KR850000198B1 - Process for preparing pyrrolo (3,4-d)(2) benzazepines - Google Patents

Abstract

Pyrrolo (3,4-d) (2)benzazepines of formula (I) and their acid addn. salts are prepd. by the ring closure of compds. of formula (B). In the formulas, R1 is H, lower alkyl, C2-7 alkenyl, or C3-7 alkynyl; R5 is H, F, Cl, or Br; and R6 is F, Cl, or Br. (I) have sedative and anxiolytic activity. Lower alkyl or alkyl is straight chain or side chain C1-7 hydrocarbon, pref. C1-4 hydrocarbon residue, e.g. methyl, ethyl, propyl, or isopropyl.

Description

Method for preparing pyrrolo [3,4-d] [2] -benz azepine

The present invention relates to a process for the preparation of pyrrolo [3,4-d] [2] -benzazine of formula (I) and pharmaceutically acceptable acid addition salts thereof useful as sedatives and anti-anxiety agents.

In the above food

R ₁ is hydrogen, lower alkyl, C ₃ to C ₇ alkenyl or C ₃ to C ₇ alkynyl,

R ₅ is halogen or hydrogen having an atomic number of 35 or less,

R ₆ is halogen having an atomic number of 35 or less.

These compounds show activity as sedatives and anti-anxiety agents.

The term "halogen" or "halo" refers to bromo, chloro or fluoro.

The term "lower alkyl" or "alkyl" means straight and branched C ₁ to C ₇ hydrocarbon groups, preferably C ₁ to C ₄ hydrocarbon residues such as methyl, ethyl, propyl, isopropyl and the like.

The term "C ₃ to C ₇ alkenyl or alkynyl" refers to C ₃ to C ₇ straight and branched chain hydrocarbon groups in which at least one carbon-carbon bond is unsaturated and a double or triple bond. However, the unsaturated point cannot be between the carbon attached to the pyrrole ring and the adjacent carbon. That is, the carbon attached to the terminal is not unsaturated.

Compound of the present invention is to ring the compound of formula (B),

(Wherein R ₁ , R ₅ and R ₆ are as defined above).

If desired, the compounds of formula (I) are prepared by converting them into pharmaceutically acceptable acid addition salts.

The process of the invention and the preparation of the starting materials used herein are described by the following scheme for purposes of illustration.

Scheme I

(Wherein R ₅ and R ₆ are as defined above.)

Ⅱ → Ⅲ

The compound of formula (II), a known starting material, is reacted in zinc powder, copper sulfate and ammonium hydroxide.

The reaction temperature ranges from about room temperature to 100 ° C., preferably 100 ° C.

Ⅲ → Ⅳ

The compound of formula III is reacted in a metal hydride such as lithium aluminum hydride or borane in an ethereal solvent such as diethyl ether or tetrahydrofuran. The reaction temperature ranges from about -78 ° C to room temperature, with about 0 ° C being preferred.

Ⅳ → Ⅴ

The compound of formula IV is reacted with pyridinium chloro chromate, manganese dioxide or other suitable oxidizing agent using methylene chloride as solvent. The reaction temperature is in the range of about reflux to the reflux temperature of the solvent, with about room temperature being preferred.

Ⅴ → Ⅵ

The compound of formula (V) is reacted with diethyl cyanomethylphosphonate using an ethereal solvent such as tetrahydrofuran in the presence of a strong base such as sodium hydride, sodium amide and the like. The reaction temperature is in the range of about 0 ° C. to room temperature, with about room temperature being preferred.

Ⅵ → Ⅶ

The compound of formula VI is reacted in a mixture of acetic acid and methylene chloride with an oxidant derived from chromium trioxide or chromium trioxide. The reaction temperature ranges from about 0 ° C. to 90 ° C., with room temperature being preferred.

Ⅷ → Ⅸ

Compounds of formula (VII) are known starting materials. The compound is reacted with acrylonitrile in the presence of acetonitrile, lower alkyl nitrite and copper chloride. The reaction temperature ranges from about 0 ° C. to 40 ° C., with room temperature being preferred.

Ⅸ → Ⅶ

The compound of formula IV is reacted with an alkali metal such as a lithium, sodium or potassium carbonate and non-carbonate mixture, preferably 1 part potassium carbonate: 3 parts potassium bicarbonate mixture. Suitable solvents include dimethyl sulfoxide, dimethylformamide or C ₁ to C ₄ alcohols such as methanol.

The reaction temperature ranges from about 20 ° C. to 50 ° C., with room temperature being preferred. The above reaction represents a dehydrohalogenation reaction known in the art.

Ⅷ → Ⅹ

Compounds of formula (IV) can be diazotized with sodium nitrite in sulfuric acid and the diazonium salt can be separated by precipitation with tetrafluoro borate salt. These salts are slurried in water and then treated with an aqueous potassium iodide solution at room temperature to obtain uridobenzophenone.

Ⅹ → Ⅶ

The compound of formula IV is reacted with acrylonitrile using acetonitrile or an aromatic hydrocarbon such as toluene in the presence of a palladium II salt such as acetate, chloride or the like as a solvent. The reaction temperature ranges from about 60 ° C. to the reflux temperature of the solvent, with reflux temperature being preferred.

Scheme II

In the above formula,

R ₁ ′ is hydrogen or lower alkyl,

R ₁ , R ₅ and R ₆ are as defined above.

Ⅶ → XI

Compounds of formula (VII) include α-tosyl C ₂ to C ₈ alkyl isocyanide, α-tosyl C ₄ to C ₈ alkenyl isocyanide or α-tosyl C ₄ to C ₈ alkynyl isocyanide and sodium The reaction is carried out in the presence of a hydride using a mixture of dimethyl sulfoxide and ethers such as diethyl ether, dioxane or tetrahydrofuran. The reaction temperature ranges from about 0 ° C. to 40 ° C., with room temperature being preferred. α-tosyl alkylisocyanide may be prepared by the method of van Lucene et al. (Van Leusen et al., Tetrahedron Letters, 3487 (1975)).

Compounds of formula (XI) or form part of the invention.

XI → Ia

The compound of formula (XI) is reacted with hydrogen using glacial acetic acid as a solvent in the presence of a transition metal catalyst such as lenni nickel at a pressure ranging from about atmospheric pressure to about 5 atmospheres. The amine corresponding to formula (B) thus formed is naturally closed in the azepine ring. The reaction temperature is about room temperature.

The ring-opening amine produced first is allowed to ring off into product (Ia) in situ without separation.

XI → XII

The compound of formula (XI) is reacted in a metal hydride reducing agent such as lithium aluminum hydride with an ethereal solvent such as tetrahydrofuran. The reaction temperature ranges from about -20 ° C to room temperature, with 0 ° C being preferred. Compounds of formula (XII) also form part of the invention.

XII → Ib

The compound of formula (XII) is reacted with manganese dioxide in a solvent such as tetrahydrofuran or toluene. The amines of formula (B) thus formed are naturally closed in the azepine ring. The reaction temperature is in the range of about room temperature to the boiling point of the solvent, preferably 40 ° C. Compounds of formula (B) also form part of the invention.

Preference is given to compounds of the general formula (I) in which R ₅ and R ₆ are halogen (in particular R ₅ is chloro or fluoro and R ₆ chloro) and R ₁ is hydrogen or lower alkyl.

Particularly preferred compound examples are as follows.

8-chloro-6- (2-chlorophenyl) -2H, 4H-pyrrolo [3,4-d] [2] -benzazine:

8-chloro-6- (2-fluorophenyl) -2H, 4H-pyrrolo [3,4-d] [2] -benzazine and

8-chloro-6- (2-chlorophenyl) -1-methyl-2H, 4H-pyrrolo [3,4-d] [2] -benzazine.

"Pharmaceutically nontoxic salts" include salts with pharmaceutically nontoxic inorganic and organic acids such as sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and p-toluenesulfonic acid. Those skilled in the art can easily prepare these salts.

Pyrrolo [3,4-d] [2] -benzazine of the present invention is useful as a sedative and anxiolytic. These compounds may be formulated in conventional pharmaceutical formulations, e. It can be mixed with a suitable conventional organic or inorganic inert pharmaceutical carrier. It may be administered in the form of a conventional pharmaceutical formulation, for example in the form of a solid such as a tablet, dragee, capsule, suppository or the like or a liquid form such as a solvent, suspension or emulsion.

Moreover, pharmaceutical compositions containing a compound of the present invention may be subjected to conventional treatments such as sterilization and may contain pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting osmotic pressure, or buffers.

The composition may also contain other therapeutically active substances.

Suitable dosage units may contain 1 to 500 mg of benzazine of the present invention, preferably 1 to 100 mg for oral administration and 1 to 50 mg for parenteral administration. However, the specific dosage regimen for a particular subject should be adjusted in accordance with the individual needs and the professional judgment of the person administering and observing the compound.

The dosage is given by way of example only and is not intended to limit the invention.

As used herein, “dose unit” refers to a pharmaceutical isolate suitable for a single dose for a mammal containing a predetermined amount of active agent calculated with the required pharmaceutical diluent, carrier or vehicle to achieve the desired therapeutic effect. Refers to a unit.

The following data are indicative of the pharmacological activity of the pyrrolo-benzazine of the present invention using pharmacological tests well known in the art.

[exam]

The summary of the above test is as follows.

Foot shock

A pair of mice is confined in a 1 liter beaker placed on a grit that causes shock on the feet. At least five struggles occur within two minutes. Mouse pairs are displayed and pretreated 1 hour before the second shock.

Logarithmic dose intervals are used up to 100 mg / kg. At 100% barrier capacity, three of the three pairs must be blocked from the struggle.

Tilt screen

The test drug (maximum dose 500 mg / Kg) was administered to a group of six male mice and left for at least 4 hours on an inclined screen to observe a severe paralysis effect sufficient to slide off the screen. If activity is observed, additional doses are administered until some, but not all, of the animals reach a sliding dose from the screen. Doses in which the mouse falls off the screen due to toxicity or excitability are not included in the calculation of PD ₅₀ .

Anesthesia cat

Treat the cat orally and observe minimal symptoms, usually ataxia. Use a 50 mg / Kg dose for one cat. If active, use up to three per dose. Display the result as the minimum effective dose.

The following examples illustrate the invention but do not limit it. All temperatures are in degrees Celsius unless otherwise noted.

Example 1

a) 2-benzyl-4-chlorobenzoic acid

300 g (4.6 mol) of activated zinc powder and 100 g (0.42 mol) of 2-benzoyl-4-chlorobenzoic acid were added to a solution of 5.0 g of copper sulfate in 3 L ammonium hydroxide. The mixture is refluxed for 3 days at which time concentrated ammonium hydroxide is added to maintain the original volume. The mixture is cooled and excess zinc is filtered off. Concentrated hydrochloric acid is added to the filtrate and acidified to pH 3. The resulting precipitate is collected by filtration and dried until it is weighed to give a white solid having a melting point of 142 to 144 ° C.

b) 2-benzyl-4-chlorobenzyl alcohol

To a solution of 28.4 g (0.75 mol) of lithium aluminum hydroxide in 800 ml of ether and cooled to 0 ° C., a solution of 85.1 g (0.345 mol) of 2-benzyl-4-chlorobenzoic acid in 250 ml of ether was added dropwise. The mixture is left to warm to room temperature and stirred for 2 hours, after which 28.5 ml of water, 28.5 ml of 10% sodium hydroxide solution and 85.5 ml of water are added to neutralize excess lithium hydride. The precipitate is filtered off and the filtrate is dehydrated with sodium sulfate.

The colorless oil obtained by removing the ether under reduced pressure is crystallized. Melting point: 46.5 to 49 ° C.

c) 2-benzyl-4-chlorobenz aldehyde

To a suspension of 238 g (1.1 mol) of pyridinium chloromate and 800 ml of methylene chloride was added 9.3 g (0.34 mol) of 2-benzyl-7-chlorobenzyl alcohol. The mixture is stirred at room temperature for 2 hours. Ether: 2.4 liters of petroleum ether (1: 1) is added to precipitate the chromium salt and filtered through celite to remove the precipitate. The solvent is removed under reduced pressure to give yellow oil which is used without further purification.

d) 3- [2-benzyl-4-chlorophenyl] -2-propenenitrile

58.4 g (0.328 mole) of diethylcyanomethyl phosphonate was added dropwise to a suspension of 10.5 g (0.437 mole) of sodium hydride from which mineral oil was removed to 1.2 liter of tetrahydrofuran. When hydrogen evolution ceased (after about 60 minutes), a solution of 69.4 g (0.3 mol) of 2-benzyl-4-chlorobenzaldehyde was added dropwise to 75 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature. The tetrahydrofuran solution is decanted and concentrated at room temperature. The residue is treated with 2 liters of water and 1.5 liters of ether to separate the layers. The ether solution is separated, washed with water and dehydrated with sodium sulfate. The ether is removed under reduced pressure to give a yellow oil which is used without further purification.

e) 3- (2-benzoyl-4-chlorophenyl) -2-propennitrile

A mixture of 28.8 g (0.14 mol) of 3- [2-benzoyl-4-chloro phenyl] -2-propenenitrile, 50 g (0.5 mol) of chromium trioxide, 100 ml of methylene chloride and 300 ml of acetic acid is stirred overnight at room temperature. Excess chromium trioxide is neutralized by the slow addition of 30 ml of ethanol. To the mixture was added 800 ml of water, diluted and extracted with 500 ml of ether. The ether solution is washed successively with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The ether solution is dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give a yellow oil without further purification. A sample of the product was purified by preparative layer chromatography (SiO ₂ : 2 mm, 1: 1 methylene chloride: pentane) to give a white solid.

Melting Point: 87-89 ° C

Alternatively, 3- (2-benzoyl-4-chlorophenyl) -2-propennitrile can be prepared as follows.

d ') α, 4-dichloro-2- (benzoyl) -benzenepropenenitrile

A solution of 92.7 g (0.4 mol) of 2-amino-5-chlorobenzophenone in 250 ml of acetonitrile was added to 70 g (0.52 mol) of copper chloride, 65 g (0.63 mol) of t-butylnitrile, 500 ml of acrylonitrile, and 500 ml of acetonitrile. To the mixture. After all the addition, stirring is continued for 2 hours at room temperature. The mixture is diluted with 80 ml of 6N hydrochloric acid and 1500 ml of water, extracted with ether and then dehydrated with anhydrous sodium sulfate. The ether solution is concentrated under reduced pressure to give a brown oil containing the final product and 2,5-dichlorobenzophenone. The oil in which the mixture is present is treated with ether and petroleum ether to give the final product as a brown solid. A small amount of the final product was recrystallized from ether and petroleum ether to give a pale yellow acicular crystal.

Melting Point: 69-71 ° C

e ') 3- (2-benzoyl-4-chlorophenyl) -2-propenenitrile

50.9 g (0.168 mol) of 4-dichloro-2- (benzoyl) -benzenepropanenitrile, 17 g (0.14 mol) of potassium carbonate, 50.9 g (0.5 mol) of potassium bicarbonate and 510 ml of dimethyl sulfoxide are stirred at room temperature for 48 hours. . The mixture is diluted with 1.5 L of water and the resulting precipitate is collected by filtration. Recrystallization with a mixture of methylene chloride and ether gives an off-white columnar crystals.

Melting Point: 89 ~ 91 ℃

f) 4- [2-benzoyl-4-chlorophenyl] -1 H-pyrrolo-3-carbonitrile

A mixture of 10.7 g (40 mmol) 3- (2-benzoyl-4-chlorophenyl) -2-propennitrile, 5.3 g (38 mmol) tosylmethyl isocyanide, 75 ml of dimethyl sulfoxide and 150 ml of ether was added to the mineral oil. To a suspension of 3.7 g (77 mmol) of 50% sodium hydride and 170 ml of ether is added dropwise. Add all and continue stirring for 2 hours. The mixture is diluted with water and the ether layer is separated. The aqueous solution is extracted with ether. The combined ether extracts are washed with water, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give dark green oil. Purification by column chromatography (800 g of silica gel, eluting with 5% ether in methylene chloride) affords the final product as off-white columnar crystals.

Melting Point: 175 to 177 ° C

g) 8-chloro-6-phenyl-2H, 4H-pyrrolo [3,4-d] [2] benzazine

A mixture of 4.0 g (13 mmol) of 4- [2-benzoyl-4-chlorophenyl] -1H-pyrrole-3-carbonitrile, 4 g of Raney Nickel and 300 ml of acetic acid is hydrogenated in a parr apparatus for 4 hours. Raney Nickel is filtered off and the filtrate is diluted to 400 ml of water resistance. Acetic acid is neutralized with sodium bicarbonate and the resulting solution is extracted with methylene chloride. The methylene chloride solution is washed with water and dehydrated with sodium sulfate. The methylene chloride solution is concentrated to give a yellow solid. Recrystallization from methylene chloride / ether gives a white solid.

Melting Point: 203-206 ℃

Example 2

a) α, 4-dichloro-2- (2-fluorobenzoyl) -benzenepropanenitrile

The α, 4-dichloro-2- (2-fluorobenzoyl) -benzenepropanenitrile was converted into pale yellow columnar crystals in the same manner as in the preparation of α, 4-dichloro-2- (2-benzoyl) -benzenepropanenitrile. To obtain.

Melting Point: 94-95 ° C

b) 3- [2- (2-fluorobenzoyl) -4-chlorophenyl] -2-propenenitrile

3- [2- (2-fluorobenzoyl) -4-chlorophenyl] -2-propene was carried out in the same manner as in the preparation of 3- (2-benzoyl-4-chlorophenyl) -2-propenenitrile. Nitrile is obtained as off-white columnar crystals.

Melting point: 137-139 degreeC.

Alternatively, the compound may be prepared as follows.

b ') 3- [2- (2-fluorobenzoyl) -4-chlorophenyl] -2-propenenitrile

A mixture of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2-iodobenzophenone, 2 ml (14.3 mmol) of triethylamine, 2 ml (30 mmol) of acrylonitrile and 35 mg (1.5 mmol) of palladium acetate It is refluxed for 16 hours under argon stream. The mixture is diluted with 100 ml of 1N hydrochloric acid and the resulting precipitate is collected by filtration. The precipitate is washed with ether and air dried to give an off white solid.

Melting point: 130-133 degreeC.

c) 4- [2- (2-fluorobenzoyl) -4-chlorophenyl] -1 H-pyrrole-3-carbonitrile

4- [2- (2-fluorobenzoyl) -4-chlorophenyl] -1H by the same method as in the preparation of 4- [2-benzoyl-4-chlorophenyl] -1H-pyrrole-3-carbonitrile -Pyrrole-3-carbonitrile is obtained with an off-white prism.

Melting Point: 177 to 179 ° C

d) 8-chloro-6- (2-fluorophenyl) -2H, 4H-pyrrolo [3,4-d] [2] benzazine

A mixture of 3.0 g (9 mmol) of 4- [2- (2-fluorobenzoyl) -4-chlorophenyl] -1H-pyrrole-3-carbonitrile, about 3 g of raninickel and 150 ml of glacial acetic acid was added under 50 psi in a Parrer. Hydrogenate for 6 hours. The raninickel is filtered off and the acetic acid is removed under reduced pressure to give a yellow oil. Pour the yellow oil on ice and extract with ammonium hydroxide basic to Hanyo methylene chloride. The methylene chloride solution is dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give tan crystals. Recrystallization with a mixture of ether and methylene chloride gives a creamy columnar crystals.

Melting point: 197-199 degreeC.

Example 3

8-chloro-9- (2-fluorophenyl) -2H, 4H-pyrrolo [3,4-d] [2] benzazine methanesulfonate

The methanesulfonate salt of 8-chloro-6- (2-fluorophenyl) -2H, 4H-pyrrolo [3,4-d] [2] benzazine is an equivalent molar amount of benzazine and methanesulfur in methanol. Prepared by adding phonic acid and precipitating by adding ether to the resulting salt. The salts are recrystallized from a mixture of methanol and ether to give orange columnar crystals.

Melting point: 220-221 캜.

Example 4

a) α, 4-dichloro-2- (2-chlorobenzoyl) -benzenepropanenitrile

The gray-white columnar crystals of α, 4-dichloro-2- (2-chlorobenzoyl) -benzenepropanenitrile are obtained by the same method as in the preparation of α, 4-dichloro-2- (benzoyl) -benzenepropanenitrile.

Melting Point: 102-103 ° C

b) 3- [2- (2-chlorobenzoyl) -4-chlorophenyl] -2-propennitrile

3- [2- (2-chlorobenzoyl) -4-chlorophenyl] -2-propennitrile was carried out in the same manner as in the preparation of 3- (2-benzoyl-4-chlorophenyl) -2-propennitrile. The off-white columnar crystals of were obtained.

Melting point: 137-139 degreeC.

c) 4- [2- (2-chlorobenzoyl) -4-chlorophenyl] -1 H-pyrrole-3-carbonitrile

4- [2-benzoyl-4-chlorophenyl] -1H-pyrrole-3-carbonitrile was carried out in the same manner as in the preparation of 4- [2- (2-chlorobenzoyl) -4-chlorophenyl] -1H- An off-white columnar crystal of pyrrole-3-carbonitrile is obtained.

Melting point: 182 to 184 ° C.

d) 8-chloro-6- (2-chlorophenyl) -2H, 4H-pyrrolo- [3,4-d] [2] benzazine

8-Chloro-6- (2-fluorophenyl) -2H, 4H-pyrrolo- [3,4-d] [2] by the same method as in the preparation of benzazine, 8-chloro-6- ( A creamy columnar crystals of 2-chlorophenyl) -2H, 4H-pyrrolo- [3,4-d] [2] benzazine are obtained.

Melting point: 204-206 degreeC.

Example 5

8-chloro-6- (2-chlorophenyl) -2H, 4H-pyrrolo- [3,4-d] [2] benzazine methanesulfonate

The methanesulfonate salt of 8-chloro-6- (2-chlorophenyl) -2H, 4H-pyrrolo- [3,4-d] [2] benzazine is an equimolar amount of benzazine and methanesulphur in methanol. It is prepared by adding phonic acid and the resulting salt is precipitated by addition of ether.

Recrystallization with methanol and ether mixtures gives an orange columnar crystals.

Melting point: 239-241 degreeC.

Example 6

a) 4- [2- (2-fluorobenzoyl) -4-chlorophenyl] -5-methyl-1H-pyrrole-3-carbonitrile

34.5 g (121 mmol) 3- [2- (2-fluorobenzoyl) -4-chlorophenyl] -2-propenenitrile, 25.3 g (121 mmol) 1-tosylethyl isocyanide, 200 ml dimethyl sulfoxide and A mixture of 400 ml of ether is added dropwise to a suspension of 8.9 g (184 mmol) of 50% sodium hydride in mineral oil and 450 ml of ether. Add all and continue stirring for 2 hours. The mixture is diluted with water and the ether layer is separated. The aqueous solution is extracted with ether. The combined ether extracts are washed with water, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to give black oil. Crystallization with ether gives off-white crystals. A small amount of this crystal is recrystallized from a mixture of methylene chloride and ether to give colorless columnar crystals.

Melting point: 201 to 202 캜.

b) 8-chloro-6- (2-fluorophenyl) -1-methyl-2H, 4H-pyrrolo [3,4-d] [2] benzazine

8-Chloro-6- (2-fluorophenyl) -2H, 4H-pyrrolo [3,4-d] [2] by the same method as in the preparation of benzazine, 8-chloro-6- (2 Colorless columnar crystals of -fluorophenyl) -1-methyl-2H, 4H-pyrrolo [3,4-d] [2] benzazine are obtained.

Melting point: 226-227 degreeC.

Example 7

8-chloro-6- (2-fluorophenyl) -1-methyl-2H, 4H-pyrrolo [3,4-d] [2] benzazine methanesulfonate

8-Chloro-6- (2-fluorophenyl) -1-methyl-2H, 4H-pyrrolo [3,4-d] [2] benzazine methanesulfonate salts are equimolar amounts of And methanesulfonic acid are added and ether is added to precipitate and separate the salts. The salts are recrystallized from a mixture of methanol and ether to give orange columnar crystals.

Melting point: 259-261 degreeC.

Example 8

a) 4- [4-chloro-2- (2-fluorobenzoyl) phenyl] -5- (2-propenyl) -1 H-pyrrole-3-carbonitrile.

3.1 g (11 mmol) 3- [2- (2-fluorobenzoyl) -4-chlorophenyl] -2-propennitrile, 3.0 g (12 mmol) 1-tosyl-3-butenyl-isosia 50 ml of an ether mixture containing nitrite and 25 ml of dimethylsulfoxide is added dropwise to 100 ml of ether suspension with mineral oil suspended with 0.8 g (16.5 mmol) of 50% sodium hydride. After the addition, stirring is continued for 2 hours. The mixture is diluted with water and the ether layer is separated. The aqueous layer is extracted with ether. The combined ether extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give dark oil. Purification by column chromatography (silica, 150g, eluent 5% ether / methylene chloride) to give a colorless needle (melting point: 142 ~ 144 ℃). Recrystallization from a mixture of ether and petroleum ether gives colorless needles (melting point: 142 to 144 ° C).

[1) A.M. Van Leusen, R, J. Bouma and O. Possel, Tetrahedron Letters, 3487 (1975).

b) 8-chloro-6- (2-fluorophenyl) -1- (2-propenyl) -2H, 4H] -pyrrolo [3,4-d] [2] benzazine

0.7 g (2 mmol) 4- [4-chloro-2- (2-fluorobenzoyl) phenyl] -5- (2-propenyl) -1H-pyrrole-3-carbonitrile and 0.7 g (18 mmol) A mixture of 50 ml of tetrahydrofuran containing lithium aluminum hydride is stirred at room temperature for 48 hours. Excess lithium aluminum hydride is released by dropwise addition of a saturated aqueous solution of potassium sodium tartarate. The mixture was diluted with methylene chloride and the methylene chloride solution was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to produce a mixture with limited rotation, 4-aminomethyl-4- {4-chloro-2-[(2-fluorophenyl) hydride. Oxymethyl] phenyl} -2- (2-propenyl) -1H-pyrrole is obtained, which is supported by thin layer chromatography and its nmr spectrum.

150 mg (0.4 mmol) of 4-aminomethyl-4- {4-chloro-2-[(2-fluorophenyl) hydroxymethyl] phenyl} -2- (2-propenyl) -1H-pyrrole and 0.6 g A mixture of 30 ml tetrahydrofuran containing (7.3 mmol) manganese dioxide is refluxed for 2 hours. The mixture is cooled and filtered over celite. The filtrate is concentrated under reduced pressure to give a red oil. Purification by column chromatography (silica gel, 10 g, eluent, 5% ether dissolved in methylene chloride) affords the final product as a tan solid (melting point: 212 to 214 ° C). Recrystallization from a mixture of ether and methylene chloride yields colorless columnar crystals (melting point: 213-215 ° C.), which are identical in all respects to the real sample.

Example 9

8-chloro-6- (2-fluorophenyl) -1-methyl-2H, 4H-pyrrolo [3,4-d] [2] benzazine

1.0 g (3 mmol) 4- [4-chloro-3- (2-fluorobenzoyl) phenyl) -5-methyl-1H-pyrrole-3-carbonitrile and 1.0 g (26 mmol) lithium aluminum hydride The mixture of 100 ml of tetrahydrofuran containing was stirred at room temperature for 24 hours. Excess lithium aluminum hydride is released by dropwise addition of a saturated aqueous solution of potassium and sodium tartarate. The mixture was diluted with methylene chloride and the methylene chloride solution was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-aminomethyl-3- {4-chloro-2-[(2-fluorophenyl) hydroxymethyl] phenyl} 2-Methyl-1H-pyrrole is obtained as a mixture with limited rotation, which is supported by thin layer chromatography and its nmr spectrum.

150 mg (0.43 mmol) 4-aminomethyl-3- {4-chloro-2-[(2-fluorophenyl) hydroxymethyl] phenyl} -2-methyl-1H-pyrrole and 600 mg (7.3 mmol) manganese dioxide This mixture of 30 ml of tetrahydrofuran is refluxed for 2 hours. The mixture is cooled and filtered over celite. The filtrate is concentrated under reduced pressure to give a tan oil. Purification by column chromatography (silica gel, 10 g, 5% ether dissolved in eluent methylene chloride) gives a cream solid. Recrystallization from ether gives colorless needle crystals (melting point: 226 to 227 ° C), which are the same in all respects to the real sample.

Example 10

a) 4- [4-chloro-2- (2-chlorobenzoyl) phenyl] -5-methyl-1H-pyrrole-3-carbonitrile (product 1) and 6-chloro-8- (2-chlorophenyl)- 1,8-dihydro-8-hydroxy-2-methylideno [2, 1-b] pyrrole-3-carbonitrile (product 2)

20 g (0.96 mol) of 1-tosylethyl isocyanide and 33.9 g (0.11 mol) of 3- [2- (2-chlorobenzoyl) -4-chlorophenyl dissolved in 150 ml of dimethyl sulfoxide and 190 ml of ether mixture ] -2-propenenitrile mixture is added dropwise to a suspension of 4.6 g (0.1 mol) of 50% mineral oil dispersion of sodium hydride dissolved in 100 ml of ether immersed in a room temperature water bath. The mixture is stirred for 2 hours at room temperature, diluted with 1.21 ml of water and 40 ml of 1N hydrochloric acid and extracted with methylene chloride. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a dark green oil. Crystallization from a mixture of ether and petroleum ether yields product 1 (melting point; 206-208 ° C.) as tan crystals. Recrystallization in ether gives product 1 as colorless crystals with a melting point of 210 to 211 ° C.

A second mass of product, product 2 (melting point: 221-225 ° C.), is obtained from ether. Recrystallization from ether yields product 2 of pale yellow columnar crystals having a melting point of 232 to 237 ° C.

b) 8-chloro-6- (2-chlorophenyl) -1-methyl-2H, 4H-pyrrolo [3,4-d] [2] benzazine

55 psi Hydrogenation is carried out overnight on a parr device at a pressure of. The catalyst is removed by filtration and acetic acid is removed under reduced pressure. The residue is diluted with water, basified with ammonium hydroxide, and the precipitated filtrate is collected by filtration. The precipitate is dissolved in tetrahydrofuran, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue is crystallized from a mixture of ether and petroleum ether to give off-white crystals. Recrystallization with a mixture of ether and methylene chloride yields colorless crystals having a melting point of 221 to 225 ° C.

Example A

Tablet formulation (wet granules)

Way:

1. Mix the components 1 to 4 in a suitable mixer.

2. Add enough distilled water to granulate to proper density.

3. Dry in a suitable oven,

4. Grind and mix with magnesium stearate over 3 minutes.

5. Compress on a suitable compressor equipped with a suitable punch.

Example B

Tablet formulation (direct compression)

Way:

1. Mix ingredient 1 with the same amount of lactose. Mix well.

2. Mix with ingredients 3 and 4 and with the rest of ingredient 2. Mix well.

3. Add magnesium stearate and mix for 3 minutes.

4. Compress on a suitable compressor equipped with a suitable punch.

Example C

Capsule formulation

Way:

1. Grind the components 1,2,3 and 5 in a suitable mixer.

2. Add talc and mix well.

3. Fill the capsule in the appropriate device.

Claims (1)

A process for preparing pyrrolo [3,4-d] [2] -benzazine of formula (I) and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (B) is closed.

Wherein R ₁ is hydrogen, lower alkyl, C ₃ to C ₇ alkenyl or C ₃ to C ₇ alkynyl, R ₅ is halogen or hydrogen of up to 35 atomic number, and R ₆ is halogen of up to 35 atomic to be.