CZ2008352A3 - Process for preparing cycloalkanecarbonitrile - Google Patents

Abstract

A process for preparing a cycloalkanecarbonitrile of formula (I) wherein n is an integer from 1 to 5 wherein 1- (2-acyl- or 1- (2-alkoxycarbonylhydrazino) cycloalkanecarbonitrile of formula (II) wherein R is hydrogen, methyl, ethyl an isopropyl group, a phenyl group, a methoxy group, an ethoxy group, or an isopropyloxy group, and n is an integer of 1 to 5, oxidized in a solvent at a temperature of 20 to 65 degC in basic pH 8-10 using an alkali metal hypochlorite oxidation system and / or an alkaline earth hypochlorite or an oxygenated oxidizing agent selected from oxygen, air, hydrogen peroxide or its mono- or disubstituted alkyl or aryl derivatives, the inorganic or organic acid peroxoderivative salt, and used in the presence of a catalytic oxidation-reduction system of the transition metal compound in the oxidation steps of M.sup.p.n. and M.sup.p-1.n., where the coefficient p takes the values +2 and +3.

Description

Technical field

The invention relates to a process for the preparation of a cycloalkanecarbonitrile of the formula I

CH ₂

(I) wherein n is an integer from 1 to 5.

BACKGROUND OF THE INVENTION

Cycloalkanecarbonitriles having four to eight carbon atoms in the cycloalkane ring are important intermediates for the pharmaceutical manufacture of certain drugs. Methods of preparation suitable for industrial use providing these compounds in adequate yield and purity are not as simple as evidenced by more than 100 original publications and patents.

Cyclohexanecarbonitrile is either accessible by multistage synthetic processes with high economic and environmental burden, very often using difficult-to-use compounds in industry, or in one synthetic step by radical reaction of cyclohexane with cyanogen chloride, hydrogen cyanide or tetraethylammonium cyanide (DE 848947 (1951), Tetrahedron 50, 47 (1994)), which in addition results from the low selectivity of the reaction of the product mixture and the process is subject to a number of other risks in addition to the large amount of waste.

Gas-phase catalytic hydrogenation at temperatures around 160 ° C on cyclohex-2-enecarbonitrile, cyclohex-1-enecarbonitrile (J. Amer. Chem. Soc. 77, 4571 (1955), Chem. Eur. J. 4, 1074 (1988)) , cyclopent-2-enecarbonitrile (J. Prakt. Chem. 330, 484 (1988)), their marrow periods (US3766237 (1973)) and the like, while providing the target product in good yield (60-70%) but accompanying impurities - cyclohexene carbonitriles, resp.

cyclohexadiene carbonitriles, and the like are complicated to separate and accompany cycloalkanecarbonitrile in other pharmaceutical syntheses to the final drug, where the impurities produced exhibit negative pharmacological effects. Similar disadvantages to the use of special catalysts are also provided by the catalytic hydrocyanation of cyclohexene (U.S. Pat

3496217 (1970).

Nucleophilic substitution of halogen or other leaving group in substituted cycloalkanes also provides the target product, but its yield is not significant due to the predominant competitive elimination or subsequent reactions (J. Amer. Chem. Soc. 73, 5034 (1950)).

Unsuitable methods for the production of cycloalkanecarbonitriles, especially from the point of view of the availability of starting materials and further burdening the process mainly with saline wastes, are dehydration of functional derivatives of cycloalkanecarboxylic acids (amides, carbaldehyde oximes, etc.) - Synt. Lett. 13, 2089 (2005).

Conversely, the known method of literature (Organic Syntheses, Coll. Vol. 6, p. 334 (1988); Vol. 58, p. 101 (1978)) described for the synthesis of cyclohexanecarbonitrile has proven suitable for the preparation of cyclohexanecarbonitrile. This is a synthesis sequence starting from cyclohexanone which, with acylhydrazine, provides the corresponding hydrazone in the methanol solution at the boiling point of the solvent. This is further converted to 1- (2-acylhydrazino) cyclohexanecarbonitrile by addition of hydrogen cyanide at 0 ° C, which is isolated in 97% yield and subsequently oxidized with bromine in excess at 25 ° C in a biphasic dichloromethane / saturated aqueous sodium bicarbonate solution to 1- (acyldiazenyl). After subsequent basic deacylation with sodium methoxide in methanol solution and cleavage of molecular nitrogen, a target product is formed at 0-10 ° C for about 30 minutes, which after separation into pentane and fractional distillation is However, the disadvantage of the described method is, from the technological point of view, the isolation of intermediates, the use of different types of solvents, the wide range of reaction temperatures, the ecological risk of using dichloromethane as solvent and the general risk and cost of using elemental bromine as an oxidant. Although it is stated that oxidizing agents such as tert-butyl hypochlorite, 4-phenyl-4H-1,2,4-triazole-3,5-dione and Jones reagent may be used instead of bromine, however, their application on an industrial scale is also irrelevant.

Another universal method is the anodic oxidation of 1- (2-acylhydrazino) cycloalkanecarbonitriles described in J. Org. Chem., 55, 1070 (1990) .The disadvantage of the industrial use of anodic oxidation, which takes place in methanol with cooling to 17 ° C, is sodium cyanide. the anode is platinum electrode, current flow approx. 0.5 A, substrate concentration approx. 0.5 mol / l are relatively low yields of cycloalkanecarbonitriles (approx. 60 '80%) at long reaction time (tens of hours) and formation of hydrogen cyanides or dicyanides .

It is an object of the invention to substantially eliminate the aforementioned drawbacks of the prior art.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of a cycloalkanecarbonitrile of formula (I)

CH ₂ ------ (CH ₂ ),

CN

(I) wherein n is an integer from 1 to 5, characterized in that the sc 1- (2-acyl- or 1- (2-alkoxycarbonylhydrazino) cycloalkanecarbonitrile of the general formula II

R a NH / HN

CH ₂ ----- c

CH ₂ ----- (CH ₂ ) _n (II) wherein R is hydrogen, methyl, ethyl, isopropyl, phenyl, methoxy, ethoxy, or isopropyloxy and n is an integer from 1 to 5, oxidized in the solvent at a temperature of 20 to 65 ° C in a basic pH of 8 to 10 using an oxidation system consisting of an alkali metal hypochlorite and / or an alkaline earth metal hypochlorite or an oxygen oxidant selected from oxygen, air, hydrogen peroxide or its mono - or disubstituted alkyl or aryl derivatives, an inorganic or organic acid salt derivative and used in the presence of a catalytic redox system consisting of a transition metal compound coexisting in the oxidation stages M ^p and M ^p '', where the coefficient p is +2 and +3 .

Preferably, the reaction mixture obtained by reacting the corresponding cycloalkanone and 1-acylhydrazine and hydrogen cyanide is used as the starting 1- (2-acyl- or 1- (2-alkoxycarbonylhydrazino) cycloalkanecarbonittil (II).

Preferably 1- (2-methoxycarbonylhydrazino) cycloalkanecarbonitrile is used as the 1- (2-alkoxycarbonylhydrazino) cycloalkanecarbonitrile of formula II.

Preferably, the solvent used is an aliphatic alcohol having 1 to 3 carbon atoms, optionally in admixture with water.

Preferably, methanol is used as the solvent, optionally in admixture with water.

Preferably, air is used as the oxygen oxidizing agent.

Preferably, a copper compound in the Cu ²⁺ oxidation stage is used as the transition metal compound coexisting in the oxidation stages M ^p and M ^p '*.

Preferably, the transition metal compound as the coexistent in oxidation states M ^p and ^{Μ ρ-1} tetraammin cupric chloride is used.

Preferably, a copper cation complex immobilized on a cation exchanger is used as the transition metal compound coexisting in the oxidation steps ^Mp and ^Mp '*.

Preferably, the transition metal compound as the coexistent in oxidation states M ^p and M ^p 'is used tetrahalogenoměďnatého complex anion, wherein the halogen is chlorine and / or bromine, immobilized on an anion exchanger.

The process for the preparation of the cycloalkanecarbonitriles according to the invention avoids or prevents the formation of the cycloalkanecarbonitriles. it significantly reduces the formation of reaction by-products, harmful and toxic waste, simplifies product finalization in high yield and purity, allows easy recycling of applied catalysts, recycling of used alcohol as solvent and separation of inorganic salts for possible further use. It also limits the use of other generally hazardous chemical substances and technological processes.

In the search for a solution for the preparation of cycloalkanecarbonitriles that would not be contaminated with even trace amounts of unsaturated analogs, 1- (2-acylhydrazino) cycloalkanecarbonitriles proved to be the most suitable substrate for their preparation. Firstly, in terms of price and availability of raw materials, but especially because 1- (2-acylhydrazino) cycloalkanecarbonitriles can be easily (technologically) directly (without any isolation in one reaction stage) after their preparation from the respective cycloalkanone, acylhydrazine and hydrogen cyanide , ecologically, at low cost) oxidize with subsequent deacylation and denitrogenation directly to ς final cycloalkanecarbonitriles. All with very high yields and purity (almost 99% of the key component), with a minimum of by-products (starting cycloalkanones resulting from hydrolysis of intermediates are up to 5% in the mixture after the reaction and recyclable by distillation).

Either alkali metal and / or alkaline earth hypochlorite are used as oxidizing agents according to the invention. In contrast to the application of bromine in dichloromethane solution as an oxidant (Organic Syntheses, Coli. Vol. 6, p. 334 (1988); Vol. 58, p. 101 (1978)), which is described for the synthesis of cyclohexanecarbonitrile from 1- (2-methoxycarbonyl). hydrazol) cyclohexanecarbonitrile, alkali metal and / or alkaline earth hypochlorites are cheaper, can be operated in (aqueous) methanol environment, and provide environmentally minimally problematic chlorides as wastes that can be easily separated from the reaction mixture in a solid state and used secondary.

Another oxidant suitable for oxidation of 1- (2-acylhydrazino) cycloalkanecarbonitrile to cycloalkanecarbonitrile may be an oxygen oxidizing agent selected from oxygen, air, hydrogen peroxide or its mono- or disubstituted alkyl or aryl derivatives, a peroxygen salt of an inorganic or organic acid, and used in the presence of a catalytic oxidation-reduction system consisting of a transition metal compound coexisting in the oxidation stages M ^p and M ^p '', where the coefficient p is +2 and +3.

Such transition metal compounds coexisting in the oxidation stages M ^p and M ^p '* may be complexes of nickel (Ni ³⁺ / Ni ²⁺ ), cobalt (Co ^{j +} / Co ²⁺ ) · iron (Fe ³⁺ / Fe ²⁺ ) and copper (Cu ² 7 Cu ⁺ ). The principle of the catalytic oxidation-reduction system formed by the compound of said transition metals is based on a reversible single electron transition between the two coexisting oxidation states of the metal compound and the ability of the metal compound to oxidize the hydrazine group of 1- (2-acylhydrazino) cycloalkanecarbonitrile to 1- (2-acyldiazenyl) The above-mentioned oxygen- ^containing reagent then re-oxidizes the metal compound from the inactive state M ^p_l to the active state M ^p , whereby the catalytic cycle is closed and the reaction can proceed further. the agent is reduced to the corresponding product, i.e. water, alcohol, phenol, inorganic or organic acid, respectively.

The transition metal compound coexisting in the oxidation stages ^Mp and ^Mp '' must be stable in the reaction solution, must not be converted to insoluble complexes or disproporated or further reduced to insoluble inactive elemental metals M. This condition is met by:

most of the aqua complexes, amine complexes, halogen complexes, and some carboxylic acid salts soluble in the form of carboxylate complexes of transition metals M.

A disadvantage of the reaction mixtures of soluble transition metal complexes M is that they remain in the residual reaction leaches after the reactions and are environmentally hazardous as heavy metals.

A modern trend in synthetic chemistry for cleaner production is the mobilization of reagents and catalysts on solid polymeric supports. The advantage of such synthetic techniques is the easy separation of reagents and catalysts after reaction from the reaction liquor for their reuse while reducing the environmental burden from chemical productions. Generally, however, such mobilized systems are very expensive compared to non-immobilized systems.

The solution according to the invention uses co-existing in the oxidation stages M ^p and M ^p 'to mobilize the transition metal ^! commercially available and cheap polymeric ion exchangers used in water treatment plants which are based on polystyrene or its copolymer with divinylbenzene, respectively. methylacrylic acid. Both strongly acidic cation exchangers with sulfonate functional groups and weakly acidic carboxylate functional groups saturated with M transition metals according to the patent were used. Furthermore, strongly basic anion exchangers saturated with anionic halogen metal complexes of transition metals M (anion exchange with terminal trimethylammonium functional groups) were used.

In the preparation of the cycloalkanecarbonitriles according to the invention, an easily recyclable solvent, extractant, excipients or catalysts is used. Saline wastes containing mainly a mixture of sodium carbonate and bicarbonate can be used as secondary raw materials for chemical production. The reaction temperature of the one-pot process is in the range of 20-65 ° C, therefore the operating costs of cooling operations are eliminated.

The invention is illustrated by the following examples without limiting the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1.

A reaction vessel equipped with a stirrer, reflux condenser, thermometer, and addition funnel was charged with 652 g (6.64 mol) of cyclohexanone, 638 g (7.09 mol) of methoxycarbonylhydrazine, 3 g of acetic acid and 1050 ml of methanol. The mixture was refluxed for 60 minutes when the concentration of unreacted cyclohexanone dropped to 0.4% (determined by gas chromatography). After cooling to room temperature, 180 g (6.66 mol) of hydrogen cyanide was added dropwise to the mixture over 60 minutes. After dosing was complete, the mixture was diluted by adding about 2100 mL of methanol and stirred at room temperature for 1 hour. The mixture was then heated to 45 ° C and dosing of sodium hypochlorite was started to the reaction mixture. Dosing was carried out at 45-50 ° C for 3.5 hours. Approximately 1500 ml of water was added to the reaction mixture 30 minutes after the end of dosing, and then the mixture was stirred for 30 minutes. Subsequently, 5400 ml of cyclohexane were added to the reaction mixture, and the mixture was stirred vigorously for 30 minutes. The phases were then separated. From the upper cyclohexane phase, which contained cyclohexanecarbonitrile and 3% cyclohexanone, the cyclohexane was fractionally redistilled and the fraction 75-76 ° C / 2.13 kPa, no = 1.4514, was collected.

667 g (92% based on starting ketone) of cyclohexanecarbonitrile were obtained which contained 0.19% cyclohexanone.

Example 2.

1- (2-Acetylhydrazino) cyclobutanecarbonitrile (153.18 g, 1 mol) was dissolved in 750 mL of methanol at 45 ° C. Powdered chlorine lime (120 g, titrated 30% active chlorine) was added to the solution at 45-50 ° C for 1 hour,

The suspension was then heated at reflux for 2 h and filtered at about 50 ° C. The filter cake was washed three times with 50 ml of boiling methanol and filtered with activated carbon. After evaporation of the methanol under normal pressure, the distillation residue was fractionated in vacuo, collecting a fraction of 84-85 ^° C / 1.33 kPa, 7np ²⁵ = 1.4320.

75.4 g (93%) of cyclobutanecarbonitrile were obtained containing 0.18% cyclobutanone. Example 3.

1- (2-Ethoxycarbonylhydrazino) cyclopentanecarbonitrile (528.7 g, 3 mol) was dissolved in 3600 ml of 95% ethanol at 40-45 ° C. To the solution was first added 50 g of an approximately 30% aqueous hydrogen peroxide solution and then a solution prepared from 30 g of copper (I) chloride dihydrate and 20 ml of a 28% aqueous ammonia solution in 150 ml of water.

An approximately 30% aqueous hydrogen peroxide solution (350 g) was added dropwise over 3 h to the resulting solution to maintain the temperature in the range of 45-50 ° C. The basicity of the medium was continuously maintained by a pH stat in the pH range of 8-9 by the automatic addition of a 20% aqueous ammonia solution. After completion of the reaction, 2700 mL of cyclohexane was added to the reaction mixture and stirred vigorously for 30 minutes. The phases were then separated. From the upper cyclohexane phase, which contained cyclopentanecarbonitrile and 4% cyclopentanone, the product was obtained by fractional vacuum distillation.

The fraction 73-75 ^° C / 4.00 kPa, n _D ^{2 :)} = 1.4405 was collected. 259.7 g (91%) of cyclicopentane carbonitrile were obtained.

Example 4.

1- (2-Formylhydrazino) cycloheptanecarbonitrile (362.4 g, 2 mol) was dissolved in 2000 mL of methanol at 40-45 ° C, then a solution prepared from 20 g of copper (I) chloride dihydrate and 10 mL of a 28% aqueous solution was added. ammonia in 750 ml of water. Oxygen gas was passed through the frit at a rate of 10 ml / min to the bottom of the vessel at a temperature of 45-50 ° C for 10 hours.

Oxygen gas was passed through a flushing vessel filled with methanol at 50 ° C. The basicity of the medium was continuously maintained by a pH-stat in the pH range of 8 * 9 by automatically adding a 1: 5 mixture of 20% aqueous ammonia and methanol. After completion of the reaction, 1800 ml of cyclohexane was added to the reaction mixture, and the mixture was stirred vigorously for 30 minutes. The phases were then separated. From the upper cyclohexane phase, which contained cycloheptanecarbonitrile and 4.8% cycloheptanone, the product was obtained by fractional vacuum distillation. Fraction 91-93 ° C / 2.00 kPa was collected, n _D ²⁵ = 1.4627.

219.3 g (89%) of cycloheptanecarbonitrile containing 0.15% cycloheptanone were obtained. Example 5.

1- (2-Methoxycarbonyl hydrazino) cyclooctanecarbonitrile (225.3 g, 1 mol) was dissolved in 900 ml of methanol at about 50 DEG C. 100 g of cation exchange resin saturated with copper tetrachloride chloride (cation exchange resin with carboxylate functional groups containing copper 2) were added. To the prepared stirred suspension at 50-50 ° C to the bottom of the flask was fed oxygen gas at a rate of 5 ml / min for 10 hours, and the oxygen gas was fed through a flushing flask filled with methanol at 50 ° C. C. The basicity of the medium was continuously maintained by a pH stat in the pH range of 8 * 9 by the automatic addition of methanolic sodium hydroxide solution (concentration 0.5 mol / l).

After completion of the reaction, 1000 ml of cyclohexane was added to the reaction mixture, and the mixture was stirred vigorously for 30 minutes. The phases were then separated. From the upper cyclohexane phase, which contained cyclooctanecarbonitrile and 3.6% cyclooctanone, the product was obtained by fractional vacuum distillation. The fraction 114-117 ° C / 2.13 kPa, n _D ^{2 :)} = 1.4735 was collected.

126.2 g (92%) of cyclooctanecarbonitrile containing 0.19% cyclooctanone were obtained.

Example 6 1- (2-Methoxycarbonyl hydrazino) cyclohexanecarbonitrile (197.2 g, 1 mol) was dissolved in 700 ml of methanol at a temperature of about 50 ° C. To the solution was added 100 g of cation exchanger saturated with copper tetrachloride chloride (cation exchanger with sulfonate functional groups with a copper content of about 2 mmol / g). Oxygen gas was passed through the frit to the bottom of the stirred slurry at 45-50 ° C at a rate of 5 ml / min for 10 hours.

Oxygen gas was passed through a flushing vessel filled with methanol at 50 ° C. The basicity of the medium was continuously maintained by a pH-stat in the pH range of 940 by the automatic addition of methanolic sodium methoxide solution (concentration 0.5 mol / l). After completion of the reaction, 1000 mL of cyclohexane was added to the reaction mixture and stirred vigorously for 30 minutes. The phases were then separated. The cyclohexane layer was treated as in Example 1.

97.2 g (89%) of cyclohexanecarbonitrile containing 0.18% of cyclohexanone were obtained.

Example 7.

1- (2-Methoxycarbonyl hydrazino) cyclohexanecarbonitrile (197.2 g, 1 mol) was dissolved in 700 ml of methanol at a temperature of about 50 DEG C. 100 g of strongly basic anion exchange resin saturated with sodium tetrachloro-copperate (anion with trimethylammonium functional groups containing copper) 2.3 mmol / g).

Oxygen gas was passed through the frit at a rate of 5 ml / min to the bottom of the vessel at 45-50 ^° C for 10 hours at a temperature of 45-50 ^° C. Oxygen gas was passed through a flushing vessel filled with methanol at 50 ° C. The basicity of the medium was continuously maintained by a pH-stat in the pH range of 8-8.5 by the automatic addition of methanolic sodium methoxide solution (concentration 0.5 mol / l). After completion of the reaction, 1000 ml of cyclohexane was added to the reaction mixture and stirred vigorously for 30 minutes. The phases were then separated. The cyclohexane layer was treated as in Example 1.

93.9 g (86%) of cyclohexanecarbonitrile containing 0.17% of cyclohexanone were obtained. Example 8.

Cyclohexanone. Methoxycarbonylhydrazine and hydrogen cyanide were reacted in the amounts and the procedure described in Example 1. The prepared methanolic solution of 1- (2-methoxycarbonylhydrazino) cyclohexanecarbonitrile was diluted by the addition of 2400 ml of methanol, and 600 g of copper chloride saturated cation exchange resin (carboxylate functional cation exchanger) was added. copper (3.8 mmol / g). At the temperature of 45-50 ^° C to the bottom of the vessel, air was fed through the frit to the prepared stirred suspension at a rate of 20 ml / min for 15 hours.

Air was introduced into the reaction vessel through a flushing vessel filled with methanol at 50 ° C. The basicity of the medium was continuously maintained by a pH stat in the pH range of 8-9 by the automatic addition of methanolic sodium methoxide solution (concentration about 0.5 mol / l). After completion of the reaction, 5400 ml of cyclohexane were added to the reaction mixture, and the mixture was stirred vigorously for 30 minutes.

The phases were then separated. The cyclohexane layer, which in addition to cyclohexanecarbonitrile contained 3.8% cyclohexanone, was treated as in Example 1.

674 g (93% based on the starting ketone) of cyclohexanecarbonitrile were obtained which contained 0.16% cyclohexanone.

Claims (10)

PATENT CLAIMS A process for the preparation of a cycloalkanecarbonitrile of the general formula I CN CH ₂ ---- (CM (I) wherein n is an integer from 1 to 5, characterized in that 1- (2-acyl- or 1- (2alkoxycarbonylhydrazino) cycloalkanecarbonitrile of formula II) R / o = c NH / CH ₂ ----- (CH ₂ ) _n (H) wherein R is hydrogen, methyl, ethyl, isopropyl, phenyl, methoxy, ethoxy or isopropyloxy and n is an integer from 1 to 5, oxidized in the solvent at a temperature of 20 to 65 ° C in a basic pH of 8 to 10 using an oxidation system consisting of an alkali metal hypochlorite and / or an alkaline earth metal hypochlorite or an oxygen oxidant selected from oxygen, air, hydrogen peroxide or its mono or a disubstituted alkyl or aryl derivative, a peroxy derivative of an inorganic or organic acid salt, and used in the presence of a catalytic redox system consisting of a transition metal compound coexisting in the oxidation stages M ^p and M ^{P 1} , where the coefficient p is +2 and +3. Process according to claim 1, characterized in that the reaction mixture obtained by reacting the corresponding cycloalkanone and 1-acylhydrazine and hydrogen cyanide is used as the starting material 1- (2-acyl- or 1- (2alkoxycarbonylhydrazino) cycloalkanecarbonitrile (II). Process according to claim 1 or 2, characterized in that 1- (2-alkoxycarbonylhydrazino) cycloalkanecarbonitrile of the formula II is 1- (2-methoxycarbonylhydrazino) cycloalkanecarbonitrile. Process according to one of Claims 1 to 3, characterized in that the solvent is an aliphatic alcohol containing 1 to 3 carbon atoms, optionally in admixture with water. Process according to Claim 4, characterized in that methanol is used as solvent, optionally in admixture with water. Method according to one of Claims 1 to 5, characterized in that air is used as the oxygen oxidizing agent. 7. Process according to claim 1-6, characterized in that the transition metal compound as the coexistent in oxidation states M ^p and M ^p_1 copper compound used in the oxidation step of Cu ^2+. 8. Process according to claim 1-6, characterized in that the transition metal compound as the coexistent in oxidation states M ^p and M ^p_1 tetraammin cupric chloride is used. Method according to any one of the preceding claims 1 to 6, characterized in that a cation exchange complex cation-exchanged copper cation is used as the transition metal compound coexisting in the oxidation stages M ^p and M 4. Process according to one of the preceding claims 1 to 6, characterized in that the transition metal compound coexisting in the oxidation steps M ^p and M 4 is a tetra-copper (I) anion complex wherein the halogen is chlorine or bromine immobilized on the anion exchange resin.