HU207292B - Process for producing pyrrolidine derivatives - Google Patents

Abstract

The present invention relates to a compound of formula (I) wherein R4 is a group of the formula wherein 1 is 1 or 2, m is 1 or 2, where (1 + m) is 2 or 3, n is 1 or 2; , Y is a C 1-4 alkoxy group, a hydrogen atom or an amino group, optionally substituted with C 1 -C 4 alkyl or C 3-5 cycloalkyl or C 1-4 alkoxycarbonylamino, for the preparation of pyrrolidine derivatives. , 1-pyrrolidinyl or 1-morpholinyl, X 1 is OH or C 1-4 alkoxy, characterized in that (a) for the preparation of compounds of formula (IIIa), wherein m is as defined above and NR'R is as defined above except for the alkoxy group and the hydrogen atom, the meaning of Y-R4-H (I) HU 207 292 BA is 10 pages (including 2 sheets)

Description

The present invention relates to a process for preparing intermediates of pharmaceutically active quinolone and naphthyridone carboxylic acid derivatives. The novel intermediates are represented by the general formula (I) wherein

R ⁴ is a group of the general formula (a) - where 1 or 2, m is 1 or 2, where (1 + m) can together be 2 or 3, n is 1 or 2, 20

Y is (C 1 -C 4) alkoxy, hydrogen, or amino, optionally substituted on one or both hydrogens with (C 1 -C 4) alkyl or (C 3 -C 5) cycloalkyl, or (C 1 -C 4) alkoxycarbonylamino, 1-pyrrolidinyl - or 1-morpholinyl,

X ¹ is OH or C 1-4 alkoxy,

Examples of the compounds of formula (I) include, and are noted, that chiral compounds as well as racemates and enantiomerically pure materials may be used:

3- (aminomethyl) -3-hydroxypyrrolidine, (3-tert-butoxycarbonylaminomethyl) -3-hydroxypyrrolidine, 3-hydroxy-3- (methylaminomethyl) pyrrolidine, 3- (ethylaminomethyl) -3-hydroxypyrrolidine, 3-hydroxy-3- (propylaminomethyl) pyrrolidine, 3- (ethylaminomethyl) -3-methoxypyrrolidine, 3- ethoxy-3- (ethylaminomethyl) pyrrolidine, 3- (dimethylaminomethyl) -3-hydroxypyrrolidine, 3-hydroxy-3- (pyrrolidinomethyl) pyrrolidine, 3-hydroxy-3- (morpholinomethyl) pyrrolidine, 3-amino-3- (hydroxymethyl) pyrrolidine,

3- (cyclopropylaminomethyl) -3-hydroxypyrrolidine, 3- (isopropylaminomethyl) -3-hydroxypinnolidine

The compounds of the formula I can be prepared as follows:

a) The nitrogen-protected spirooxirane of formula (1) [J. Med. Chem. 30, 222 (1987); U.S. Pat. No. 4,568,724; European Patent No. 189370.50], reacted with an amine of formula (2), the ring is opened to form the hydroxyamines of formula (3). Cleavage of protecting group B affords the compound of formula (IIIa) (see Scheme 2), wherein -NR'R 'is an alkoxy group 55 and except Y is hydrogen.

3-Hydroxy-3-methylpyrrolidine can be prepared by reduction of lithium aluminum hydride of 4-hydroxy-4-methylpyrrolidin-2-one [Zh. Org. Khim. 14, 7, 1420. o. (1978)] or by debenzylation of 1-benzyl-3-hydroxy-3-methylpyrrolidine (see European Patent No. 132845), b) Compound of Formula I wherein Y is hydrogen or C 1-4 alkoxy; hydrogenation of a compound of formula 4 wherein B is benzyl, X ^{1 is} hydroxy, Y is hydrogen or C 1-4 alkoxy, m, η, 1 are 1.

The hydroxy group in the compound of formula (IIIa) may be optionally alkylated.

The preparation of compounds of formula I is illustrated by the following examples:

Example A)

3- (ethylamino) -3-hydroxypyrrolidine

a) Ethyl 5-Aza-1-oxaspiro [2,4] heptane-5-carboxylic acid

Trimethylsulfoxonium iodide (23.5 g, 107 mmol) and sodium hydride (3.3 g, 80% in paraffin oil) were mixed and 80 mL of anhydrous dimethyl sulfoxide was added at 10 ° C. After stirring for 1 hour at room temperature, 15.7 g (100 mmol) of 3-oxo-pyrrolidine-1-carboxylic acid ethyl ester [J. Med. Pharm. Chem., 5, 35752 (1962)] dissolved in 20 ml of absolute dimethylsulfoxide. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice-saturated NaCl solution and extracted with diethyl ether. The ethereal solution was washed with brine, dried over sodium sulfate, evaporated and distilled.

Yield: 6 g Mp .: 80 ° C / 0.15 mbar.

b) Ethyl 3- (ethylaminomethyl) -3-hydroxypyrrolidine-1-carboxylate

Ethyl 5-aza-1-oxaspiro [2,4] heptane-5-carboxylic acid (8 g, 46.7 mmol) was added dropwise to 50 ml of a 50% aqueous solution of ethylamine and stirred overnight at room temperature. The mixture is evaporated and the residue is distilled off. Yield: 8 g

Mp .: 130 ° C / 0.05 mbar. 3- (ethylamino) -3-hydroxy-pirtolidin

A solution of 4-ethylaminomethyl-3-hydroxypyrrolidine-1-carboxylic acid ethyl ester (7.7 g, 35.6 mmol) in a solution of 22 g of barium hydroxide * 8 H ₂ O in 220 ml of water was heated under reflux overnight. . The barium carbonate is filtered off with suction and concentrated. The residue was boiled with dioxane (5 x 100 mL) and the dioxane solution was evaporated and distilled.

Yield: 4.2 g

Mp: 70-75 ° C / 0.1 lbar.

'

HU 207 292 B

Example B)

3- (Aminomethyl) -3-hydroxypyrrolidine

a) 3-Aminomethyl-1-benzyl-3-hydroxypyrrolidine

9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro [2,4] heptane (U.S. Pat. No. 4,887,224) are added dropwise to 50 ml of ammonia solution (25%) and stir overnight at room temperature. The mixture was evaporated and the residue was distilled.

Yield: 4.4 g

Mp .: 135 ° Q0.4mbar.

b) 3- (aminomethyl) -3-hydroxypyrrolidine

A solution of 3.9 g (18.9 mmol) of 3- (aminomethyl) -1-benzyl-3-hydroxypyrrolidine in 25 ml of methanol is hydrogenated over 1 g of 10% palladium on carbon at 90 ° C and 95 bar. The catalyst was filtered off, the filtrate was evaporated and the residue was distilled. Yield: 1.2 g

MP: 80 ° C / 0.14mbar.

Example C)

3- (ethylamino) -3-hydroxypyrrolidine

a) 1-Benzyl-3- (ethylaminomethyl) -3-hydroxypyrrolidine

5-Benzyl-5-aza-1-oxaspiro [2,4] heptane (10.2 g, 53.9 mmol) was added dropwise to 60 ml of a 50% aqueous solution of ethylamine and stirred overnight at room temperature. Evaporate and distill.

Yield: 10.7 g

MP: 120 ° C / 0.18 mbar.

b) A mixture of 3- (ethylaminomethyl) -3-hydroxypyrrolidine g (42.7 mmol) in 1-benzyl-3- (ethylaminomethyl) -3-hydroxypyrrolidine in 60 mL of methanol was treated with 2 g of 10% methanol. hydrogenated at a temperature of 97 ° C and a pressure of 107 bar. The catalyst was filtered off, the filtrate was evaporated and the residue was distilled.

Yield: 4.8 g

MP: 74 ° C / 0.08 mbar.

Example D)

3-Hydroxy-3- (methylamino) pyrrolidine dihydrochloride

a) 1-Benzyl-3-hydroxy-3- (methylaminomethyl) pyrrolidine dihydrochloride

5-Benzyl-5-aza-1-oxaspiro [2,4] heptane (10.2 g, 58.3 mmol) was added dropwise to 70 ml of a 30% aqueous methylamine solution and stirred overnight at room temperature. The mixture was evaporated and the residue was distilled.

Yield: 8.8 g

Mp: 145 ° C / 0.35 mbar.

The distillate was dissolved in dilute hydrochloric acid and the solution was evaporated. The crystalline residue is triturated with isopropanol, filtered off with suction and dried.

Yield: 7.3 g

Mp 202 ° C.

b) 3-Hydroxy-3- (methylaminomethyl) pyrrolidine dihydrochloride

6.9 g (23.5 mmol) of 1-benzyl-3-hydroxy-3- (methylaminomethyl) -pyrrolidine dihydrochloride are hydrogenated in 100 ml of methanol at 10 g of 10% palladium on carbon at 100 ° C. bar pressure. The catalyst is suctioned off, the solution is evaporated and the residue is triturated with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.

Yield: 4 g

M.p. 231-232 ° C.

Example E)

3- (Cyclopropyl-methyl-amino) -3-hydroxy-pirrolidindihidroklorid

a) 1-Benzyl-3- (cyclopropylaminomethyl) -3-hydroxypyrrolidine dihydrochloride

9.7 g (51.3 mmol) of 5-benzyl-5-aza-1-oxaspiro [2,4] heptane was added dropwise to a mixture of 9.7 g (0.17 mol) of cyclopropylamine in 40 ml of water and overnight. stir at room temperature. The mixture was evaporated and the residue was distilled.

Yield: 8 g

Mp .: 130 ° C / 0.08 mbar.

The distillate was dissolved in dilute hydrochloric acid and the solution was concentrated. The crystallization residue is triturated with acetone, filtered off with suction and dried.

Yield: 8.3 g

182-184 °.

b) 3- (Cyclopropylaminomethyl) -3-hydroxypyrrolidine dihydrochloride

A mixture of 7.9 g (24.7 mmol) of 1-benzyl-3- (cyclopropylaminomethyl) -3-hydroxypyrrolidine dihydrochloride in 100 ml of methanol was treated with 2 g of 10% palladium on carbon at 50 ° C and 100 bar. Suction, evaporate and triturate with butanol. The crystalline salt is filtered off with suction, washed with acetone and dried.

Yield: 3.4 g.

Example F)

3- (Aminomethyl) -3-hydroxypiperidine

a) 5-Aza-1-oxaspiro [2,5] octane-5-carboxylic acid methyl ester

Trimethylsulfoxonium iodide (23.5 g, 107 mmol) and sodium hydride in 80% paraffin oil (3.4 g, 100 mmol) were added dropwise to 80 mL of anhydrous dimethyl sulfoxide at 10 ° C. After stirring for 1 hour at room temperature, 15.8 g (100 mmol) of 3-piperidone-1-carboxylic acid methyl ester (Acta Chem. Scand. B 30, 1976, p. 884]. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice and saturated brine and extracted with diethyl ether. The ethereal solution was washed with brine, dried over sodium sulfate, evaporated and distilled.

Yield: 8 g

Mp 68 ° C / 0.15 mbar.

b) 3- (Aminomethyl) -3-hydroxy-piperidine-1-carboxylic acid methyl ester

9.1 g (53.2 mmol) of 5-aza-1-oxaspiro [2,5] octane-5-carboxylic acid methyl ester are added dropwise to 50 ml of 25% ammonia solution and stirred overnight at room temperature. Evaporate and distill the residue.

HU 207 292 Β

Yield: 5.6 g

Mp .: 103 ° C / 0.1 lbar.

c) 3-Aminomethyl-3-hydroxypiperidine

5.1 g (27.1 mmol) of methyl 3-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid was heated with 15.8 g of barium hydroxide x 8 H ₂ O in 150 mL of water overnight. under refrigeration. The barium carbonate is filtered off with suction and concentrated. The residue is boiled with five times 70 ml of dioxane, the dioxane solutions are concentrated and distilled.

Yield: 1.8 g

Mp: 63 ° C / 0.05 mbar.

Example G)

-Hydroxy-3- (methylaminomethyl) piperidine

a) Methyl 3-hydroxy-3- (methylaminomethyl) piperidine-1-carboxylic acid

Methyl 5-aza-1-oxaspiro [2,5] octane-5-carboxylic acid (9.3 g, 54.3 mmol) was added dropwise to 50 ml of a 25% aqueous solution of methylamine and stirred overnight at room temperature. The reaction mixture is concentrated and the residue is distilled. Yield: 9.2 g

Mp: 83-95 ° C / 0.1 mbar.

b) 3-Hydroxy-3- (methylaminomethyl) piperidine

Methyl 3-hydroxy-3- (methylaminomethyl) piperidine-1-carboxylic acid methyl ester (8.7 g, 43 mmol) was heated to reflux overnight with 24 g of barium hydroxide x 8 H ₂ O in 240 mL of water. The barium carbonate is filtered off with suction and concentrated. The residue was boiled with dioxane (5 x 100 mL) and the dioxane solution was evaporated and then distilled. Yield: 4.2 g

MP: 56 ° C / 0.05 mbar.

Example H)

3- (ethylaminomethyl) -3-hydroxypiperidine

a) Methyl 3- (ethylaminomethyl) -3-hydroxypiperidine-1-carboxylic acid

9.3 g (54.3 mmol) of 5-aza-1-oxaspiro [2,5] octane-5-carboxylic acid methyl ester are added dropwise to 50 ml of a 50% aqueous solution of ethylamine and stirred overnight at room temperature. The reaction mixture was concentrated and the residue was distilled.

Yield: 11.2 g

Mp .: 104-108 ° C / 0.2 mbar.

b) 3- (Ethylaminomethyl) -3-hydroxypiperidine g (46.2 mmol) methyl 3- (ethylaminomethyl) -3-hydroxypiperidine-1-carboxylic acid methyl ester (28.5 g) H ₂ O was heated to reflux overnight with 280 mL of water. The barium carbonate is filtered off with suction, evaporated, the residue is boiled with 5 x 120 ml of dioxane, the dioxane solution is evaporated and distilled.

Yield: 4.5 g

MP: 70 ° C / 0.09 mbar.

Example I)

4- (aminomethyl) -4-hydroxypiperidine dihydrochloride a) 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylic acid ethyl ester

Ethyl 6-aza-1-oxaspiro [2,5] octane-6-carboxylic acid ethyl ester (13.4 g, 72.3 mmol) (EP 189 370) was added dropwise to 60 ml of 25% ammonia solution and overnight. stir at room temperature. It is then concentrated and distilled.

Yield: 8.1 g

Mp .: 110-130 ° C / 0.04 mbar. b) 4- (Aminomethyl) -4-hydroxypiperidine dihydrochloride Ethyl 4-aminomethyl-4-hydroxypiperidine 1-carboxylic acid ethyl ester (1 g, 4.9 mmol) was heated with 10 ml of concentrated hydrochloric acid. overnight under reflux, then evaporated and the crystals triturated with acetone. It is aspirated and dried in a vacuum dryer over phosphorus pentoxide. Yield: 1 g

Mp: 230-233 ° C.

Example J)

4-Hydroxy-4- (methylamino) piperidine dihydrochloride

a) 4-Hydroxy-4- (methylaminomethyl) piperidine-1-carboxylic acid ethyl ester

Ethyl 6-aza-1-oxaspiro [2.5] octane-6-carboxylic acid (5.2 g, 28 mmol) was added dropwise to 30 ml of a 25% aqueous solution of methylamine and stirred overnight at room temperature and evaporated. and recrystallized from wash gas (hygroscopic crystals).

Yield: 3.3 g.

b) 4-Hydroxy-4- (methylaminomethyl) piperidine dihydrochloride g (13.9 mmol) 4-hydroxy-4- (methylaminomethyl) piperidine-1-carboxylic acid ethyl ester in 30 ml concentrated hydrochloric acid was refluxed overnight, evaporated, the crystals were stirred with acetone, filtered off with suction and dried in a vacuum dryer over phosphorus pentoxide.

Yield: 2.7 g Mp: 236-238 ° C.

Example K)

4- (Dimethylamino) -4-hydroxypiperidine dihydrochloride

a) Ethyl 4- (dimethylaminomethyl) -4-hydroxy-piperidine-1-carboxylic acid

Ethyl 6-aza-1-oxaspiro [2.5] octane-6-carboxylic acid (5.2 g, 28 mmol) was added dropwise to a solution of dimethylamine (30 mL), a 40% aqueous solution, and stirred overnight. at room temperature. It is then concentrated and distilled.

Yield: 5.2 g Mp: 150-155 ° C / 3 mbar.

b) 4- (Dimethylaminomethyl) -4-hydroxypiperidine dihydrochloride

Ethyl 4- (dimethylaminomethyl) -4-hydroxypiperidine-1-carboxylic acid (4.5 g, 19.4 mmol) was heated to reflux overnight with 35 mL of concentrated hydrochloric acid, and the crystals were evaporated and the crystals were evaporated. triturate with acetone. It is aspirated and dried in a vacuum dryer over phosphorus pentoxide.

Yield: 4.1 g Mp: 224-227 ° C.

HU 207 292 Β

Example L)

4- (ethylamino) -4-hydroxypiperidine dihydrochloride

a) Ethyl 4- (ethylaminophenyl) -4-hydroxypiperidine-1-carboxylic acid

Ethyl 6-aza-1-oxaspiro [2.5] octane-6-carboxylic acid (5.7 g, 30.8 mmol) was added dropwise to a 50% aqueous solution of ethylamine (30 mL), stirred overnight at room temperature and evaporated. and distill. Yield: 5.5 g

Mp .: 100-104 ° C / 0.01 mbar.

b) 4- (Ethylaminomethyl) -4-hydroxypiperidine dihydrochloride

Ethyl 4- (ethylaminomethyl) -4-hydroxypiperidine-1-carboxylic acid ethyl ester (4.6 g, 20 mmol) was heated under reflux overnight with 35 mL concentrated hydrochloric acid. After evaporation, the crystals are triturated with acetone, filtered off with suction and dried in a vacuum dryer over phosphorus pentoxide. Yield: 4.2 g

Mp: 225-229 ° C.

Example M)

3-Hydroxy-3-methylpyrrolidine (78.4 mmol) 1-benzyl-3-hydroxy-3-methylpyrrolidine (EP 132 845) was dissolved in 150 ml ethanol and 2 g 10% palladium hydrogenated at 100 bar and 90 ° C. The catalyst is suctioned off, the filtrate is evaporated and the residue is distilled. Yield: 4.6 g

MP: 60-64 ° C / 0.08 mbar.

Example N)

3- (Dimethylamino) -3-hydroxypyrrolidine

a) 1-Benzyl-3- (dimethylaminomethyl) -3-hydroxypyrrolidine

9.6 g (50 mmol) of 5-benzyl-5-aza-1-oxaspiro [2,4] heptane are added dropwise to 50 ml of 50% dimethylamine solution and stirred overnight at room temperature. The mixture was evaporated and the residue was distilled. Yield: 10.3 g

Mp .: 94 ° C / 0.05 mbar.

b) 3- (Dimethylaminomethyl) -3-hydroxypyrrolidine

9.4 g (39 mmol) of 1-benzyl-3- (dimethylaminomethyl) 3-hydroxypyrrolidine are hydrogenated in 60 ml of methanol in the presence of 2 g of 5% palladium on carbon at 100 ° C at 90 bar. The catalyst was filtered off, the filtrate was evaporated and the residue was distilled.

Yield: 4.3 g

Mp .: 51 ° C / 0.06 mbar.

Example O)

3-Hydroxy-3- (methoxymethyl) pyrrolidine (a) 1-Benzyl-3-hydroxy-3- (methoxymethyl) pyrrolidine

5-Benzyl-1-oxa-5-azaspiro [2,4] -heptane (26.8 g, 0.14 mol) was heated to reflux overnight with 2.6 ml (14 mmol) of a 30% sodium methylate solution in 200 ml of absolute methanol. under refrigeration. Evaporate and distill.

Yield: 25.6 g (83%)

Mp: 107-112 ° C / 0.15 mbar.

b) 3-Hydroxy-3- (methoxymethyl) pyrrolidine (45 mmol) 1-benzyl-3-hydroxy-3-methoxymethylpyrrolidine was hydrogenated in 200 ml of methanol in the presence of 3 g of 10% palladium on carbon. At a pressure of 100 bar at 100 ° C. The catalyst is suctioned off, the filtrate is evaporated and the residue is distilled. Yield: 4.7 g (80%)

Mp .: 65 ° C / 0.4mbar.

Example P)

3- (tert-butoxycarbonyl-aminomethyl) -3-hydroxypyrrolidine

a) 1-Benzyl-3- (tert-butoxycarbonylaminomethyl) -3-hydroxypyrrolidine

3.2 g (80 mmol) of sodium hydroxide are dissolved in 40 ml of water, 15.6 g (75 mmol) of 3- (aminomethyl) -1-benzyl-3-hydroxypyrrolidine and 50 ml of tert-butanol are added dropwise at room temperature.

17.7 g (79 mmol) of di-tert-butyl ester of disic acid. After stirring overnight at room temperature, the product is filtered off with suction and the crystals are washed with dichloromethane and the filtrate is extracted with dichloromethane. The extracts were dried over potassium carbonate, evaporated and the residue was recrystallized from diisopropyl ether.

Yield: 19.1 g (83%).

117-119 ° C.

b) 3- (tert-Butoxycarbonylaminomethyl) -3-hydroxypyrrolidine

1-Benzyl-3- (tert-butoxycarbonylaminomethyl) -3-hydroxypyrrolidine (18.7 g, 61 mmol) was dissolved in methanol (120 mL) and in the presence of 3 g of 5% palladium on carbon in 90 ° C. hydrogenation at 100 bar. The catalyst was filtered off, the filtrate was evaporated and the residue was recrystallized from ethyl acetate.

Yield: 9.2 g (70%).

124-127 ° C.

Example Q)

3-Methoxy-3-methylamino-pyrrolidin

a) 1-Benzyl-3-N-benzyl-N-methylaminomethyl-3-hydroxypyrrolidine

A solution of N-benzyl-N-methylamine (15.6 mL, 0.115 mmol) in water (300 mL) was added dropwise

18.2 g (95 mmol) of 5-benzyl-1-oxa-5-azaspiro [2,4] heptane are stirred for 15 hours at room temperature. It was extracted with dichloromethane and the extracts were dried over potassium carbonate, concentrated and distilled to 160 ° C (oil bath temperature).

Crude yield: 27.1 g

According to gas chromatography the content is 100%.

b) 1-Benzyl-3-N-benzyl-N-methylaminomethyl) -3-methoxypyrrolidine (83 mmol) crude 1-benzyl-3-N-benzyl-N-methylaminomethyl) -3 -Hydroxypyrrolidine A solution of 50 g of absolute tetrahydrofuran in 50 ml of anhydrous tetrahydrofuran is added dropwise to a solution of 4 g of 80% sodium hydride in 100 ml of anhydrous tetrahydrofuran. THE

After the evolution of hydrogen had ceased, 12.4 g (87 mmol) of methyl iodide was slowly added dropwise, followed by heating overnight under reflux. The mixture was poured into ice water, extracted with toluene, dried over potassium carbonate, evaporated and distilled. Yield: 16.5 g.

Boiling range: 140-173 ° C / 0.1-0.23 mbar Yield: 9.1 g (26%) after further distillation Gas chromatographic content: 80%

Mp: 141 ° C / 0.07 mbar.

c) 3-Methoxy-3- (methylaminomethyl) pyrrolidine

A solution of 8.4 g (20 mmol) of 80% 1-benzyl-3- (benzylmethylaminomethyl) -3-methoxypyrrolidine in 100 ml of methanol was combined with 4.4 ml of concentrated hydrochloric acid and 4 g of 10% palladium hydrogenated on charcoal at 80 ° C and 120 bar. The catalyst was filtered, evaporated and a solution of 3 g of potassium hydroxide in 50 ml of methanol was added. The potassium chloride was filtered off and evaporated. The residue was taken up in chloroform again, filtered, concentrated and distilled.

Yield: 1.7 g (59%)

Mp: 33 ° C / 0.08 mbar.

Example R)

3- (isopropylamino-methyl) -3-hydroxypyrrolidine

a) 1-Benzyl-3- (isopropylaminomethyl) -3-hydroxypyrrolidine

To 20.65 g (0.35 mole) of isopropylamine in 75 ml of water was added dropwise 18.9 g (0.1 mole) of 5-benzyl-1-oxa-5-azaspiro [2,4] heptane and stirred for 15 hours at room temperature. After extraction with chloroform, the extract is dried over potassium carbonate, concentrated and the residue is distilled.

Yield: 22.3 g (90%)

Boiling point: 111 ° C / 0.1 lbar.

b) 3- (Isopropylaminomethyl) -3-hydroxypyrrolidine

17.4 g (70 mmol) of 1-benzyl-3-isopropylaminomethyl-3-hydroxypyrrolidine are hydrogenated in 200 ml of ethanol in the presence of 10 g of Pd-C (10%) at 100 bar and 100 ° C. The catalyst was filtered off, the filtrate was evaporated and the residue was distilled.

Yield: 7.3 g (66%).

By analogy to Example R, the following compounds were prepared from the corresponding amines.

Example S)

3-diethylamino-methyl-3-hydroxypyrrolidine

a) 1-Benzyl-3-diethylaminomethyl-3-hydroxypyrrolidine

Yield: 85%

Boiling point: 120 ° C / 0.01 mbar.

b) 3-diethylaminomethyl-3-hydroxypyrrolidine

Yield: 72%

Boiling point: 90 ° C / 0.05 mbar.

Example T)

3-Hydroxy-3- (1-pyrrolidinyl) pyrrolidine a) 1-Benzyl-3-hydroxy-3- (1-pyrrolidinyl) pyrrolidine Yield: 79%

Boiling point: 132 ° C / 0.07 mbar.

b) 3-hydroxy-3- (1-pyrrolidinyl) pyrrolidine

Yield: 65%

Boiling point: 112 ° C / 0.07 mbar.

Example U)

3-Hydroxy-3- (4-morpholinyl) pyrrolidine

a) 1-Benzyl-3-hydroxy-3- (4-morpholinyl) pyrrolidine Yield: 88%

Boiling point: 154 ° C / 0.4 mbar.

b) 3-hydroxy-3- (4-morpholinyl) pyrrolidine

Yield: 60%

Boiling point: 104 ° C / 0.2 mbar.

Example V)

3- (N-ethyl-N-methylamino) -3-hydroxypyrrolidine

a) 1-Benzyl-3- (N-ethyl-N-methylaminomethyl) -3-hydroxypyrrolidine

Yield: 76%

Boiling point: 110 ° C / 0.08 mbar.

b) 3- (N-Ethyl-N-methylaminomethyl) -3-hydroxypyrrolidine Yield: 67%

Boiling point: 70 ° C / 0.08 mbar.

c) Process for the preparation of 1-benzyl-3- (N-ethyl-1-N-methylaminomethyl) -3-hydroxypyrrolidine by other methods 21.8 g (93 mmol) of the l- (Benzylethylaminomethyl) -3-hydroxypyrrolidine in 9.5 g formic acid was stirred with 8.5 g 37% aqueous formaldehyde solution at 80 ° C for 4 hours. The solution is concentrated, the residue is taken up in a little water, made basic with potassium carbonate, extracted with chloroform, dried over potassium carbonate, concentrated and distilled.

Yield: 17.8 g (85%)

Boiling point: 110 ° C / 0.08 mbar.

Claims (1)

Patent Claim Point Process Compounds of Formula I - wherein R ⁴ is a group of formula (a): wherein 1 is 1 or 2, m is 1 or 2, wherein (1 + m) may be together 2 or 3, n is 1 or 2, Y is (C 1 -C 4) alkoxy, hydrogen, or amino, optionally substituted on one or both hydrogens with (C 1 -C 4) alkyl or (C 3 -C 5) cycloalkyl, or (C 1 -C 4) alkoxycarbonylamino, 1-pyrrolidinyl; or 1-morpholinyl, X 'for OH or C 1-4 alkoxy, characterized in that a) for the preparation of compounds of formula (IIIa), wherein 1, m is as defined above, and NR'R' is for alkoxy and hydrogen, except for Y; reacting a compound of formula (1) with an amine of formula (2) and the resulting compound of formula (3), wherein 1, m is as defined above, NR'R 'is except for alkoxy and hydrogen; HU 207 292 Β The amino groups given in Y, B is COO-alkyl, or CH ₂ C ₆ H ₅ are converted to the compound of formula (IIIa) and, if desired, the hydroxyl or Y of the compound of formula (IIa) can be alkylated, or b) for the preparation of compounds of formula I wherein Y is hydrogen or C1-C4 alkoxy, a compound of formula 4 - where B is benzyl, X ¹ is hydroxy, Y is C 1 -C 4 alkoxy or hydrogen and m is 1.1 is 1, n is 1 hydrogenation.