JPH0533707B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] The present invention relates to a novel method for producing 4-cyanoquinuclidine or a salt thereof.

The compound of the present invention is useful as a synthetic intermediate for medicines, chemical reagents, etc., but its unique structure makes it difficult to synthesize. For example, [Helvetica chimica acta No. 194]
Examples of its synthesis are reported in Vol. 195, pp. 1672-1679 (1954) and Vol. 195, pp. 1680-1680 (1954). In the same document, 4-cyanoquinuclidine uses 4-carbamoylpiperidine as a starting material, and N-methyl-4-carbamoylpiperidine, N-methyl-4-cyanopiperidine, and N-methyl-4-cyanoquinuclidine. However, there are problems in that the number of steps is large because N-methylation is performed first and demethylation is performed last, and the yield of the conversion step from piperidine to quinuclidine is as low as 17%. be.

Therefore, an object of the present invention is to provide an industrially excellent method for producing 4-cyanoquinuclidine or a salt thereof.

[Structure of the invention]

The present invention has the general formula: A formula characterized by reacting a compound represented by [wherein X represents a halogen atom] or a salt thereof with a base: This is a method for producing 4-cyanoquinuclidine or a salt thereof represented by:

Examples of the halogen atom for X in the above general formula () include a chlorine atom, a bromine atom, an iodine atom, and the like. In addition, salts of compounds of general formula () and formula () include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, carbonate, and bicarbonate; acetate, maleic acid salt, etc. acid salt, lactate, tartrate,
Examples include organic carboxylates such as trifluoroacetate; organic sulfonates such as methanesulfonate, benzenesulfonate, and toluenesulfonate; amino acid salts such as aspartate and glutamate.

Examples of the base used in the present invention include sodium amide, lithium amide, potassium amide, lithium diisypropylamide, lithium diethylamide, lithium hexamethyldisilazane, potassium t-butoxide, sodium hydride, potassium hydride, lithium hydride, and lithium trifluoride. Examples include enylmethane, sodium triphenylmethane, potassium triphenylmethane, and sodium benzene.

This reaction can be carried out at -100°C to solvent reflux temperature. Reaction solvents include 1,2-dimethoxyethane, tetrahydrofuran, diethyl ether, dioxane, benzene, xylene, toluene, methanol, ethanol, isopropanol, n-propanol, n-butanol, t-butanol, dimethylsulfoxide, dimethylformamide. , liquid ammonia, or a mixed solvent thereof.

Next, the present invention will be explained in more detail by showing experimental examples and examples.

Experimental example 1 N-(2-hydroxyethyl)-4-carbamoylpiperidine 4-carbamoylpiperidine 35g ethanol
23.9 ml of 2-chloroethanol, 82.0 g of potassium carbonate and 4.5 g of sodium iodide were added to the 500 ml solution, and the mixture was refluxed for 20 hours. After the reaction solution was cooled to room temperature, it was filtered through Celite. The liquid was concentrated under reduced pressure, and the residue was washed and dried to obtain 46.6 g of the target product.

Melting point: 141-142℃ Infrared absorption spectrum (cm ^-1 , Nujiol):
3360, 3160, 1650, 1610 NMR spectrum (δ, DMSO- _d6 ): 1.2-2.1
(7H, m), 2.26 (2H, t, J=8Hz), 2.6
~2.9 (2H, m), 4.39 (2H, t, J=8
Hz), 4.32 (1H, br.s), 6.59 (1H, br.s),
7.11 (1H, br.s) Experimental example 2 N-(2-chloroethyl)-4-cyanopiperidine hydrochloride Acetonitrile 390 of 38.7 g of the compound of Experimental Example 1
ml suspension, add 1 82 ml of thionyl chloride under ice-cooling and stirring.
It took a while to form into drops. The resulting solution was refluxed for 4 hours and then concentrated. Isopropanol 100 to the residue
ml and refluxed for 10 minutes. The solution was cooled to room temperature and the resulting crystals were collected. Further, isopropyl ether was added to the liquid and the resulting crystals were collected. A total of 43.1 g of the target product was obtained as colorless crystals.

Melting point: 176-178℃ Infrared absorption spectrum (cm ^-1 , Nujiol):
2220 NMR spectrum (δ, DMSO- _d6 ): 1.7-2.3
(4H, m), 2.6-3.8 (7H, m), 3.98 (2H,
t, J=8Hz) Experimental example 3 N-(2-chloroethyl)-4-cyanopiperidine A solution of 2.63 g of 4-cyanopiperidine in 50 ml of isopropanol and 2.6 g of 1-bromo-2-chloroethane
ml and 6.6 g of potassium carbonate were added, and the mixture was refluxed for 10 hours. The reaction solution was concentrated under reduced pressure, and a 50% aqueous potassium carbonate solution was added to the residue, followed by extraction with diethyl ether. The extract was washed with saturated brine, dried over anhydrous potassium carbonate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent:
The product was purified using methanol-chloroform) to obtain 0.31 g of the target product as an oil.

Infrared absorption spectrum (cm ^-1 , neat): 2220 NMR spectrum (δ, CDCl ₃ ): 1.7-2.1 (4H,
m), 2.3-2.9 (7H, m), 3.56 (2H, t,
J=8Hz) Example 1 4-cyanoquinuclidine and its P-toluenesulfonate 150 g of sodium amide and 7.2 g of sodium iodide were suspended in 1.5 g of 1,2-dimethoxyethane and stirred at room temperature for 1 hour. 100 g of the compound of Experimental Example 2 was added to this and stirred for 24 hours. The reaction solution was added to ice water 2 and filtered through Celite. The residue was washed with 300 ml of diethyl ether. The organic layer of the above liquid and this washing liquid were combined and dried by adding anhydrous potassium carbonate. This was concentrated to obtain 78.7 g of 4-cyanoquinuclidine. Further, 1 kg of anhydrous potassium carbonate was added to the aqueous layer of the liquid, and then extracted with chloroform. The extract was dried by adding anhydrous potassium carbonate and concentrated to obtain 18.9 g of 4-cyanoquinuclidine. Total 4-cyanoquinuclidine 97.6g (yield
66.3%).

85.0g of 4-cyanoquinuclidine in ethanol
A solution of 119 g of p-toluenesulfonic acid monohydrate in 350 ml of ethanol was added, and the mixture was stirred at 40°C for 1 hour. The reaction solution was cooled with ice, and the precipitated crystals were collected. This was washed with ethanol and diethyl ether, and 4-cyanoquinuclidine p-
182.9g of colorless crystals of toluenesulfonate (yield
95%).

4-Cyanoquinuclidine Melting point: 133°C Infrared absorption spectrum (cm ^-1 , Nudiol):
2225 NMR spectrum (δ, _CDCl3 ): 1.6-2.0 (6H,
m), 2.7 to 3.0 (6H, m) 4-cyanoquinuclidine p-toluenesulfonate Melting point: 220°C or higher Infrared absorption spectrum (cm ^-1 , Nudiol):
2220 NMR spectrum (δ, DMSO- _d6 ): 2.0-2.3
(6H, m), 2.27 (3H, s), 3.1~3.5 (6H,
m), 7.08 (2H, d, J=10Hz), 7.45 (2H,
d, J = 10Hz) Example 2 4-cyanoquinuclidine n-Butyllithium 19.9% in a solution of 4.7ml diisopropylamine in 70ml tetrahydrofuran at -78°C.
ml was added and stirred for 10 minutes. A solution of 5.0 g of the compound of Experimental Example 3 in 30 ml of tetrahydrofuran was added dropwise to the obtained lithium diisopropylamide solution over 10 minutes at the same temperature. After stirring at the same temperature for 20 minutes,
The mixture was further stirred at 0°C for 30 minutes. The reaction solution was washed with saturated brine and then extracted with chloroform. The extract was concentrated and the residue was sublimated to obtain 2.6 g of the target product (yield:
65.3%).

Melting point: 133°C Infrared absorption spectrum (cm ^-1 , Nujiol):
2225 NMR spectrum (δ, _CDCl3 ): 1.6-2.0 (6H,
m), 2.7-3.0 (6H, m)

Claims (1)

[Claims] 1. General formula: A formula characterized by reacting a compound represented by [wherein X represents a halogen atom] or a salt thereof with a base: A method for producing 4-cyanoquinuclidine or a salt thereof represented by: