Organic compounds -- part of the class 532-570 series – Organic compounds – Imidate esters
Reexamination Certificate
1999-11-15
2001-06-26
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Imidate esters
Reexamination Certificate
active
06252103
ABSTRACT:
The present invention relates to a process for the preparation of O-alkylisoureas in the form of their acid addition salts.
O-Alkylisoureas and their acid addition salts are useful intermediates which can be reacted, for example, with primary or secondary amines to give substituted guanidinium compounds. Substituted guanidinium compounds are widespread in nature. Important members of this class of substances are, for example, amino acids, such as arginine and creatine. In addition, substituted guanidine compounds are known as sterically hindered bases, as biocides and as complex ligands. Owing to the high preparation costs, the majority of the compounds of this type are, however, greatly restricted in their industrial applicability.
One possibility for the preparation of O-alkylisoureas is the reaction of urea with alkyl-transferring reagents, such as dialkyl sulfates. The synthesis of O-methylisourea by alkylating urea with dimethyl sulfate is possible, for example, by suspending the urea in the dialkyl sulfate and heating the mixture. The reaction is strongly exothermic. A disadvantage is the poor solubility of the urea in the dialkyl sulfate. The reaction is therefore slow to start. As the reaction progresses, however, more and more urea is dissolved, which may lead to the reaction rapidly going out of control. This is a serious problem from the point of view of safety. Undesired N-alkylations and multiple alkylations are observed as a result of an uncontrolled reaction. Moreover, O-alkylisoureas undergo thermal decomposition above 100° C. The purity and the yield of the product are impaired by said circumstances.
JP 62-030983 recommends carrying out the reaction of urea and dimethyl sulfate in the presence of from 7 to 30 ml of methanol per mol of urea or dimethyl sulfate. This is said to achieve evaporative cooling, i.e. the temperature increase during the exothermic reaction is limited because some of the heat of reaction is consumed by the heat of evaporation of the methanol. However, the disadvantage of this process is that dimethyl ether is formed from methanol and dimethyl sulfate in a secondary reaction. This is undesirable owing to the danger of explosion of the dimethyl ether and the loss of alkylating agent. The formation of dimethyl ether and the vaporization of the methanol moreover lead to a considerable pressure increase and volume increase, respectively, complicating the industrial implementation of the reaction described.
It is an object of the present invention to provide an economical and easily carried out process for the preparation of O-alkylisoureas in the form of their acid addition salts, which process permits a simple reaction and leads to a particularly pure product in high yield.
We have found, surprisingly, that this object is achieved by a continuous reaction of urea with an alkyl-transferring reagent.
The present invention therefore relates to a process for the preparation of an O-alkylisourea of the formula I,
where R
1
is C
1
- to C
20
-alkyl, in the form of an acid addition salt, in which urea and an alkyl-tranferring reagent, if required dissolved or suspended in a diluent, are reacted at 40-200° C. in a continuously operated reactor.
The O-alkylisourea is obtained in the form of an acid addition salt by initially taking the isourea in protonated form together with an anion which originates from the alkyl-transferring reagent. The anion may be, for example, a halide, such as chloride, bromide or iodide, sulfate or a C
1
-C
20
-alkylsulfate, such as methylsulfate. The O-alkylisourea acid addition salt is obtained as a rule in the form of an oily substance. The O-alkylisourea acid addition salts often have melting points close to or below the handling temperature, or their crystallization is kinetically inhibited. If desired, the free O-alkylisourea can be isolated therefrom by conventional methods.
According to the invention, the urea and alkyl-transferring reagent are reacted at 40-200° C., preferably 60-120° C., in a continuous reactor. Suitable continuous reactors are all conventional reactor types, for example a continuous tubular reactor, a continuous stirred reactor or a continuous stirred kettle cascade.
The reaction of urea with alkyl-transferring reagents initially requires a supply of energy in order to provide the activation energy of the reaction. As soon as the reaction is initiated, the enthalpy of the exothermic reaction is liberated. On the other hand, decomposition reactions and secondary reactions become increasingly important at higher temperatures. The continuous reaction according to the invention makes it possible to overcome these problems in a surprisingly simple and elegant manner, since, in contrast to the batchwise operation, only a comparatively small amount, per unit time, of the mixture of urea and alkyl-transferring reagent is brought to the reaction temperature. The heat of reaction which is evolved in the reaction of this small amount of mixture per unit time can, on the other hand, be rapidly removed or absorbed by the diluent present. There are therefore no temporary peaks of heat quantities to be transferred, but heat flows which are essentially constant as a function of time.
The novel process is preferably carried out in a tubular reactor. The tubular reactor is a flow tube whose cross-section is small compared to the length. The shape of the cross-section, for example circular or rectangular, is not critical for the novel process. The tubular reactor is preferably operated in such a way that a narrow residence time spectrum of the reaction mixture is obtained. The individual stages of the progressing reaction occur locally in succession.
When a tubular reactor is used, energy is supplied to the entering mixture of urea and alkyl-transferring reagent, for example in a first segment of the tubular reactor, until the reaction is initiated. The mixture briefly undergoes an adiabatic temperature increase, and energy transport in the opposite direction takes place in a second segment of the tubular reactor. The tubular reactor can be thermostatted at a uniform temperature along its length. Alternatively, different temperatures can be set along the length of the tubular reactor, for example a higher temperature in the vicinity of the reactor entrance and a lower temperature in the vicinity of the reactor exit. It may sometimes be advantageous to combine an essentially adiabatically operated main reactor with an essentially isothermically operated downstream reactor.
The novel process may also be carried out using a stirred kettle cascade.
In a particularly advantageous further development of the novel process, a diluent is used for dissolving or dispersing urea and/or alkyl-transferring reagent, the diluent having a heat capacity such that the resulting heat of reaction in an essentially adiabatic reaction leads to an increase in the temperature of the reaction mixture of not more than 150° C., preferably not more than 100° C., for example not more than 80° C., in particular not more than 60° C.
Preferably, the diluent used is inert with respect to the alkyl-transferring reagent under the reaction conditions of the novel process.
Diluents having a suitable heat capacity and suitable amounts thereof for use can be readily determined by a person skilled in the art, by simple experiments or by calculations based on the known or easily determinable enthalpy of reaction for the reaction of urea with alkyl-transferring reagent. Thus, the reaction of urea with dimethyl sulfate has, for example, an enthalpy of reaction of −53.7 kJmol
−1
. The diluent absorbs a major part of the resulting heat of reaction and thus limits the temperature increase at the start of the reaction. Decomposition reactions and secondary reactions are limited in this manner. Preferred diluents have a specific heat capacity of from 1.5 to 3 JK
−1
g
−1
and are preferably used in an amount of from 0.2 to 1.0 mol per mol of reaction-limiting component. Reaction-limiting component is understood as meaning that component,
Biedermann Norbert
Bogenstatter Thomas
Greindl Thomas
Kessel Knut
Kluge Michael
BASF - Aktiengesellschaft
Keil & Weinakuf
Vollano Jean F.
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