Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2000-03-21
2001-06-26
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S357000, C544S399000, C546S190000, C548S524000, C564S452000, C564S473000
Reexamination Certificate
active
06252071
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is concerned with the aminomethylation of the unsubstituted positions on the benzene ring of tocopherols, especially the complete aminomethylation of &dgr;-tocopherol either alone or as a component of a mixture of several so-called “non-&agr;-tocopherols” containing this tocopherol as well as, e.g., &bgr;- and &ggr;-tocopherol.
It is known from the relevant literature that the conversion of &dgr;-tocopherol, which differs from &agr;-tocopherol by the presence of two unsubstituted positions (5- and 7-) on the benzene ring, into the corresponding 5,7-bis(aminomethyl) derivatives takes place only incompletely. An incomplete aminomethylation of &dgr;-tocopherol leads, after the catalytic reduction performed subsequently in order to convert the aminomethylated product to &agr;-tocopherol, to an &agr;/&bgr;-tocopherol mixture which can only then be converted into &agr;-tocopherol by an additional reaction cycle of aminomethylation+catalytic reduction. As an alternative to this additional cycle, the initially-produced &agr;-tocopherol can be separated from the mixture of &agr;/&bgr;-tocopherols, which of course likewise leads to an unsatisfactorily low yield of &agr;-tocopherol, which tocopherol is preferred for known biological reasons over the non-&agr;-tocopherols. For these reasons, the previously known processes for the aminomethylation of &dgr;-tocopherol have been found to be expensive and accordingly uneconomical, which also applies to the aminomethylation of tocopherol mixtures containing &dgr;-tocopherol.
Thus, Nakamura and Kijima [Chem. Pharm. Bull. 19(11), 2318-2324 (1971)] have reacted &dgr;-tocopherol with in each case eight mol equivalents of aqueous dimethylamine solution and 37% formalin at reflux temperature for 4 hours and in this way obtained (see pages 2320 and 2322) a mixture of the 5-mono-substituted product, 5-dimethylaminomethyl-&dgr;-tocopherol (57% yield), and the 5,7-disubstituted product, 5,7-bis(dimethylamino-methyl)-&dgr;-tocopherol (only 31% yield). This result is obviously due to the fact that the 5-position of the &dgr;-tocopherol molecule is substantially more reactive to aminomethylation than the 7-position and that the substitutability of the still free 7-position is further impeded by the introduction of the first amino substituent. The problem of incomplete aminomethylation is also evident in European Patent Publication (EP) 159 018 of the Henkel Corp., where the aminomethylation of a tocopherol mixture and the subsequent separation of the aminomethylated &bgr;-, &dgr;- and &ggr;-tocopherols from the unreacted &agr;-tocopherol are disclosed. After catalytic hydrogenation of the aminomethylated tocopherols, the thus-obtained mixture of &agr;-, &bgr;, &dgr;- and &ggr;-tocopherols is again aminomethylated and hydrogenated in order to obtain (see pages 16-19) a product having a high as possible content of &agr;-tocopherol. This second round of aminomethylation and hydrogenation comprises the aforementioned “additional reaction cycle” which the incomplete aminomethylation of the prior art required.
SUMMARY OF THE INVENTION
The object of the present invention is to carry out the aminomethylation of &dgr;-tocopherol or of tocopherol mixtures containing &dgr;-tocopherol as completely and accordingly as economically as possible. This object is achieved by performing the aminomethylation reaction using a Mannich reagent (reaction product of formaldehyde or a formaldehyde-producing compound and a secondary amine) which has been produced by reacting formaldehyde or a formaldehyde-producing compound, preferably paraformaldehyde as the formaldehyde-producing compound, with a secondary amine in the complete or almost complete absence of a solvent. Accordingly, the present invention is concerned with the aminomethylation process carried out in this manner, the process for the production of the Mannich reagent itself, as well as the Mannich reagent produced in this manner.
DETAILED DESCRIPTION OF THE INVENTION
The process in accordance with the invention for the aminomethylation of the unsubstituted positions of the benzene ring of &dgr;-tocopherol or of tocopherol mixtures containing &dgr;-tocopherol comprises reacting the &dgr;-tocopherol or tocopherol mixture with a Mannich reagent which has been produced by reacting formaldehyde or a formaldehyde-producing compound with a secondary amine in the complete or almost complete absence of a solvent. The separate (carried out prior to the actual aminomethylation) production of the Mannich reagent, as well as the thus-produced Mannich reagent itself are further aspects of the present invention.
A Mannich reagent is the product of a reaction between formaldehyde and a secondary amine. The reaction ultimately forms an iminium ion which is the reactive species. However, the iminium ion exists in equilibrium with the reactants and an intermediate hydroxymethyl-secondary amine, as follows:
In accordance with the invention, formaldehyde or a formaldehyde-producing compound may be reacted with the secondary amine to produce the Mannich reagent. For the purposes of this invention, a formaldehyde-producing compound is any compound which acts as a source of formaldehyde to react with the secondary amine to form the Mannich reagent. The preferred formaldehyde-producing compound is paraformaldehyde. For simplicity, reference to formaldehyde herein also includes formaldehyde-producing compounds.
For the production of the Mannich reagent, the formaldehyde is added to the secondary amine portionwise and sufficiently slowly such that the temperature of the reaction mixture does not rise too rapidly (the reaction is exothermic). Moreover, the mixture is preferably stirred during and after completion of the addition. Preferably, between 0.7 and 1.2 mole equivalents of formaldehyde, more preferably between 0.9 and 1.1 mole equivalents, are used per mole equivalent of the secondary amine.
The temperature at which the Mannich reagent is prepared is not critical. Any temperature at which formaldehyde will react with a given secondary amine may be used in accordance with the invention. Since—as mentioned above—the reaction is exothermic, it is usually not necessary to heat the reaction mixture above the required initial reaction temperature which, depending on the secondary amine used, normally lies in the range of about 50° C. to about 70° C. Having regard to the exothermic nature of the reaction, the temperature tends to increase in the course of the reaction by a few degrees, normally by up to about 20 degrees Celsius, i.e. up to about 70° C.-90° C.
Therefore, one aspect of the invention comprises a process for the production of a Mannich reagent, which process comprises reacting formaldehyde in the absence of an inert solvent with a secondary amine of the formula:
wherein R
1
and R
2
are the same or different and are C
1-6
-alkyl, C
2-6
-hydroxyalkyl or C
2-6
-alkoxyalkyl, or taken together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclic ring, which is unsubstituted or substituted by C
1-6
-alkyl, and which heterocyclic ring contains at most one additional heteroatom selected from the group consisting of oxygen and nitrogen,
wherein the ratio of said formaldehyde to said secondary amine in said reaction in mole equivalents is in the range from 0.7:1 to 1.2:1, so that said formaldehyde and said secondary amine are eacted to produce said Mannich reagent.
Preferably, 0.9 to 1.1 mol equivalents of formaldehyde are reacted with 1 mol equivalent of secondary amine. As noted above, the form of formaldehyde used is preferably paraformaldehyde.
In principle, any secondary amine which conventionally comes into consideration for aminomethylation can be used for the production of the Mannich reagent. For practical reasons, there is, however, preferably used a di(C
1-6
-alkyl)amine, a di(C
2-6
-hydroxyalkyl)amine, a di(C
2-6
-alkoxyalkyl)amine or a cyclic amine formed when R
1
and R
2
, above, are taken together with the nitrogen atom to w
Muller Robert Karl
Schneider Heinz
Bryan Cave LLP
Haracz Stephen M.
McKane Joseph K.
Roche Vitamins Inc.
Solola Taofiq A.
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