Continuous process for the preparation of amines

Details Continuous process for the preparation of amines Continuous process for the preparation of amines

2002-11-06

2004-01-27

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S414000, C564S488000

Reexamination Certificate

active

06683216

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for the preparation of amines. More specifically, this invention pertains to a continuous process for the preparation of amines by the reaction of alkaline hypohalites with carbox-amides.
BACKGROUND OF THE INVENTION
Amines are important intermediates for the preparation of liquid crystal polymers, agrochemical, and pharmaceutical compounds. Although many simple aliphatic and aromatic amines are available by efficient, low cost processes, such as reductive amination, displacement of halides with ammonia, or amination of alcohols, many synthetically difficult, hindered, or more reactive amines are prepared from their corresponding carboxamides by the Hofmann reaction. These more complex amines are especially useful in the production of agrochemical and pharmaceutical compounds. For example, cyclopropylamine is particularly useful as an agrochemical and pharmaceutical intermediate and is produced from cyclopropanecarboxamide by the Hofmann reaction.
The Hofmann reaction suffers from a number of disadvantages and often provides only moderate yields and selectivities. With complex and reactive carboxamides, for example, the Hofmann reaction is frequently subject to troublesome side reactions, such as hydrolysis of the carbox-amide, overhalogenation, and formation of acyl ureas (see, for example, E. S. Wallis and J. F. Lane,
Org. Reactions,
3, (1946), 267). To avoid these side reactions, it is often necessary to use expensive reagents, such as sodium methoxide, bromine, or phase transfer catalysts. These expensive reagents render the process uneconomical for commercial production. In addition, the Hofmann reaction is usually carried out in a complex, multistep process that is often not practical for the more efficient continuous mode of operation.
Several modifications of the Hofmann reaction have appeared in the patent literature that attempt to circumvent these problems. For example, U.S. Pat. No.'s. 4,590,292; 5,032,687; 5,728,873; and British Patent No. 1,257,097; describe process modifications to reduce hydrolysis of the starting carboxamide, first, by adding the hypochlorite at low temperature (<20° C.) to form the N-chlorocarboxamide intermediate, then by adding base to allow the rearrangement to proceed. Although this method of addition reduces hydrolysis of the carboxamide prior to chlorination, it can lead to the formation of acyl ureas which have low solubility and can cause plugging of process lines and equipment.
Many of the above-mentioned problems are exacerbated when the Hofmann reaction is conducted in a continuous reaction mode. For example, the formation of acyl urea by-products becomes especially troublesome in a continuous operation. This by-product is often insoluble in the reaction milieux and causes plugged process lines and valves. Maintaining the bleach to carboxamide ratio at optimum levels is important under continuous conditions. Incomplete conversion of the carboxamide and poor yields result if too little bleach is used. By contrast, too much bleach results in overchlorination to produce N-chloramines. These N-chloroamines subsequently may undergo decomposition, degradation to nitriles, or further reaction with the amine product to form hydrazines (see for example, Vaidyananthan and Wilson,
J. Org. Chem.,
54, (1989), 1815. and Schiessel in
Kirk
-
Othmer Encyclopedia of Chemical Technology,
4
th
ed., vol.13 (1995), p. 560). In a continuous process, these dangerous and toxic materials may accumulate which presents health and physical hazards and makes purification of the desired product difficult.
Accurately controlling hypohalite concentrations is difficult because of the variability in concentration of commercial hypohalite and because of the instability of aqueous hypohalite solutions. As a consequence of this instability, the concentration of hypohalite continuously declines upon storage. Frequent analysis of the hypohalite solutions are required to insure that proper amounts are used. For a commercial process, such analytical requirements can be expensive and subject to errors that, in turn, cause operational delays and poor quality product.
There have been several processes that describe the operation of a Hofmann reaction to produce amines in a continuous or semi-continuous mode. German Patent Application No. 3,909,142 A2 discloses a continuous process for producing amines,.including cyclopropylamine, where an aqueous solution of sodium hydroxide and sodium hypochlorite is mixed with an aqueous solution of carboxamides in a tubular reactor operating at a temperature of 45 to 260° C. U.S. Pat. No. 3,847,974 discloses a continuous process utilizing a 2-stage reactor system to produce the intermediate N-chlorocarboxamide and to convert the N-chlorocarboxamide to the amine. Koizumi et al. in
Kogyo Kagaku Zasshi
(1965), 68(1), 102-105 (Chem. Abstracts No. 62:90867) disclose the preparation of 5-methyl-3-aminoisoxazole from 5-methylisoxazole-3-carboxamide using a continuous flow 3-stage stirred tank reactor. These processes do not provide a means to accurately measure and control the concentration of hypohalite and, hence, the extent of reaction. As a consequence, these processes are subject to operational and purification difficulties from the formation of side products. U.S. Pat. No. 5,728,873 describes a 2-stage, semicontinuous process wherein the reaction of cyclopropanecarboxamide with hypochlorite is conducted batchwise at a temperature range of 0-20° C. and then, the reaction product is subsequently fed continuously to a tubular reactor at a temperature range of 45-260° C. Although this process may avoid some of the problems associated with side reactions, its productivity is reduced because of the less efficient, semicontinuous mode.
As is evident from the processes described hereinabove, the known methods for the preparation of amines through the Hofmann reaction require multiple, complex processing steps to avoid side reactions. These processes are difficult to conduct in a continuous manner and thus operate with low space-time yields. Of the known continuous processes, none provide a method to operate the Hofmann reaction-in a selective manner that is generally applicable to a wide range of carboxamides.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of amines comprising the following steps:
I. continuously feeding a carboxamide reactant, an aqueous alkaline hypohalite reactant, and an aqueous alkaline hydroxide reactant to a first reaction zone wherein the carboxamide, hypohalite, and hydroxide react to form a first reaction mixture comprising a plurality of components wherein at least one of the components is an N-halo-carboxamide;
II. continuously removing the first reaction mixture from the first reaction zone;
III. measuring the concentration of at least one component in the first reaction mixture and using the result of that measurement to control the feed rate of at least one of the reactants of step I to achieve at least 90% conversion of the carboxamide in the first reaction zone; and
IV. continuously feeding the first reaction mixture to a second reaction zone wherein the first reaction mixture further reacts to form a second reaction mixture comprising an aqueous solution of an amine.
Although a variety of reactor types may be used, a preferred embodiment of this invention is a continuous process wherein the first reaction zone comprises a tubular reactor which enables the conversion of the carboxamide to occur under substantially plug-flow conditions.
Another embodiment of the present invention is a continuous process wherein the measurement of components in the first reaction mixture is carried out using UV-Visible spectroscopy, infrared spectroscopy, or a combination thereof. Yet another embodiment of the present invention is a continuous process for the preparation of cyclopropylamines which comprises the steps of:
I. continuously feeding (i) an aqueous solution of a cyclopropanecarboxamide and (ii) a solutio

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