NO850454L - PROCEDURE FOR THE PREPARATION OF CARBZOLD DERIVATIVES - Google Patents

Description

The present invention relates to a new method by

production of 6-chloro-α-methylcarbazole-2-acetic acid, a known anti-inflammatory agent, and new intermediates in the production of these.

This method consists of

a) chlorination of a compound of the formula

where B?~ is hydrogen, acetyl or propionyl,

and either

b) treating a resulting compound of formula

where R''" is as defined above,

with a reducing agent,

c) acylation of the resulting compound 2-(1-hydroxyethyl)-6-chlorocarbazole, and

d) treating the resulting compound with formula

where R 2 is hydrogen, C^_^Q-alkyl, C 2_^Q-alkenyl,

C 1-7 cycloalkyl, aryl or a 5- or 6-membered

heterocyclic group,

with a substitution agent, or

e) reacting the compound of formula II, wherein R 1 is hydrogen, 2-acetyl-6-chlorocarbazole, with tosylmethyl isocyanide

in the presence of potassium t-butoxide, or

f) reacting 2-acetyl-6-chlorocarbazole with a tri-(straight-chain C 1-4 alkyl)-silyl cyanide, and g) treating the resulting compound with the formula

3 4 5

wherein R , R , and R are straight-chain C 1-3 alkyl groups,

with stannous chloride, and

h) hydrolyzing the product of process step d), e) or g), 2-(1-cyanoethyl)-6-chlorocarbazole.

The terms "alkyl" and "alkenyl" as used herein mean straight chain or branched groups such as isopropyl, butyl, t-butyl, neopentyl, pentyl or heptyl, and ethenyl, propenyl, butenyl, pentenyl, hexenyl, isopropenyl or isobutenyl. Cycloalkyl means cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. "Aryl" means an aromatic group without heteroatoms in the ring itself, i.e. phenyl or naphthyl, but optionally substituted with nitro, fluorine, chlorine, bromine,

iodo, alkoxy or alkyl, e.g. 4-ethylphenyl, 4-nitrophenyl, 4-chlorophenyl, 4-methoxyphenyl or 1-(3-methylnaphthyl). A "5- or 6-membered heterocyclic group" means an aromatic or non-aromatic group with up to 3, preferably 1 or 2 hetero atoms, e.g. pyridyl, pyrimidinyl, imida-

zolyl, furyl, thiazolyl, oxazolyl, isoxazolyl, pyrazinyl, piperidyl, tetrahydrofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, 1,2,4-triazinyl, benzimidazolyl or pyridazinyl, optionally substituted as described above for the aryl groups, e.g. e.g. 2-chloro-, 2-nitro- or 2-methoxypyridyl or 2-methyltetrahydrofuranyl. "Acyloxy" means an alkanoyloxy or aroyloxy group, or the residue of a heterocyclic carboxylic acid, e.g. formyloxy, acetoxy, propio-nyloxy, butyryloxy, valeryloxy, hexanoyloxy, octanoyloxy, decanoyloxy, benzoyloxy, 4-methylbenzoyloxy or 2-thienoyloxy.

The compounds of formula I are known or can be prepared analogously to known compounds. E.g. carbazole is reacted with propionyl anhydride or chloride in the presence of a base such as pyridine or lutidine at reflux temperature. The resulting 9-propionylcarbaol is reacted with acetyl chloride in the presence of a Friedel-Crafts reagent, e.g. anhydrous aluminum chloride to form 9^propionyl-2-acetylcarbazole.

In a preferred embodiment of the above-mentioned chlorination step a), 2-acetyl-9-propionylcarbazole or 2,9-diacetylcarbazole is reacted with sulfuryl chloride, sodium hypochlorite or trichloroisocyanuric acid, in a polar solvent such as acetic acid, triethyl phosphate, 1,2 -dichloroethane or dimethylformamide (DMF). Most preferably, this reaction is carried out with trichloroisocyanuric acid in DMF, at approx. 40 to 60°C, suitable at approx. 50°C, for approx. 2 to 10 hours. Under these conditions, little or no 3,6-dichloro compound is formed as a by-product.

In a further preferred embodiment of step a), 2-acetylcarbazole is chlorinated with 1-^chlorobenzotriazole in a polar solvent, such as methylene chloride or 1,2-dichloroethane at about room temperature for from 1 to 18 hours to form 2-acetyl-6- chlorocarbazole. More preferably, 2-acetylcarbazole is treated with trichloroisocyanuric acid in triethyl phosphate in the presence of a Lewis acid such as aluminum chloride, or suitable boron trifluoride etherate or fluoroboric acid, at approx. -10 to 25°C within 1 to 7 hours. 2-Acetyl-6-chlorocarbazole is recovered by evaporation of the solvent, treatment of the reaction mixture with sodium hydroxide to remove cyanuric acid, and crystallization of the product from a hot mixture of DMF and acetonitrile.

Alternatively, 2-acetyl-6-chlorocarbazole can be prepared by the hydrolysis of 6-chloro-2,9-diacetylcarbazole, e.g. with a base such as sodium or potassium hydroxide, in an alcohol such as ethanol or propanol, at reflux temperature.

The reduction step b) is preferably carried out with sodium borohydride alone or with concentrated sodium hydroxide. Other possible reducing agents are lithium aluminum hydride, lithium borohydride or diisobutylaluminum hydride. The reduction can be carried out in a solvent such as a lower alkanol, e.g. methanol, ethanol or propanol. The temperature of the reaction mixture is not critical. Preferably, the reduction is carried out using 10% sodium borohydride, based on the weight of the compound of formula II, in refluxing boiling ethanol. The resulting 2-(1-hydroxyethyl)-6-chlorocarbazole can be recovered by evaporation of the solvent, trituration of the resulting product with water and drying.

To achieve acylation step c), an acid chloride or a

2 2 acid anhydride derived from an acid R C(0)OH, in which R is as above, e.g. acetic anhydride, benzoyl chloride or the mixed anhydride of formic acid and acetic acid are used. The acylation is suitably carried out in the presence of a non-hydroxyl containing solvent, such as ethyl acetate, tetrahydrofuran, ether, dioxane, toluene or methylene chloride. An acylation catalyst can be used, e.g. in an amount of from approx. 0.05 to 5%, based on the weight of the reactants, although it is not necessary when the acylating agent is an acid chloride. Tertiary amine catalysts can suitably be used, e.g.

4-Dimethylaminopyridine. The temperature of the acylation reaction is not critical. The resulting compounds of formula III can be recovered from the reaction mixture by conventional means, such as by evaporation of the solvent and trituration of the residue with water.

Preferred compounds of formula III are those in which R 2 is alkyl, phenyl or substituted phenyl. Examples of compounds of formula III are 2-(1-acetoxyethyl)-, 2-(1-benzoyloxyethyl)- and 2-(1-formoxyethyl)-6-chlorocarbazole.

The reaction step d) can be carried out using an exchange agent such as an alkali metal cyanide, e.g. potassium, lithium or sodium cyanide, in a polar aprotic solvent, such as dimethylsulfoxide (DMSO), DMF, N-methyl-pyrrolidone, sulfolane or hexamethylphosphoramide, at a temperature in the range from approx. 100 to 200°C, preferably at about 125-155°C, provided the temperature does not exceed the decomposition temperature of the solvent (about 135°C for DMSO). The most preferred reaction temperature in DMSO is from 125-135°C, and in DMF the reflux temperature. DMSO is preferred when sodium cyanide is used, and DMF when lithium cyanide is used. The reaction is carried out under essentially anhydrous conditions to avoid unwanted formation of the corresponding alcohol, i.e. 2-(1-hydroxyethyl)-6-chlorocarbazole. This can usually be achieved by drying the solvent and the alkali metal cyanide before the reaction and carrying out the reaction"under an inert atmosphere, e.g. under nitrogen or argon.

The reaction step e) is conveniently carried out at room temperature in DMSO. The resulting 2-(1-cyanoethyl)-6-chlorocarbazole can be recovered by conventional means, such as by filtration and recrystallization. However, it is not necessary to isolate this compound before it is converted to 6-chloro-a-methyl-carbazole-2-acetic acid, provided that the solvent is removed by stripping and replaced by a solvent suitable for the hydrolysis, i.e. a polar solvent, such as water, ethylene glycol, water and ethylene glycol or water and methanol.

The hydrolysis step h) can either be acid-catalyzed, e.g. by sulfuric or hydrochloric acid, or base-catalyzed, e.g. with aqueous sodium hydroxide in an alcohol, such as methanol, or ethylene glycol. The temperature is not critical, and the reaction progresses satisfactorily at a temperature from approx. 50 to 80°C.

After hydrolysis, 6-chloro-α-methylcarbazole-2-acetic acid can be recovered by conventional means, e.g. by removing the solvent by vacuum distillation, dilution with water, and in the case of base hydrolysis by acidification, filtration, washing and drying. The product thus obtained can be purified by precipitation from an organic solvent, preferably acetone, in the form of a salt with an organic base, such as a tri-alkylamine, e.g. trimethyl-, tripropyl-, tributyl-, triiso-butyl- or preferably triethylamine, and then washing, drying and converting the product back to the acid by acid

ring with hydrochloric acid. The product can also be recrystallized, either as the salt or the acid, from an organic solvent such as methanol/ethyl acetate in the case of the salt or ethyl acetyl/toluene in the case of the acid.

The reaction step f) is conveniently carried out in chloroform in the presence of a catalytic amount of a Lewis acid, e.g. a zinc halide, ie zinc fluoride, chloride, bromide or preferably iodide, suitably at the reflux temperature of the reaction mixture and under an inert atmosphere, e.g. under nitrogen or argon.

The resulting 6-chloro-α-methyl-α-tri(straight-chain C^_^-alkyl)-silyloxy-9H-carbazole-2-acetonitrile of formula IV, e.g. 6-Chloro-α-methyl-α-trimethylsilyloxy-9H-carbazole-2-acetonitrile is unstable and has a marked tendency to revert to the starting ketone. Consequently, it is appropriate to convert the nitrile in situ to 2-(1-cyanoethyl)-6-chlorocarbazole, which in turn is converted in situ to 6-chloro-α-methylcarbazole-2-acetic acid. This can be achieved by using stannous chloride in a mixture of hydrochloric acid and acetic acid.

Alternatively, 6-chloro-α-methyl-α-tri (C 1 -alkyl)-silyl-oxy-9H-carbazole-2-acetonitrile can be converted to 2-(1-cyanoethyl)-6-chlorocarbazole by avoiding hydrolytic conditions under the reduction with stannous chloride, e.g. by quenching the reaction mixture with a solution of sodium bicarbonate and separating the organic layer for work-up. The resulting compound can then be converted to 6-chloro-α-methyl-carbazole-2-acetic acid as described above.

The present invention relates to compounds with formulas II, III and IV as described above, i.e. with formula

where R is hydrogen, acetyl or propionyl, and Q is acetyl; or R is hydrogen and Q is C(H,CH^)OC(0)R<2>or C(CN,CH3)OSi(R<3>,R<4>,R<5>), where R is hydrogen, C-^_-^Q-alkyl, C2_-^Q-alkenyl, C. 7-cycloalkyl, aryl or a 5- or 6-membered 3 4 5 heterocyclic group, and R , R , and R are straight chain C- ^_ 4-alkyl groups.

EXAMPLE 1

100.00 g of 2-acetyl-6-chlorocarbazole, 10.00 g of powdered sodium borohydride and 1000 ml of ethanol were heated and stirring was initiated. After 1 hour, during which 650 ml of ethanol was recovered by stirring, 2000 ml of hot water was added gradually to the hot slurry and stirring was continued for 10 minutes. After cooling, the product was collected by filtration, washed with water and dried. The resulting 2-(1-hydroxyethyl)-6-chlorocarbazole, which was obtained in approximately 100% yield, was a colorless crystalline solid weighing 101.3 g, m.p. 190-198°C.

EXAMPLE 2

101.3 g of the product of Example 1, 1000 ml of ethyl acetate, 100 ml of acetic anhydride and 0.50 g of 4-dimethylaminopyridine were heated on a steam bath with periodic swirling until a clear solution was formed. The steam was turned off and the solution was allowed to stand for 3 hours. The solvent was removed under reduced pressure leaving a solid residue of crude acetate and yielding 936 mL of recovered ethyl acetate, which contained acetic acid and acetic anhydride as impurities. The product was triturated with 500 ml of water, collected, washed on a filter and dried. The resulting 2-(1-acetoxyethyl)-6-chlorocarbazole, which was obtained in 98.5% yield, was a colorless crystalline solid weighing 116.35 g, m.p. 140-145°C.

EXAMPLE 3

116.35 g of the product from Example 2, 116.35 g of dry sodium cyanide and 750 ml of dry DMSO were stirred and heated under argon in an oil bath. With a bath temperature of 97°C and a pressure of 2.5 mm Hg, approx. 75 ml of DMSO distilled off. Argon was introduced into the apparatus. The bath temperature was increased to 130-132°C and the reaction continued with stirring for 9 1/2 hours. 710 mL of DMSO was recovered by vacuum distillation. The oil bath was removed and the reaction was quenched by adding 500 g of ice and 500 ml of cold water. The resulting mixture was stirred overnight. The product was collected by filter-

ring and washed with water, and then dried for 3 hours to give 121 g of 2-(1-cyano-ethyl)-6-chlorocarbazole, as a moist pale yellow solid, m.p. 117-130°C.

EXAMPLE 4

To a stirred suspension of 740 ml of anhydrous DMF and 6.36 g of lithium hydride under argon was carefully added 68.0 g of acetone cyanohydrin. The mixture was stirred at 50°C for 2 hours, treated with 115.08 g of 2-(1-acetoxyethyl)-6-chlorocarbazole and refluxed for 5 hours. The solvent was then removed in vacuo at 90°C. 1.0 L of hot water was added to the residue and the resulting lumps were broken up by stirring. The product was collected by filtration, washed with 2.0 L of water and sucked dry to give 111.8 g of 2-(1-cyanoethyl)-6-chlorocarbazole as a golden brown colored solid of 88% purity.

EXAMPLE 5

121 g of the product from example 3, 100 g of sodium hydroxide and 1000 ml of ethylene glycol were heated and stirred under argon for 2 1/2 hours in an oil bath at 180-185°C. Then 530 ml of the ethylene glycol was distilled off under vacuum. 500 g of ice and 500 ml of water were added to the remaining mixture. The resulting solution was acidified with 300 ml of concentrated hydrochloric acid. After stirring, the product was 6-chloro-a-methyl-carbazole-2-acetic acid, collected by filtration and washed with 500 ml of water. After drying, 130.3 g of gray powder was obtained, which contains 87% by weight of this acid (moisture and inorganic salts not included).

EXAMPLE 6

A mixture of 5 ml of concentrated hydrochloric acid, 10 ml of glacial acetic acid, 5 ml of water and 1.00 g of 2-(1-cyanoethyl)-6-chlorocarbazole was refluxed overnight. The resulting solution was allowed to cool to room temperature and stirred for 24 hours. Filtration followed by washing with water and vacuum drying gave 0.88 g of 6-chloro-α-methylcarbazole-2-acetic acid (95%) in 82% yield.

EXAMPLE 7

The product in Example 5 was dissolved in 750 ml of acetone and the solution was dried by adding 20 g of anhydrous sodium sulphate. The solution was filtered and the filter cake was washed with 50 ml of acetone, 75 ml of triethylamine was then added to the filtrate. When crystallization of the salt began, the mixture was stored in the cold overnight. The salt was collected by filtration, washed with acetone and dried for several hours to give 118.73 g (77%<1>ig yield) of the triethylamine salt of 6-chloro-α-methylcarbazole-2-acetic acid as colorless crystals. The salt was dissolved in 400 ml of methanol and the solution acidified with 110 ml of 3N hydrochloric acid. The resulting solution was diluted to 1800 ml with hot water, cooled and filtered. The resulting product was collected, washed with water and dried to give 89.2 g of colorless solid, containing 99.0% of the desired product. This material was recrystallized by dissolving in 700 ml of ether and 300 ml of toluene, decolorizing with 10 g of charcoal and concentrating to approx. 250 ml when boiling. After storage in the cold, the crystals were collected and washed with 200 ml of toluene. The product was dried in vacuo to give 77.4 g of colorless, crystalline 6-chloro-c-methylcarbazole-2-acetic acid, contaminated with a small amount of triethylamine hydrochloride. To remove this, the material was dissolved in 225 ml of hot methanol and precipitated by the gradual addition of 1400 ml of water. The product was collected, washed with water and dried to give 75.9 g of 6-chloro-α-methylcarbazole-2-acetic acid as a colorless powder with a melting point of 185-188°C and a purity of 99.4%.

EXAMPLE 8

5.0 g of crude 6-chloro-a-methylcarbazole-2-acetic acid, 25 ml of acetone and 5.0 ml of tributylamine were mixed and stirred for 5 minutes and then allowed to stand at room temperature. The mixture was then refrigerated at 0°C. The resulting salt was filtered, washed with acetone and dried to give 7.38 g of the tributylamine salt: of 6-chloro-α-methylcarbazole-2-acetic acid. This salt is converted back to the acid by treatment with methanol and hydrochloric acid, and recrystallization in accordance with

the procedure in example 7.

EXAMPLE 9

157.0 g of 2-(1-acetoxyethyl)-6-chlorocarbazole, 78.5 g of dry sodium cyanide and 790 ml of dry DMSO were heated with stirring at 100°C under a vacuum of 2 mm Hg. After 80 mL of DMSO was distilled and collected, the mixture was kept under 1 atmosphere of argon at 130°C for 10 hours with stirring. The remainder of the DMSO<1> was recovered by distillation under vacuum. The rest was allowed to cool. 120 g of sodium hydroxide pellets, 100 ml of methanol and 200 ml of water were added. The temperature was raised to 115°C as the mixture was brought to reflux. Reflux treatment with stirring in an argon atmosphere was continued for 24 hours. Then 930 ml of methanol was recovered by distillation. The residue was allowed to cool to room temperature and diluted with 1500 ml of water. The mixture was acidified by adding 380 ml of concentrated hydrochloric acid. 500 ml of ethyl acetate was added to the resulting slurry and stirring was continued until a two-phase solution had formed. The bath temperature was raised to 35°C. 440 ml of ethyl acetate were recovered by vacuum distillation with stirring. The product, 6-chloro-α-methylcarbazole-2-acetic acid, was separated in granular form. After stirring for 1 hour at room temperature, the product was collected by filtration, washed with water and dried. The product yield was 178.8 g obtained as light green granules.

EXAMPLE 10

A mixture of 10.0 g of 2-(1-hydroxyethyl)-6-chlorocarbazole,

50 ml of pyridine, 8.25 g of benzoyl chloride and 30 mg of 4-dimethylaminopyridine were stirred for 2 hours. The solvent was evaporated under reduced pressure. The residue was triturated in 800 ml of cold water and the product was filtered. After washing with water, the filter cake was dried overnight to give 15.75 g of an off-white powder slightly moist with pyridine. Recrystallization from ether/hexane gave 11.55 g (88%) of 2-(1-benzoyloxyethyl)-6-chlorocarbazole as a colorless crystalline solid.

EXAMPLE 11

A mixture of 10.0 g of 2-(1-benzoyloxyethyl)-6-chlorocarbazole, 10.0 g of dry sodium cyanide and 75 ml of dry DMSO was heated in an oil bath with stirring. The pressure inside the system was reduced to 5 mm Hg. At 90°C, 20 ml of DMSO was distilled and collected. The bath temperature was raised to 128-130°C under argon (1 atm.) and the mixture was stirred for 2 hours. The oil bath was allowed to cool to 100°C and vacuum was applied until the pressure reached 1 mm Hg. The DMSO was allowed to distill off. The bottle was cooled to room temperature. 100 ml of hot water was added to the residue and the mixture was stirred for several hours. The product was collected by filtration, washed with hot water and dried to give 7.0 g of 2-(1-cyanoethyl)-6-chlorocarbazole as a yellow powder.

EXAMPLE 12

A mixture of 5.0 g of 2-(1-hydroxyethyl)-6-chlorocarbazole, 50 ml of ethyl acetate, 6 ml of acetic formic anhydride and 50 ml of 4-dimethylaminopyridine was heated on a steam bath with swirling. The solution was then allowed to stand at room temperature. Evaporation of the solvent gave a solid residue of raw for-food. This was dissolved in water and filtered. The filter cake was washed with water and dried. 2-(1-formyloxyethyl)-6-chlorocarbazole was obtained as a beige colored powder in a yield of 98.5%.

EXAMPLE 13

5.0 g of 2-(1-formyloxyethyl)-6-chlorocarbazole, 5.0 g of sodium cyanide and 40 ml of DMSO were reacted in the same manner as described in example 3. 80% of 2-(1-cyanoethyl)- 6-Chlorocarbazole.

EXAMPLE 14

To a stirred solution of 5.2 g of 2-acetyl-6-chlorocarbazole i

To 35 ml of chloroform, 5.08 g of trimethylsilyl cyanide and 150 mg of zinc iodide were added under argon. The mixture was refluxed, treated with an additional 2.5 g trimethylsilyl cyanide and 150 mg zinc iodide. Boiling was continued for 18 hours. The mixture was cooled to room temperature, passed through silica gel and evaporated to give 6.1 g (83% yield) of 6-chloro-α-methyl-α-trimethylsilyloxy-9H-carbazole-2-acetonitrile. Part of this was purified by chromatography on silica gel with 4% methylene chloride in acetone and gave a solid, which was crystallized from methylene chloride-hexene, m.p. 151-154°C.

EXAMPLE 15

171 mg of 6-chloro-α-methyl-trimethylsilyloxy-9H-carbazole-2-acetonitrile and 5 ml of acetic acid were stirred at room temperature under nitrogen. To the resulting solution was added 450

mg of stannous chloride dihydrate followed by 1 ml of hydrochloric acid. The mixture was stirred at room temperature, then poured into 150 ml of saturated sodium bicarbonate and extracted with 100 ml of ethyl acetate. The organic layer was washed with brine, dried, filtered and concentrated to dryness. The resulting pro-

product is a mixture of a small amount of 6-chloro-α-methyl-α-hydroxy-9H-carbazole-2-acetonitrile and a larger amount of 2-(1-cyanoethyl)-6-chlorocarbazole.

EXAMPLE 16

A mixture of 1.71 g of the crude 6-chloro-α-methyl-2-trimethylsilyloxy-9H-carbazole-2-acetonitrile obtained in Example 14, 2.25 g of stannous chloride dihydrate and 10 ml of acetic acid was stirred under nitrogen for 10 minutes, treated with 20 ml of concentrated hydrochloric acid, stirred at 25°C for 18 hours and then at 100°C for 2 1/2 hours. It was concentrated in vacuo, diluted

net with 40 ml of water and extracted with 100 ml of ethyl acetate. The extract was evaporated and the residue basified with 40 ml of 3N sodium hydroxide. After extraction with 80 ml of methylene chloride, the aqueous layer was acidified with concentrated hydrochloric acid and extracted with 100 ml of ethyl acetate. The extract was washed with 50 ml of saturated salt solution and stirred with anhydrous magnesium sulfate and 1 g of charcoal. The mixture was filtered and the filtrate was evaporated to give 1.35 g of 6-chloro-α-methylcarbazole-2-acetic acid as a pale gray solid.

EXAMPLE 17

31.0 g of potassium butoxide was added to a stirred solution of 19.52 g of tosylmethyl isocyanide in 150 ml of DMSO while cooling in an ice bath. The mixture was stirred for 5 minutes, then 2.50 ml of methanol was added. After stirring for an additional 5 minutes, 12.15 g of 2-acetyl-6-chlorocarbazole was added, and the resulting solution was stirred at room temperature. 150 ml of water, 28 ml of concentrated hydrochloric acid and 100 ml of methylene chloride were added and the resulting 2-phase system was stirred for 5 minutes. The methylene chloride layer was separated and washed with a saturated sodium bicarbonate solution and with water. The methylene chloride was evaporated under reduced pressure. The remaining solid was triturated with 200 ml of toluene and the toluene was evaporated under reduced pressure. The residue was dissolved in 121 ml of toluene under reflux. 121 ml of hexane was added at reflux and the mixture was filtered. The toluene/hexane solution was cooled to -10°C under stirring for 0.5 hours. Filtration of the resulting solid gave 6.6 g of 2-(1-cyanoethyl)-6-chlorocarbazole in 53% yield.

EXAMPLE 18

263 g of 2,9-diacetylcarbazole was treated with 700 ml of DMF. 100 g of trichloroisocyanuric acid was added in small portions with constant swirling. The temperature was not allowed to exceed 40°C. The resulting solution was stirred for 1 hour and then a stream of hydrochloric acid gas was passed into the air over the solution for 2 minutes. The solution was cooled in a water bath, stirred at room temperature and then cooled for 3 hours. Separation of the product by suction filtration was carried out in a cold room. The filtrate was used to clean all the solids and the filter cake was pressed free of DMF. The product was taken up in 1000 ml of hot acetic acid and filtered. The solid was washed with 50 ml of hot acetic acid. The filtrate and washing liquid were left at room temperature. The product crystallized out, was filtered, washed with 150 ml of acetic acid and dried to give 159.38 g of 6-chloro-2,9-diacetylcarbazole as pale yellow crystals, m.p. 154-158°C.

EXAMPLE 19

A mixture of 159.38 g of recrystallized 6-chloro-2,9-diacetylcarbazole, 1600 ml of ethanol and 100 ml of a 4.4 M solution of sodium borohydride in 14 N sodium hydroxide was heated to reflux. 1320 ml of the ethanol used was recovered by distillation. The residue was slurried in 2500 ml of hot water and allowed to stand overnight. The product was filtered and washed with water, until the washing liquids were neutral. The product was pressed dry and dried at 70°C. The result was 134.3 g (98%) of 2-(1-hydroxyethyl)-6-chlorocarbazole as a colorless powder, m.p. 194-198°C.

EXAMPLE 20

A mixture of 1 L of anhydrous triethyl phosphate and 52.25 g of 2-acetylcarbazole was heated under nitrogen with stirring. The resulting solution was cooled to room temperature, treated with 1.5 ml of 48% anhydrous hydrofluoric acid and cooled to 5°C. 21.6 g of trichloroisocyanuric acid in 250 ml of anhydrous triethyl phosphate was then added dropwise. The mixture was stirred at 5°C for 1 hour and at room temperature for 3 hours, it was then concentrated in vacuo on a steam bath. To the residue was added 1 liter of 1N sodium hydroxide while stirring. The product was filtered, washed with water and dried to give 61 g of 2-acetyl-6-chlorocarbazole. This was dissolved in 110 ml of DMF at 130°C and treated with charcoal. The mixture was filtered and the filter cake was washed with 30 ml of DMF. The filtrate and the washing liquid were heated with stirring. 280 ml of hot acetonitrile was added to the solution obtained. The mixture was stirred until it reached room temperature, then cooled to 10°C. The product was filtered, washed with acetonitrile and dried in vacuo at 90°C to give 41.7 g of 2-acetyl-6-chlorocarbazole as yellow crystals, m.p. 250-251^0.

EXAMPLE'21

A mixture of 52.25 g of 2-acetylcarbazole in 1 liter of anhydrous triethyl phosphate was stirred and heated under nitrogen, then cooled to 5°C and treated with 5 ml of boron trifluoride etherate.

The mixture was stirred for 15 minutes and treated dropwise with a solution of 22 g of trichloroisocyanuric acid in 250 ml of water

o

free triethyl phosphate. The mixture was stirred at 0-5°C for 1 hour and at room temperature for 4 hours. It was then evaporated in vacuo on a steam bath to recover 0.9 L of triethyl phosphate. To the resulting slurry was added 600 ml of water at 60°C and the mixture was stirred for 20 minutes and filtered. The product was washed successively with water, IN sodium hydroxide and water. The product was dried in vacuo at 90°C and gave 55.6 g of 2-acetyl-6-chlorocarbazole. This was suspended in 110 ml of DMF and treated with stirring. To the hot solution was added 220 ml of hot acetonitrile. The solution was allowed to cool, with stirring, to room temperature, then to 10°C, and filtered. The product was washed with acetonitrile at 0°C and dried in vacuo at 80°C to give 4 2.1 g of 2-acetyl-6-chlorocarbazole as yellow crystals, m.p. 249-251°C.

Claims (6)

1. Process for the production of 6-chloro-a-methyl-carbazole-2-acetic acid, characterized by a) chlorination of a compound with the formula where R"*" is hydrogen, acetyl or propionyl, and either b) treating a resulting compound of formula where R"*" is as defined above, with a reducing agent, c) acylation of the resulting compound 2-(1-hydroxyethyl)-6-chlorocarbazole, and d) treating the resulting compound with formula where R 2 is hydrogen, C1_1Q -alkyl, C2_10 -alkenyl, C1_7~ cycloalkyl, aryl or a 5- or 6-membered heterocyclic group, with a substitution agent, or e) reacting the compound of formula II, wherein R"<*>" is hydrogen, 2-acetyl-6-chlorocarbazole, with tosylmethyl isocyanide in the presence of potassium t-butoxide, or f) reacting 2-acetyl-6-chlorocarbazole with a tri-(straight-chain C 1 -4 alkyl)silyl cyanide, and g)" treatment of the resulting compound with formula in which R 3 , R 4 and R 5 are straight-chain C1 _4~ alkyl groups, with stannous chloride, and h) hydrolyzing product of process step d), e) or g), 2-(1-cyanoethyl)-6-chlorocarbazole. 2. Procedure for the preparation of a compound of formula wherein R"*" is hydrogen, acetyl or propionyl, characterized by either a) reacting 2,9-diacetyl- or 2-acetyl-9-propionyl-carbazole with trichloroisocyanuric acid, sulfonyl chloride or sodium hypochlorite in a polar solvent selected from dimethylformamide, 1,2-dichloroethane and triethyl phosphate, and b) reacting 2-acetylcarbazole with 1-chlorobenzotriazole or trichloroisocyanuric acid in a polar solvent selected from methylene chloride and 1,2-dichloroethane. 3. Process for the production of 2-(1-cyanoethyl)-6-chlorocarbazole, characterized by entena) reacting a compound with the formula wherein R 2 is hydrogen, C 10 -alkyl, C 2 -10 alkenyl, C 1 -cycloalkyl, aryl or a 5- or 6-membered heterocyclic group, with an alkali metal cyanide under substantially anhydrous conditions in a polar aprotic solvent, or b) reacting 2-acetyl-6-chlorocarbazole with toslylmethyl isocyanide in the presence of potassium t-butoxide in one inert atmosphere. 4. Procedure for the preparation of a compound with the formula wherein R 3 , R 4 and R 5 are straight-chain C-^_^-alkyl groups, characterized by reacting 2-acetyl-6-chlorocarbazole with a tri-(straight-chain C^ _^ -alkyl)-silyl cyanide and a Lewis -acid in a polar aprotic solvent under an inert atmosphere. 5. Connection with formula wherein R is hydrogen, acetyl or propionyl, and Q is acetyl; or R is hydrogen and Q is C(H,CH3 )0C(0)R <2> or C(CN,CH3 )OSi(R <3> ,R <4> ,R <5> ), in which R<2> is hydrogen, C^_10~ alkyl, C^-^-alkenyl, C. --cycloalkyl, aryl or a 5- or 6-membered heterocyclic group, and R 3 , R 4 and R 5 are straight-chain C 1 -alkyl groups. 6. Compound according to claim 5, selected from the group consisting of 2-acetyl-, 2,9-diacetyl-, 2-acetyl-9-propionyl-, 2-(1-acetoxyethyl)-, 2-(1-benzoyloxyethyl) )- and 2-(1-formoxyethyl)-6-chlorocarbazole and 6-chloro-α-methyl-α-trimethyl-silyloxy-9H-carbazole-2-acetonitrile.