Example 16) was dissolved in 118 cm ³ of acetonitrile and a ratio of 30 grams per 100 grams. It is added to aqueous formaldehyde solution.

Again add 60 cm ³ of tetrahydrofuran and 2.86 grams of sodium cyano borohydride. The whole was stirred for 1 hour and kept at 20-25 ° C., then diluted with 100 cm ³ of water and 150 cm ³ of ethyl acetate, decanted, and the organic layer was recovered and washed with water. It is dried over sodium sulfate and dried in vacuo.

7.8 grams of crude product is obtained, which is purified by chromatography on silica and eluted with a 9: 1: 1 mixture of benzene / ethylacetate / triethylamine to give 3.7 grams of 4-chloro 7-dimethylaminomethyl 6,7 -Dihydro [5H] benzocycloheptene is obtained.

[Production of Hydrochloride]

3.7 grams of 4-chloro 7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene is dissolved in 370 cm ³ of ethyl ether, and dropwise addition of an ether ether solution saturated with hydrochloric acid is added.

The whole was filtered under reduced pressure, washed with ether and dried to afford 3.21 grams of 4-chloro 7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride in the form of white crystals (melting point = 230 ° C.). .

Example 18

4-Chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride

2.07 grams 1-chloro 5-hydroxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene is dissolved in 41 cm ³ of dioxane. The whole is brought to 120 ° C. and 4.1 cm ³ of 18N sulfuric acid is added thereto.

It was refluxed for 1 hour, cooled, 40 g of ice was added, and then ammonia was added to bring the pH to 10 or more.

The aqueous layer was saturated with sodium chloride, extracted with ethyl acetate, and the organic layer was washed with half-saturated sodium chloride and then again with saturated sodium chloride.

It is dried, concentrated to dryness and dissolved in benzene again. After filtration and drying, 1.68 grams of crude product is recovered in the form of yellow oil.

Thus, the total product is 5.20 grams by adding 3.52 grams manufactured in the above process to the crude product thus obtained under the same conditions.

It was purified by chromatography on silica and eluted as a mixture of 95: 5: 10 benzene / ethanol / triethylamine to give 2 grams of 4-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene. This yellow oil is separated.

[Production of Hydrochloride]

2 grams of 4-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene was dissolved in 250 cm ³ of ethyl ether, followed by dropwise addition of a saturated ether solution of hydrochloric acid. The whole was vacuum filtered, washed with ethyl ether and dried.

2.1 grams of hydrochloride (melting point = 166 ° C.) are obtained which are recrystallized from isopropanol.

1.72 grams of 4-chloro 7-methylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride is finally recovered in the form of white crystals (melting point = 169 ° C.).

1-Chloro 5-hydroxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene used as starting material can be prepared as follows.

Step A: 1-Chloro 7-formylaminomethyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene

Dissolve 16.6 grams 1-chloro 5-hydroxy 7-aminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene (prepared as indicated in Example 16) in 250 cm ³ of ethyl acetate Let's do it.

250 cm ³ of tetrahydrofuran was added, the whole was cooled to 0 °-+ 5 ° C., and then 30.5 grams of dicyclohexylcarbodiimide was quickly added, followed by 5.6 cm ³ of formic acid in 30 cm ³ of ethyl acetate over 20 minutes. The dissolved solution is added.

The whole is stirred for 45 min at 0 ° C .- + 5 ° C., then filtered, washed with water saturated with sodium bicarbonate, again with water saturated with sodium chloride and dried over sodium sulfate. 19.39 grams of crude product are obtained, which are recrystallized from ethyl acetate.

6.95 grams of the expected product are obtained (melting point = 159 ° C.).

Step B: 1-Chloro 5-hydroxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene

5.2 grams of lithium aluminum hydride is added to 140 cm ³ of cooled tetrahydrofuran. A solution of 6.95 grams of 1-chloro 7-formylaminomethyl 5-hydroxy 6,7,8,9-tetrahydro [5H] benzocycloheptene was then dissolved in 69 cm ³ of tetrahydrofuran at + 5 ° C. Add over 20 minutes.

The whole was heated to reflux for 3 hours 30 minutes, cooled in an ice bath and 10 cm ³ of saturated water with ammonium chloride was added.

The whole is filtered, extracted as ethyl acetate, washed with water saturated with sodium chloride and saturated with sodium chloride.

Drying over sodium sulfate gave 6.1 grams of 1-chloro 5-hydroxy 7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene in the form of white crystals (melting point = 176 ° C). .

Chemical Analysis: C ₁₈ H ₁₈ ClNO

Calculation: Cl% 14.19

Experimental Value: 14.0

Example 19

The following devices were manufactured.

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

The amount of excipients purified per dog (excipients: lactose, talc, starch, magnesium stearate). 200 mg

Example 20

Injection solutions corresponding to the following preparations were prepared.

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

Liquid excipients used to prepare injections. … … … … … … … … … … … … … … … 2mg

Example 21

Tablets corresponding to the following preparations were prepared.

7-methylaminomethyl 6,7,8,9-tetrahydro [5H] benzocycloheptene hydrochloride. 25mg

Amount of excipient per tablet (excipients: lactose, talc, starch, magnesium stearate)... 200 mg

Example 22

Tablets corresponding to the following formulations were prepared:

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

Amount of excipient per tablet (excipients: lactose, talc, starch, magnesium stearate)... 200 mg

Example 23

Tablets corresponding to the following formulations were prepared:

4-Chloro 7-dimethylaminomethyl 6,7-dihydro [5H] benzocycloheptene hydrochloride… … 25mg

Amount of excipient per tablet (excipients: lactose, talc, starch, magnesium stearate)... 200 mg

Claims (1)

The amino methylbenzocycloheptene represented by Structural Formula (I) by dehydration of the substance of formula Process for the preparation of new derivatives.

In the above formula, X is a hydrogen atom or a halogen atom except fluorine, a halogen atom is at position 2 or 4 of the phenyl nucleus, R is a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms, a phenyl group, and fluorine Or a chlorine atom, and represents a methyl or methoxy group or a benzyl group, R also represents a benzylidene group together with Y, Y represents a hydrogen atom or a benzylidene group together with R, and Y represents Z and Together form a double carbon-carbon bond, Z represents a hydrogen atom, or together with Y form a double carbon-carbon bond, R ₁ and R ₂ represent the same or different hydrogen atoms or methyl groups.