NO180301B - Process for the preparation of azaspiroalkane derivatives - Google Patents

Description

US Patent Nos. 4,024,175 and 4,087,544 mention cyclic amino acids of formula A

where R 1 is a hydrogen atom or a lower alkyl radical, and n is 4, 5 or 6, as well as the pharmacologically compatible salts thereof.

The compounds described in the above-mentioned US patents are useful in the treatment of certain cerebral diseases, for example they can be used in the therapy of certain forms of epilepsy, vertigo attacks, hypokinesia and cranial lesions. In addition, they lead to improvement of cerebral functions and are thus useful in the treatment of geriatric patients. Particularly valuable is 1-(aminoethyl)-cyclohexaneacetic acid (gabapentin).

Gamma-aminobutyric acid (GABA) is an inhibitory amino acid found in the central nervous system (CNS) of mammals. It has been described how dysfunction with GABA neurotransmission in the CNS can contribute to or even cause psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson's disease",^Huntington's chorea and dyskinesia (Saletu, B. et al, International Journal of Clinical Pharmacolooy . Therapy and Toxicoloay. 24, pages 362 to 373 (1986)). Gabapentin was designated as a GABA analog that would cross the blood-brain barrier. It was found that gabapentin had anticonvulsant and antispastic activity with extremely low toxicity in the human being.

The above-mentioned compounds of formula A including gabapentin are prepared from a compound of formula

where R2 is an alkyl radical containing up to eight carbon atoms, and n is as defined above, by means of well-known standard reactions such as Hofmann, Curtius or Lossen rearrangements of the amino derivatives of formula A. Although these reactions provide the target compounds, they require a large number of synthesis steps and in some cases involve potentially explosive intermediates. US Patent No. 4,152,326 describes cyclic sulfonyloxyimides of formula

where R 2 is a saturated, straight-chain or branched or cyclic lower aliphatic radical or an unsubstituted or substituted aryl radical, and n is 4, 5 or 6, which can be converted into a compound of formula A. In the same way, like the previous methods , this method requires a large number of synthetic steps to obtain a compound of formula A. Finally, all of the preceding methods require, as the penultimate step, the conversion of an intermediate salt of the target compound into an amino acid of formula A.

It is the purpose of the present invention to provide an improved method for the preparation of a compound of formula VI

where n is an integer between one and three.

The compound of formula VI is a valuable intermediate for the preparation of a compound of formula I

and pharmaceutically acceptable salts thereof, where n is an integer between one and three. The present invention thus relates to an improved method for producing a compound of formula VI

where n is an integer between one and three, which method includes, that one:

Step (a)

reacts a compound of formula V

where n is as above defined with a compound of formula where R is alkyl of one to six carbon atoms, in a solvent and an acid to obtain in situ, after removal of excess acid, a compound of formula IV

where n and R are as defined above,

Step (h)

adding water and then adjusting the pH with an aqueous base, adding a water-immiscible solvent and removing the aqueous phase to obtain, after removal of the water-immiscible solvent, a compound of formula III

where n and R are as defined above,

Step ( c )

treating a compound of formula III with hydrogen in the presence of a catalyst and a solvent to obtain a compound of formula VI.

A compound of formula VI

where n is as defined above, can be hydrolyzed in a conventional manner to obtain a salt of a compound of formula I, which can be converted into a compound of formula I in a conventional manner, and if desired, the resulting compound of formula I can be converted into a corresponding pharmaceutically acceptable salt in a conventional manner.

In the present invention, the term "alkyl" means a straight-chain or branched hydrocarbon group with one to twelve carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary-butyl, n-pentyl, n-hexyl , n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl and the like.

"Alkali metal" is a metal in group IA of the periodic table and includes, for example, lithium, sodium, potassium and

the like.

"Alkaline earth metal" is a metal in group IIA in the periodic table and includes, for example, calcium, barium, strontium, magnesium and the like.

"Phase transfer agent" means a solvent which is mutually soluble in the aqueous phase and in the organic phase and includes, for example, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane and the like.

The compounds of formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All these forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of formula I include salts derived from non-toxic inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and the like, as well as the salts derived from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedic acids, aromatic acids, aliphatic and aromatic sulphonic acids etc. Such salts thus include sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide , iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacatV fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also included are salts of amino acids such as arginate and the like and gluconate, galacturonate (see for example Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science. Volume 66, pages 1-19 (1977)).

The acid addition salts of the above base compounds are prepared by bringing the free base form into contact with a sufficient amount of the desired acid to obtain the salt in a conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ from their respective salt forms to some extent with respect to certain physical properties such as solubility in polar solvents, but apart from this the salts are equivalent to their respective free bases, as far as the purposes of the present invention are concerned.

Pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine (see for example Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science. 66. pages 1-19 (1977)).

The base addition salts of the above-mentioned acid compounds are prepared by bringing the free acid form into contact with a sufficient amount of the desired base to prepare the salt in a conventional manner. The free acid form can be regenerated by contacting the salt with an acid and isolating the free acid in a conventional manner. The free acid forms differ to some extent from their respective salt forms with respect to certain physical properties such as solubility in polar solvents, but apart from this the salts are equivalent to their respective free acids, as far as the purposes of the present invention are concerned.

Certain of the subject compounds can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to the unsolvated forms and are within the scope of the present invention.

US Patent Application No. 188819 describes gabapentin monohydrate and a process for preparing gabapentin monohydrate.

A preferred compound of formula VI prepared by means of the improved method according to the present invention is:

2-azaspiro[4.5]decan-3-one

As described above, the compounds of formula I are useful in the treatment of certain forms of epilepsy, vertigo attacks, hypokinesia and cranial lesions.

The process according to the invention and the further conversion of a compound VI into a compound I is shown in the diagram below.

Thus, a compound of formula V, where n is an integer between one and three, is treated with approx. one equivalent of a compound of formula

where R is alkyl with one to six carbon atoms, in approx. one to five days in a solvent, such as, for example, toluene, ethyl acetate, methylene chloride, ethanol, methanol and the like, and approx. one to three equivalents of an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid and the like at a pressure of approx. 2 mm to approx. 50 pounds per square inch (psig) and at approx. 20°C to approx. 55°C to obtain, after removal of excess acid, a compound of formula IV, where n and R are as defined above, which is not isolated. The reaction is preferably carried out by adding approx. two equivalents of anhydrous hydrogen chloride at a pressure of approx. 3 mm to approx. 10 mm Hg and approx. 10°C to an airless flask containing dinitrile of formula V in toluene containing approx. 2 equivalents of ethanol or methanol, stirring for two days and removing excess acid by distillation.

Water is added, and the pH is adjusted to approx. 4 to 4.5 by means of an aqueous base such as an aqueous alkali or alkaline earth metal hydroxide or carbonate, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate and the like. The mixture is stirred for approx. one to 36 hours at approx. 0°C to approx.

50°C, and a non-water-miscible solvent such as toluene, ethyl acetate, methyl chloride, hexane, heptane, octane, isooctane, tertiary butyl methyl ether and the like is added to obtain, after removal of the aqueous phase, a compound of formula III, where n and R are as defined above. The reaction is preferably carried out by adjusting the pH with aqueous sodium hydroxide, stirring for approx. 24 hours and addition of toluene.

A compound of formula III is isolated and treated with hydrogen in the presence of a catalyst such as, for example, rhodium-on-carbon containing palladium, rhodium-on-carbon containing platinum, rhodium-on-calcium carbonate containing palladium, rhodium-on-alumina containing palladium, palladium-on-carbon, palladium-on-carbon in the presence of a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like, Raney nickel, Raney nickel and a base such as an alkali metal hydroxide, ammonium hydroxide and the like, Raney- cobalt, metal hydrides such as lithium aluminum hydride, rhodium hydride complex, ruthenium hydride complex, borane methyl sulphide complex and the like and metals such as iron, cobalt, nickel, rhodium and the like in a solvent such as methanol, ethanol and the like at approx. -20°C to about 50°C to obtain a compound of formula I, where n is as defined above. The reaction is preferably carried out with 0.5% to 10% rhodium-on-carbon" containing 1% to 10% palladium in methanol at about room temperature.

A compound of formula VI is converted into a salt of a compound of formula I by means of conventional acid or base hydrolysis such as acid hydrolysis with hydrochloric acid, sulfuric acid and the like or base hydrolysis with sodium hydroxide, potassium hydroxide and the like, and then converted into a compound of formula In using conventional methods such as ion exchange techniques.

A compound of formula V can be prepared by that of Schafer, H., Liebia's Annalen der Chemie. 688, pages 113 to 121

(1965) described methodology.

The following non-limiting example illustrates the invention.

EXAMPLE 1

1-(Aminomethyl)-cyclohexaneacetic acid

METHOD OF PROCEDURE A

Step A: Preparation of 1-cyanocyclohexaneacetic acid

A 2 1 flask is filled with 242 g (1.63 mol) of 1-cyanocyclohexane-acetonitrile, 150 g of ethanol and 536 ml of toluene. The flask is cooled to 10°C and evacuated. Anhydrous hydrogen chloride (159 g, 4.35 mol) is added to the vacuum flask, causing the pressure to rise to ambient pressure. The mixture is kept cold for three days, after which a further 40 g of hydrogen chloride gas is added. The mixture is stirred cold for a further four days, after which solvent and excess hydrogen chloride are removed by distillation under vacuum, the flask being kept below 25°C. The mixture is cooled in an ice bath, and 1500 ml of water is added over a 30 minute period. Aqueous sodium hydroxide is added to raise the pH to 4 to 4.5. This mixture is stirred for 24 hours, and then 300 ml of toluene is added. The aqueous phase is removed and 100 ml of methanol and 600 ml of 3M sodium hydroxide are added to the toluene phase. The mixture is heated to 40°C and stirred for four hours. The toluene phase is removed and the aqueous phase is cooled to 0°C to 5°C, then the pH of the aqueous phase is adjusted to 3 with concentrated hydrochloric acid with stirring at 0 to 5°C and filtered. The filter cake is dried to obtain 212.5 g (78% theoretical) of white crystalline 1-cyanocyclohexaneacetic acid,

m.p. 102-103°C.

Step B: Preparation of 1-(aminomethyl)-cyclohexaneacetic acid

One gram of 10% rhodium on carbon, containing 1% palladium, (Pearlman, W. M., Tetrahedron Letters, pages 1663-1664 (1967)) is suspended in 30 ml of methanol and reduced under hydrogen in a Parr shaker. 1-Cyanocyclohexaneacetic acid (16.7 g, 0.1 mol) is dissolved in 40 ml of methanol and combined with the reduced catalyst. The mixture is placed under 50 pounds per

square inch (psig) of hydrogen and shaken for two hours at room temperature. The catalyst is removed by filtration, and the filtrate is condensed to a volume of 25 ml by vacuum distillation. Isopropanol, 100 ml, is added, and a further 25 to 50 ml of the solvent is removed by vacuum distillation. The resulting slurry is cooled at 0 to 5°C for 24 hours and filtered and dried to obtain 13.65 g (79% theoretical) of 1-(aminomethyl)-cyclohexaneacetic acid,

m.p. 162-163°C.

PROCEDURE B

To a 500 ml Parr bomb is added 23.5 g (0.1 mol) 1-cyanocyclohexaneacetic acid, 28% water-moistened, 16 g 50% water-moistened Raney nickel #30 and a cooled (20°C) methyl alcohol (160 ml) and 50% aqueous sodium hydroxide ((8.8 g, 0.11 mol) solution. The reaction mixture is stirred at 22°C to 25°C for 21 hours at 180 pounds per square inch (psig) of hydrogen. After 21 hours, the hydrogen is vented, and the reduced mixture is flushed with nitrogen.

The reaction mixture is pressure filtered over celite, washed with methyl alcohol (100 ml) and stripped to a volume of 50 ml at 35°C on the rotary evaporator. Isopropyl alcohol (100 ml) is added, followed by dropwise addition of 6.6 g (0.11 mol) acetic acid. The product solution is stripped on the rotary evaporator to a volume of 50 ml. Tetrahydrofuran (125 ml) is added to the concentrated product solution, the solution is cooled in an ice bath, suction filtered and washed using 50 ml of tetrahydrofuran. The raw product cake is dried under vacuum at 45°C for 16 hours.

The crude product is recrystallized from methyl alcohol, demineralized water and isopropyl alcohol to obtain 10.3 g of 1-(aminomethyl)-cyclohexaneacetic acid as a crystalline white solid. The high pressure liquid chromatography (HPLC) results show no organic impurities observed with 97.2% weight/weight (w/w) purity.

PROCEDURE C

Step A: Preparation of ethyl-1-cyanocyclohexane acetate

A 1 1 pressure flask is filled with 148 g (1 mol) of 1-cyanocyclohexaneacetonitrile, 206 ml of ethanol and 100 ml of toluene. The mixture is cooled to 5°C and evacuated. Anhydrous hydrogen chloride (148 g, 4.05 mol) is added to the vacuum flask, causing the pressure to rise to 10 psig. square inch (psig), while allowing the temperature to rise to 35°C. This temperature is maintained for 7 hours, during which time additional hydrogen chloride (25 g, 0.68 mole) is added to maintain a pressure of 5 pounds per psi. square inch (psig). At the end of the 7-hour period, excess hydrogen chloride and ethanol are removed by vacuum distillation, the mixture being kept below 25°C. To the resulting slurry is added 200 ml of toluene, which is then removed by vacuum distillation. This procedure is repeated twice more with 150 ml of toluene. After the last distillation, 150 ml of toluene and 500 ml of ice water are added, and the pH is adjusted to four with aqueous sodium hydroxide solution. After stirring for 18 hours, the mixture is filtered, the filtrate phases are separated, the aqueous phase is washed with 100 ml of toluene, and then the combined toluene phases are washed with 100 ml of 1 N aqueous sodium hydroxide solution, followed by two washings with water of 50 ml each. The toluene solution is then dried by azeotropic distillation, which is followed by vacuum distillation to remove the toluene. The remaining yellow oil (166 g) is 91% ethyl 1-cyanocyclohexane acetate. Further purification is achieved by vacuum distillation, the distillate being collected at b.p. 85° to 95°C at 0.2 to 0.3 mm Hg.

Step B: Preparation of 1-cvanocvchlorohexaneacetic acid

A suitable reactor is filled with 120 ml of water, 32 kg of 50% aqueous sodium hydroxide solution, 21 l of methanol and 70 kg of ethyl-1-cyanocyclohexane acetate. The mixture is stirred at 50°C for 1 hour, after which 40 to 60 1 of the solvent is removed by vacuum distillation, while keeping the temperature below 50°C. After cooling to 20° to 25°C, the reaction mixture is filtered through a 0.45 micron Pall filter. The filtered solution is then diluted with 70 L of water and extracted with 20 L of methylene chloride, followed by a second extraction with 15 L of methylene chloride. The aqueous solution is topped up with 37% hydrochloric acid solution to a pH of 8. 6 to 8 kg of 37% hydrochloric acid solution is required. The solution is then extracted twice with 20 l each of methylene chloride. After the final extraction, the aqueous solution is stirred under full vacuum at 20° to 30°C for a minimum of 30 minutes, then cooled to 3° to 10°C. While maintaining this temperature, 37% hydrochloric acid solution is added to a pH of 3. Approx. 32 to 36 kg of 37% hydrochloric acid solution. After the addition is complete, the product slurry is stirred at 3° to 10°C for 30 minutes. The product is then collected in a centrifuge and washed with 300 to 400 L of water pre-cooled to 5°C or lower. The product is spun as dry as possible in the centrifuge and then removed from the centrifuge and stored as a wet cake in a cold room at 5°C or below. After vacuum drying at 40° for 24 hours, 1-cyanocyclohexaneacetic acid is obtained,

m.p. 103°-105°C.

Step C: Preparation of 1-(aminomethyl)-cyclohexaneacetic acid

Using method B, 1-cyanocyclohexaneacetic acid is converted to 1-(aminomethyl)cyclohexaneacetic acid.

PROCEDURE D

Step A: Preparation of sodium-1-cyanocyclohexane acetate

7.1 g (0.13 mol) of sodium methoxide are added to a 250 ml flask under nitrogen, followed by 20 ml of methyl alcohol and 270 ml of tetrahydrofuran. The solution is suction filtered over celite and washed using 10 ml of tetrahydrofuran. The filtrates are combined and transferred to a separatory funnel on a 500 ml flask containing 20 g of 1-cyanocyclohexaneacetic acid and 100 ml of tetrahydrofuran. The sodium methoxide solution is added over 3 minutes to the latter solution. The precipitated product is cooled in an ice bath, suction filtered and washed using 20 ml of tetrahydrofuran. The filter cake is dried in a vacuum oven at 50°C for 16 hours to obtain 21.9 g of sodium 1-cyanocyclohexane acetate as an off-white, crystalline solid,

m.p. 206°-209°C.

Step B; Preparation of 1-(aminomethyl)-cyclohexaneacetic acid

Using method B, sodium 1-cyanocyclohexane acetate is converted to 1-(aminomethyl)-cyclohexaneacetic acid.

PROCEDURE E

Step A; Preparation<g> of potassium-1-cyanocyclohexane acetate

To a 250 ml flask under nitrogen is added 14.8 g (0.13 mol) of potassium tertiary butoxide followed by 74 ml of tetrahydrofuran. The solution is stirred for 10 minutes, filtered with suction and washed using 50 ml of tetrahydrofuran. The filtrates are collected and transferred to a separatory funnel on a separate 250 ml flask containing 20 g (0.12 mol) of dried 1-cyanocyclohexaneacetic acid and 100 ml of tetrahydrofuran. The potassium tert-butoxide solution is added dropwise over 5 minutes to the latter solution. The precipitate is cooled in an ice bath, suction filtered and washed with 25 ml of cold tetrahydrofuran. The filter cake is dried in a vacuum oven at 50°C for 16 hours to obtain 24.8 g of potassium l-cyanocyclohexane acetate as a white, crystalline solid,

m.p. 196-199°C.

Step B: Preparation of 1-aminomethyl)-cyclohexaneacetic acid

Using method B, potassium 1-cyanocyclohexane acetate is converted to 1-(aminomethyl)-cyclohexaneacetic acid.

Claims (3)

1. Process for preparing a compound of formula VI where n is an integer between one and three, characterize t by: Step fa) reacts a compound of formula V where n is as defined above, with a compound of formula where R is alkyl of one to six carbon atoms, in a solvent and an acid to obtain in situ, after removal of excess acid, a compound of formula IV where n and R are as defined above, Step (b) adding water and then adjusting the pH with an aqueous base, adding a water-immiscible solvent and removing the aqueous phase to obtain, after removal of the water-immiscible solvent, a compound of formula III where n and R are as defined above, Step ( c ) treating a compound of formula III with hydrogen in the presence of a catalyst and a solvent to obtain a compound of formula VI. 2. Method according to claim 1, characterized by atpHi step (b) is adjusted to 4 to 4.5. 3. Method according to claim 1, kar a~*k terized in that 2-aza-spiro[4.5]decan-3-one is produced.