Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine

Details Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine

2001-03-20

2002-04-02

Ford, John M. (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06365740

ABSTRACT:

The present invention relates to an improved process for preparing 2-methyl-4-amino-5-aminomethylpyrimidine of the formula 1 (hereinafter abbreviated as AMP),
starting from a 2-methyl-4-amino-5-alkoxymethylpyrimidine of the formula 2,
where
R is C
1
-C
6
alkyl.
The derivative of the formula 2 in which R=methyl will hereinafter be referred to as MMP(‘methoxymethylpyrimidine’).
AMP 1 (formula 1) is the central intermediate in all industrially relevant processes for preparing vitamin B 1 (thiamine). Since the demand for this vitamin is continually increasing, many attempts have already been made to develop an advantageous process for preparing the pyrimidine part of thiamine.
An up-to-date and comprehensive review of these processes has appeared in, for example, Ullmann's Encyclopedia of Industrial Chemistry, Vol. A27 (1996), pp. 515-517. Starting materials used are generally acrylonitrile, malononitrile or acetonitrile.
In all these processes, the desired product AMP is not obtained directly, but rather the processes essentially give firstly AMP derivatives which are either in the wrong oxidation state or bear an N-acyl function. In all these processes, the aminomethyl side chain of AMP has to be generated by complicated and expensive reduction processes (hydrogenation of a nitrile group (1) or reductive amination of a formyl group (2)) or by hydrolysis of the N-acyl group (3).
Transformation of functional groups on valuable intermediates generally make a process cumbersome and thus uneconomical.
The known processes are also unfavorable in respect of the starting materials. Malononitrile 3 is very expensive and not unproblematical in terms of safety. The formation of the pyrimidine skeleton starting from acetonitrile 4 is time-consuming and cumbersome because of the additional process steps for introducing the C
1
building block. The synthetic routes from acrylonitrile 5 go via either &bgr;-dialkoxypropionitriles 6, N-functionalized &bgr;-aminopropionitriles 8 or &bgr;-alkoxypropionitriles 7.
The route via &bgr;-dialkoxypropionitrile 6 includes the abovementioned cumbersome reductive amination of a formylpyrimidine intermediate.
On the other hand, &bgr;-aminopropionitrile is not unproblematical in terms of safety and is also a very toxic substance. In contrast, &bgr;-alkoxypropionitriles are virtually nontoxic (Ullmann's Encyclopedie der technischen Chemie, 4th edition, volume 17 (1979), p. 330). The preparation of AMP from &bgr;-alkoxypropionitriles, which are readily handleable precursors because of their low toxicity, has been described repeatedly in the literature (cf., for example, Chem. Ber. 106 (1973), 893; Bull. Chem. Soc. Japan 45 (1972), 1127;DE-A 1016266).
A particularly disadvantageous aspect of the process carried out hitherto is that an additional equivalent of the expensive acetamidine is consumed for introduction of the aminomethylene nitrogen. The resulting N-acetyl-AMP has to be saponified under drastic conditions to form the free amine:
Furthermore, this process forms, as by-product, MMP which is not converted into AMP, thus adversely affecting the efficiency of the overall process.
In the literature, benzyl ethers of the type 2 have been subjected to various ether cleavages (Chim. Ther. 8 (1973) 1, 98; BE 590665;Khim.-Farm. Zh. 23 (1989), 11, 1374; U.S. Pat. No. 3,161,642; GB 953,875). These generally require drastic conditions (strong mineral acids).
The corresponding benzyl halide formed is reacted with NH
3
in a further step (Otkrytiya, Izobret., Prom. Obraztsy, Tovarnye Znaki 1969, 46 (8), 22). The selectivity of the monoalkylation of NH
3
with reactive halides is known to be poor. In view of the number and complexity of the steps, this process, too, is therefore very unfavorable.
It is an object of the present invention to develop a process which starts from the precursor &bgr;-alkoxypropionitrile and leads directly in a few simple steps to AMP without having the disadvantages of the prior art.
We have found that this object is achieved by converting 5-alkoxymethylpyrimidines of the formula 2, where R is C
1
-C
6
-alkyl, directly into AMP (1) with high selectivity by reaction with NH
3
in the presence of catalysts so as to replace the alkoxy radical.
Unless indicated otherwise, C
1
-C
6
-alkyl in the radical R is, either alone or in combination with, for example, alkoxy, a straight-chain, branched, saturated or unsaturated radical having 1-6 carbon atoms, e.g. a methyl, ethyl, propyl or isopropyl radical, preferably a methyl radical.
In the process of the present invention, 2 is initially charged in an inert organic solvent or in ammonia itself. Preferred solvents are aliphatic or aromatic organic solvents, for example cycloalkanes such as cyclohexane or decalin or else benzene, toluene, xylene or mesytilene. The solvents can be used either alone or in admixture with one another or with ammonia. 2 is preferably initially charged in ammonia itself.
After addition of the catalyst, the reaction is carried out in a temperature range of about 50-400° C., preferably about 180-350° C., particularly preferably in a range of 210-300° C.
Catalysts used are Lewis or Bronsted acids, preferably Lewis-acid oxidic compounds of the elements of groups IV A and III B, particularly preferably Al
2
O
3
.
Ammonia is used in an amount of 1-500 equivalents, preferably 10-300 equivalents, particularly preferably 25-250 equivalents, per equivalent of 2.
Starting materials for the amination are 2-methyl-4-amino-5-alkoxymethylpyrimidines of the formula 2. The synthesis of 2 from the corresponding &bgr;-alkoxypropionitriles is described in the prior art (Pharm. Chem. J. 5 (1971), 8, 495; Khim.-Farm. Zh., 12 (1978), 7, 106).
For this purpose, the &bgr;-alkoxypropionitrile is firstly converted into the alkali metal enolate of the corresponding &agr;-formyl-&bgr;-alkoxypropionitrile by condensation with a C
1
-C
6
-alkyl formate in the presence of an alkali metal alkoxide or by pressure reaction with carbon monoxide in a lower alkanol in the presence of an alkali metal alkoxide (DE-A 2107990). The &agr;-formyl-&bgr;-alkoxypropionitrile is alkylated (e.g. using dimethyl sulfate: R″=CH
3
) to give the corresponding enol ether. Condensation with acetamidine gives the 5-alkoxymethylpyrimidine of the formula 2 (see Scheme 3).
The process of the present invention for the direct conversion of 2 into AMP (1) thus provides a short and attractive route to this valuable vitamin B 1 precursor, starting from a favorable and readily handleable starting material.
The following examples illustrate the invention without restricting its scope.


REFERENCES:
patent: 1 016 266 (1957-09-01), None
Nishino et al. “The Reaction Mechanism of 2-Dimethoxymethyl-3-methoxypropionitrile with Acetamidine. I. A Revised Structure of the Intermediate” Bulletin of the Chemical Society of Japan, vol. 45, (1972) pp. 1127-1132.
Morimoto et al. “Bildungsmechanismus von 4-Amino-5-aminomethyl-2-methyl-pyrimidin aus 3-Athoxy-2-(diäthoxymethyl)propionitril und Acetamidin” Chemische Berichte vol. 106 (1973) pp. 893-901.
Ullmann's Encyklopädie der Technischen Chemie vol. 4, Band 17 pp. 330-332.
Ullmann's Encyclopedia of Industrial Chemistry vol. A27 pp. 515-517.
Rubtsov et al Chemical Abstract accession No. 1969:413139 for SU 237154.

Affiliated with

Also associated with

Rating

Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2856159