METHOD FOR PREPARING 4-CYANOPIPERIDINE HYDROCHLORIDE

Abstract

The present invention describes a novel method for preparing 4-cyanopiperidine hydrochloride.

Claims

1. A method for preparing 4-cyanopiperidine hydrochloride of formula (I), ##STR00005## in high yield and with high purity, wherein isonipecotamide (II) ##STR00006## is dehydrated with thionyl chloride in a diluent in the presence of a formamide of formula (III), wherein the formamide of formula (III) is defined as follows: ##STR00007## R.sup.1, R.sup.2 are mutually independently hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.6-C.sub.10-aryl or together form a —CH.sub.2—CH.sub.2—X.sub.n—CH.sub.2—CH.sub.2— residue, in which X is CH.sub.2, oxygen or sulphur and n is 0 or 1.

2. A method according to claim 1, wherein the formamide of formula (III) is defined as follows: R.sup.1, R.sup.2 are mutually independently hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, isobutyl, tertiary butyl or together form a —CH.sub.2—CH.sub.2—X.sub.n—CH.sub.2—CH.sub.2 residue; X is CH.sub.2 or oxygen, and n is 0 or 1.

3. A method according to claim 1, wherein the formamide of formula (III) is defined as follows: R.sup.1, R.sup.2 are 1-butyl.

4. A method according to of claim 1, wherein 1 to 5 mol equivalents of formamide are used, based on isonipecotamide, optionally 1.5 to 3.5 mol equivalents, optionally 2 to 3 mol equivalents.

5. A method according to of claim 1, wherein 0.1 to 3 mol equivalents of formamide are used, based on isonipecotamide, optionally 0.3 to 2 mol equivalents, optionally 0.5 to 1.5 mol equivalents.

6. A method according to claim 1, wherein the reactant isonipecotamide has a water content of less than 5%, optionally less than 2%.

7. A method according to claim 1, wherein the diluent is toluene, ortho-xylene, meta-xylene, para-xylene, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or mixtures thereof.

Description

EXAMPLE 1

[0037] 11.9 g [75.7 mmol] of dibutylformamide (99%) were added to a suspension of 10 g [75.7 mmol] of isonipecotamide (97%) in 50 ml of n-propyl acetate at 20° C. over 5 minutes. After 5 minutes, the addition of 18.91 g [158.9 mmol] of thionyl chloride at 20° C. was initiated. This addition required 45 minutes in which the temperature was maintained constantly at 20° C. After the end of the addition, the mixture was stirred at 20° C. for a further 18 hours. The suspension was filtered and the filter residue was washed with n-propyl acetate. After drying there remained 8.55 g of a colourless solid. Analysis by quantitative NMR spectroscopy gave a 4-cyanopiperidine hydrochloride content of 95% (w/w). A yield of 73% of theory is calculated therefrom.

[0038] Chloride content by ion chromatography (IC): 26.4% (calc.: 24.8%).

[0039] .sup.1H-NMR (600 MHz, d.sub.6-DMSO): δ=1.91-2.13 (m, 2H), 2.08-2.13 (m, 2H), 2.97-3.00 (m, 2H), 3.12-3.2 (m, 3H), 9.27 (s, br, 2H) ppm.

EXAMPLE 2

[0040] In a 1 litre jacketed vessel, 111.56 g [0.702 mol] of dibutylformamide (99%) were added to a suspension of 92.8 g [0.702 mol] of isonipecotamide (97%) in 450 ml of n-propyl acetate at 20° C. over 10 minutes. After 5 minutes, the addition of 175.46 g [1.475 mol] of thionyl chloride at 20° C. was initiated. This addition required 60 minutes in which the temperature was maintained constantly at 20° C. After the end of the addition, the mixture was stirred at 20° C. for a further 18 hours. The suspension was released from the reactor and filtered. The filter cake was washed three times each with 150 ml of n-propyl acetate and then dried. 83.07 g of a colourless solid were obtained. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 98.1% (w/w). A yield of 79.1% of theory is calculated therefrom.

EXAMPLE 3

[0041] In a 1 litre jacketed vessel, 111.56 g [0.702 mol] of dibutylformamide (99%) were added to a suspension of 92.8 g [0.702 mol] of isonipecotamide (97%) in 450 ml of n-propyl acetate at 20° C. over 10 minutes. After 5 minutes, the addition of 175.46 g [1.475 mol] of thionyl chloride at 20° C. was initiated. This addition required 60 minutes in which the temperature was maintained constantly at 20° C. After the end of the addition, the mixture was stirred at 20° C. for a further 18 hours. The suspension was released from the reactor and filtered. The filter cake was washed three times each with 150 ml of n-propyl acetate and then dissolved in 532 g of methanol. From the resulting 681.2 g of solution, 10 g were concentrated under vacuum from which 1.2 g of colourless solid were obtained as residue. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 98.5% (w/w). A yield of 78.1% of theory is calculated therefrom.

EXAMPLE 4

[0042] 56.8 g [56.8 mmol] of dibutylformamide (99%) were added to a suspension of 10 g [75.7 mmol] of isonipecotamide (97%) in 50 ml of n-propyl acetate at 20° C. over 5 minutes. After 5 minutes, the addition of 18.91 g [158.9 mmol] of thionyl chloride at 20° C. was initiated. This addition required 45 minutes in which the temperature was maintained constantly at 20° C. After the end of the addition, the mixture was stirred at 20° C. for a further 18 hours. The suspension was filtered and the filter residue was washed with n-propyl acetate. After drying there remained 9.92 g of a colourless solid. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 95.9% (w/w). A yield of 85.7% of theory is calculated therefrom.

EXAMPLE 5

[0043] 11.9 g [75.7 mmol] of dibutylformamide (99%) were added to a suspension of 10 g [75.7 mmol] of isonipecotamide (97%) in 50 ml of toluene at 20° C. over 5 minutes. After 5 minutes, the addition of 18.91 g [158.9 mmol] of thionyl chloride at 20° C. was initiated. This addition required 45 minutes in which the temperature was maintained constantly at 20° C. After the end of the addition, the mixture was stirred at 20° C. for a further 18 hours. The suspension was filtered and the filter residue was washed with toluene. After drying there remained 9.63 g of a colourless solid. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 99.7% (w/w). A yield of 86.5% of theory is calculated therefrom.

EXAMPLE 6

[0044] In a 1 litre jacketed vessel, 111.56 g [0.702 mol] of dibutylformamide (99%) were added to a suspension of 92.8 g [0.702 mol] of isonipecotamide (97%; water content: 0.95%) in 450 ml of toluene at 20° C. over 10 minutes. After 5 minutes, the addition of 175.46 g [1.475 mol] of thionyl chloride at 20° C. was initiated. This addition required 60 minutes in which the temperature was maintained constantly at 20° C. After the end of the addition, the mixture was stirred at 20° C. for a further 18.5 hours. The suspension was released from the reactor and filtered. The filter cake was washed three times each with 150 ml of toluene and then dried. 79.92 g of a colourless solid were obtained. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 98.4% (w/w). A yield of 76.4% of theory is calculated therefrom.

EXAMPLE 7

[0045] To a stirred suspension of 5 g [39 mmol] of isonipecotamide and 12.3 g [78.0 mmol] of dibutylformamide in 29 ml of toluene were added dropwise 13.9 g [117 mmol] of thionyl chloride at 0° C. over 15 min, whereupon the temperature increased up to 10° C. The mixture was then stirred at 0° C. for 3 days. The suspension was filtered off and the filter residue was washed with toluene. After drying under vacuum, 4.43 g of a colourless solid were obtained. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 96.4% (w/w). A yield of 74.7% of theory is calculated therefrom.

EXAMPLE 8

[0046] To a stirred suspension of 5 g [39 mmol] of isonipecotamide and 0.29 g [3.9 mmol] of dimethylformamide in 40 ml of n-propyl acetate were slowly added dropwise 13.9 g [117 mmol] of thionyl chloride at 10° C., whereupon the temperature increased up to 15° C. The mixture was then stirred at 20° C. for 38 hours. A further 1.16 g [15.6 mmol] of dimethylformamide were then added, and the mixture was stirred at 20° C. for a further 21 h. The suspension was filtered off and the filter residue was washed with n-propyl acetate. After drying under vacuum at 50° C., 4.55 g of a beige solid were obtained. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 92.2% (w/w). A yield of 73.3% of theory is calculated therefrom.

EXAMPLE 9

[0047] To a stirred suspension of 10 g [78 mmol] of isonipecotamide and 12.3 g [78.0 mmol] of dibutylformamide in 50 ml of n-butyl acetate were slowly added dropwise 19.5 g [163 mmol] of thionyl chloride at 20° C., whereupon the temperature increased up to 30° C. The mixture was then stirred at 20° C. for 20 hours. The suspension was filtered off and the filter residue was washed with n-butyl acetate. After drying under vacuum, 10.8 g of a colourless solid were obtained. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 81.7% (w/w). A yield of 77.1% of theory is calculated therefrom.

COMPARATIVE EXAMPLE 1 (ACCORDING TO THE PROCEDURE IN US 2006/0084808 A1)

[0048] At the start, 10 g [75.7 mmol] of isonipecotamide (97%) were added in portions to 23.2 g [195 mmol] of thionyl chloride at 20° C., whereupon the temperature increased to 35° C. Already after addition of about 2 g of the isonipecotamide, a viscous, sticky lump formed which adhered to the wall of the flask and even with relatively rapid stirring could not be detached and comminuted. The experiment therefore had to be terminated