MXPA99009263A - Process for producing 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof - Google Patents

Abstract

La presente invención provee un procedimiento seguro y fácilmente operable para producir 1-clorocarbonil-4-piperidinopiperidina o clorhidrato del mismo en un alto rendimiento;específicamente descrita, la presente invención se refiere a un procedimiento para producir 1-clorocarbonil-4-piperidinopiperidina o clorhidrato de la misma, que consiste en hacer reaccionar 4-piperidinopiperidina con un halogenuro de trialquilsililo para obtener un trialquilsililo de 4-piperidinopiperidilo, haciéndolo reaccionar con un gas de dióxido de carbono para obtener un derivado de trialquilsililcarbarnato de piperidinapiperidinilo, haciendo reaccionar el derivado con cloruro de tionilo o similar para obtener clorhidrato de 1-clorocarbonil-4-piperidinopiperidina y opcionalmente tratándolo con una base fuerte.

Description

PROCEDURE TO PRODUCE 1-CHLOROCARBONIL-4- PIPERIDINOPIPERIDINA OR CHLORHYDRATE OF THE SAME TECHNICAL FIELD The present invention relates to a novel process for producing 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof, which is an important intermediate as an amido group and is used in the field of pharmaceuticals and the like.

TECHNICAL BACKGROUND 1-Chlorocarbonyl-4-piperidinopiperidine and hydrochloride thereof are important intermediates as members of the amido group and are widely used in the field of pharmaceuticals and the like. As an example of the process for producing 1- chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof, there is a report by S. Sawada (S. Sawada, Chem. Pharm. Bull., 39, 1446 (1991)), whose procedure is characterized by reacting 4-piperidinopiperidine with a phosgene dimer (TCF), removing an unreacted portion of the phosgene dimer to obtain 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride and, if necessary, treating this hydrochloride with a solution water from a weak base such as sodium bicarbonate or potassium carbonate. However, this procedure is not suitable for a large-scale production of 1-chlorocarbonyl-4-piperidinopiperidine and its hydrochloride, since the phosgene dimer is extremely toxic and must be treated using special devices in a special operating area and also , your transportation is strictly regulated. In addition, this product is precipitated as a hydrochloride in a form similar to agar and it takes a long time for the unreacted phosgene dimer to filter, this represents a high risk in which operators may be exposed to the toxicity of the dimer of phosgene. In addition, the yield obtained by this procedure is scarce. Since the precipitated hydrochloride is dissolved directly in aqueous solution and hydrolyzed under the condition of a weak base of the aqueous solution, each part of the hydrochlorides can not be converted to 1-chlorocarbonyl-4-piperidinopiperidine. An object of the present invention is therefore to provide a very safe and easily operable process for producing 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof in a high yield. sk ^^ sA In view of the above circumstances, the inventors of the present have conducted an extensive investigation with the intention of achieving the above object. As a result, it has been found that 1-chlorocarbonyl-4-piperidinopiperidine or hydrochloride thereof can be obtained easily and safely in a high yield by trialkylsilylation of 4-piperidinopiperidine, by reacting the resulting compound with a carbon dioxide gas and subsequently with thionyl chloride or the like and optionally treating with a strong base, leading to the termination of the present invention. The present invention can be represented by the following reaction schemes: (1 ) carbon imilar (3) (4) (5) where R1, R2 and R3 are the same or different and each represents a linear or branched C-? -6 alkyl group. Specifically described, in the present invention, a method is thus provided for producing 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride represented by the formula (4) or 1-chlorocarbonyl-4-piperidinopiperidine represented by the formula (5) , which consists of reacting (step 1) 4-piperidinopiperidine represented by the formula (1) with a trialkylsilyl halide to obtain a 4-piperidinopiperidinyltrialkylsilyl represented by the formula (2), by reacting (step 3) the resulting compound with a carbon dioxide gas to form a 4-piperidinopiperidinyl trialkylsilylcarbamate derivative represented by the formula (3), by reacting the resulting derivative with one or more substances selected from ~ £ 3mt¡et * ¿? - ^ * j¿ ~. a group consisting of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride and phosphoryl trichloride to obtain 1-chlorobarbonyl-4-piperidinopiperidine hydrochloride represented by the formula (4) and subsequently optionally treating the resulting hydrochloride with a strong base.

BEST METHODS TO CARRY OUT THE INVENTION The method of the present invention will be described hereinafter in relation to the steps. (1) Step 1 The trialkylsilyl halide to be reacted with 4-piperidinopiperidine has a structure in which the silicon atom is bonded by three alkyl groups on a halogen atom. Examples of the alkyl group include linear or branched C? -6 groups. Each of the three alkyl groups may be the same or different. Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl and cyclopentyl. In the present invention, C1-4 alkyl groups are particularly preferred. Examples of the halogen atom include chlorine, bromine and iodine, and chlorine is particularly preferred. In a suitable solvent such as methylene chloride, benzene or acetonitrile, a trialkylsilyl halide and 4-piperidinopiperidine are i? ^^ m ^^^^^ j ^^ iiSS ^ - ^ & ^^^ js & Á ^,, .i dissolved separately. While one of the resulting solutions is stirred as needed, the other is gradually added dropwise thereto at room temperature or lower, by means of which they react. Stirring is continued for 30 minutes at an additional 6 hours to obtain 4-piperidinopiperidinyltrialkylsilyl (2). It is preferred to carry out the reaction, for example, under a nitrogen atmosphere. In addition, it is preferred to add trialkylsilyl halide in an amount (molar ratio) greater than 4-piperidinopiperidine. (2) Step 2 While the solution obtained in step 1 is stirred as needed, a carbon dioxide gas is blown into the solution, where a 4-piperidinopiperidinyl trialkylsilylcarbamate derivative is formed. It is preferred that the carbon dioxide gas is blown into the solution in an amount (molar ratio) twice greater than 4-piperidinopiperidine at room temperature and atmospheric pressure for 30 minutes to 6 hours. (3) Step 3 To the solution obtained in step 2, one or more substances selected from the group consisting of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphoryl trichloride and the like are added dropwise at room temperature or lower. oxalyl chloride. After finishing the dropwise addition, stirring is continued for about 1 to 48 hours. The reaction mixture is subsequently filtered to remove the remaining 4-piperidinopiperidine hydrochloride, whereby 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride of the present invention is obtained in the filtrate. The reaction up to this point is preferably conducted, for example, under a nitrogen atmosphere. It is preferred to add thionyl chloride or the like in an equal amount (molar ratio) to the trialkylsilyl halide.

The hydrochloride thus obtained is washed with water, dried, concentrated and recrystallized in a manner known per se in the art, whereby a high purity 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride is obtained. (4) Step 4 The filtrate obtained in step 3 is added to an aqueous solution of a strong base. Examples of the strong base used herein include sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide and ammonium hydroxide. No particular limitation is imposed on the concentration of said strong base, but 0.5 to 50% by weight, preferably 1 to 30% by weight is preferred. By said treatment, 1-chlorocarbonyl-4-piperidinopiperidine is obtained in an organic layer. The product thus obtained is washed with water, dried, concentrated and recrystallized in a manner known per se in the art, whereby high purity 1-chlorocarbonyl-4-piperidinopiperidine (5) can be obtained in high yield. In the present invention, the steps 1 to 4 described above can be performed in the reactor of step 1, which cause a significant improvement in performance compared to the conventional method. Alternatively, in the case where preferential synthesis of 1-chlorocarbonyl-4-piperidinopiperidine (in the free form) is proposed, it is possible to incorporate a basic substance, such as triethylamine, for use as a hydrogen chloride scavenger in step 3 .

EXAMPLE The present invention will now be described in more detail by means of an example; however, it must be borne in mind that the present invention is not limited to the following example or by the same.

EXAMPLE 1 Synthesis of 1-chlorocarbonyl-4-piperidinopiperidine (1-5) In 300 ml of methylene chloride, 20 ml (158 mmol) of trimethylsilyl chloride was dissolved. While the resulting solution was stirred under ice cooling under a nitrogen atmosphere, a solution of 22 g (131 mmol) of 4-piperidinopiperidine (1-1) dissolved in 100 ml of methylene chloride was gradually added dropwise during a hour. The resulting mixture was stirred at room temperature for one hour, whereby a solution with trimethylsilyl of 4-piperidinopiperidinyl (1-2) was obtained. While the resulting solution was stirred, 5.9 liters (262 mmoles) of a carbon dioxide gas of atomic pressure was blown into the solution for one hour, whereby a solution containing a 4-piperidinopiperidinyl trimethylsilylcarbamate derivative was obtained (1-3). To the resulting solution, 11.5 ml (158 mmol) of thionyl chloride was added dropwise over 10 minutes under ice-cooling and nitrogen atmosphere, followed by stirring at room temperature for 18 hours, whereby a solution was obtained which contained 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (1-4). The solution was filtered and 8.8 g (33%) of 4-piperidinopiperidine hydrochloride was recovered as a residue. Under cooling with ice, the filtrate was added to 330 ml of a 10% aqueous solution of sodium hydroxide.

Subsequently, the organic layer obtained by separation was washed with water, dried over anhydrous magnesium sulfate and subsequently concentrated under a lower pressure. Isopropyl ether (50 ml) was added to a concentrate to dissolve the latter in the above, followed by cooling to 0 ° C for 2 hours. The precipitate was subsequently removed by filtration and the residue was concentrated under reduced pressure. The concentrate thus obtained was recrystallized from 50 ml of n-hexane, whereby 15 g of the title compound (1-5) was obtained. The compound thus obtained had the following physical properties: Melting point: 63.8 ° C Titration with HCl: 96.46% IR cnT1: 1725, 1409 ^^ i ^ -a-a ^^ - =. ^ -.

NMR d: 1.0-2.1 (10H, m), 2.1-3.4 (7H, m), 4.1-4.6 (2H, m).

EXPLOITATION CAPACITY IN THE INDUSTRY The process of the present invention makes it possible to provide, by safe and easy operation, 1-chlorocarbonyl-4-piperidinopiperidine or high purity hydrochloride thereof in high yield.

Claims (1)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for producing 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride represented by the following formula (4): or 1-chlorocarbonyl-4-piperidinopiperidine represented by the following formula (5): which is to react 4-piperidinopiperidina represented by the following formula (1): with a trialkylsilyl halide to obtain a 4-piperidinopiperidinyltrialkylsilyl represented by the following formula (2): wherein R1, R2 and R3 are the same or different and each independently represents a linear or branched C-? 6 alkyl group; by reacting the resulting compound with a carbon dioxide gas to obtain 4-piperidinopiperidinyl trialkylsilylcarbamate derivative represented by the following formula (3): where R1, R2 and R3 have the same meanings as described above; reacting the derivative with one or more substances selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride and phosphoryl trichloride; and optionally making it react with a strong base.