Process for preparing guanidine derivatives

Details Process for preparing guanidine derivatives Process for preparing guanidine derivatives

2000-02-07

2003-01-21

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Carboxylic acids and salts thereof

Reexamination Certificate

active

06509497

ABSTRACT:

The present invention relates to a process for preparing guanidine derivatives of the formula I
in which
R
1
is C
1
-C
8
-alkylene or a divalent cycloaliphatic radical having 5 to 10 carbon atoms,
R
2
is H or C
1
-C
8
-alkyl, or
R
1
and R
2
represent, together with the N atom to which they are bonded, a 5- or 6-membered Z-substituted ring,
Z is COOR
3
, SO
2
OR
3
or PO(OR
3
)(OR
4
),
R
3
is in each case independently H, one equivalent of an alkali metal or alkaline earth metal,
R
4
is H, one equivalent of an alkali metal or alkaline earth metal or C
1
-C
6
-alkyl, and R
5
and R
6
are independently H or C
1
-C
8
-alkyl,
by reacting a cyanamide derivative of the formula II
in which R
5
′ and R
6
′ are independently H, the equivalent of an alkali metal or alkaline earth metal or C
1
-C
8
-alkyl,
with an amine of the formula III
in which R
1
, R
2
and Z have the stated meanings.
The invention in particular relates to a process for preparing creatine from cyanamide or its salts and sarcosinate.
Guanidine compounds of the formula I are widespread in nature. Important representatives of this class of substances are, for example, compounds such as arginine and creatine. Creatine occurs in vertebrate muscle tissue, in particular as creatine phosphate, and plays an important part as energy carrier in the cell. Creatine is increasingly being used as dietary supplement to enhance physical performance. Creatine is additionally used for treating disorders of muscle function characterized by increased creatine excretion in the urine.
EP-A 0754679 describes a process for preparing creatine by reacting cyanamide with sodium or potassium sarcosinate. The reaction is carried out batchwise, and it is stated that this is usually complete after 2-5 h. The batchwise process is disadvantageous because the batches of reaction product, which results in the form of an aqueous suspension, must either be worked up batchwise as they are produced or be stored temporarily in stirred buffer tanks. Batchwise synthesis is moreover staff-intensive and susceptible to errors. In addition, an unwanted reduction in the yield of product arises because the creatine-saturated washing water is not recycled to the process.
It is an object of the present invention to develop the process mentioned at the outset further so that guanidine derivatives of the formula I are obtained continuously in high purity and in high yield in a simple manner.
We have found that this object is achieved by continuously combining the cyanamide derivative of the formula II with the amine of the formula III in the presence of seed crystals of the guanidine derivative of the formula I. “Continuous combination” means that the addition of the reactants takes place in such a way that the ratio of concentrations of the reactants—apart, where appropriate, from the start-up phase—in the reaction mixture is essentially constant over the time taken for the reaction. This is not the case in particular when one reactant is introduced first and the other reactant is metered in over a lengthy period.
The novel process makes use of a cyanamide derivative of the formula II. These are—as in the case of cyanamide and its salts—commercially available or the synthesis thereof is well known to the skilled worker.
R
5
and R
6
in formula I are independently H or branched or unbranched C
1
-C
8
-alkyl, in particular methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, with C
1
-C
4
-alkyl such as methyl, ethyl, propyl, isopropyl, butyl being preferred. Preference is given to R
5
=R
6
=H.
R
5
′ and R
6
′ in formula II have the meanings stated for R
5
and R
6
respectively and may additionally be the equivalent of an alkali metal or alkaline earth metal. Particular preference is given to R
5
=R
6
′=H or R
5
′=H and R
6
′=alkali metal or R
5
′ and R
6
′ together are an alkaline earth metal, in particular calcium. Cyanamide is the most preferred cyanamide derivative of the formula II.
The other starting material employed is an amine of the formula III. R
1
is a branched or unbranched C
1
-C
8
-alkylene radical, preferably methylene, ethylene, n-propylene, 1-methylethylene, n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, 2,2-dimethylpropylene, 1-ethylpropylene, n-hexylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, 4-methylpentylene, 1,1-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,2-dimethylbutylene, 2,3-dimethylbutylene, 3,3-dimethylbutylene, 1-ethylbutylene, 2-ethylbutylene, 1,1,2-trimethylpropylene, 1,2,2-trimethylpropylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, n-heptylene, n-octylene or a divalent cycloaliphatic radical having 5 to 10 carbon atoms, such as 1,2-, 1,3-, 1,4-cyclohexylene, 1,2- or 1,3-cyclopentylene or radicals of the following structure:
in which n and m may assume the values 0, 1 or 2, with the proviso that n and/or m is different from 0. The cycloaliphatic radicals may be in either the cis or the trans configuration. C
1
-C
6
-alkylene such as methylene and ethylene are preferred.
The R
1
radical may be substituted by one or more, for example 1 to 3, substituents selected from an optionally protected amino, hydroxyl or cyano group.
R
2
is H or C
1
-C
8
-alkyl, preferably H, methyl or ethyl. Z is COOR
3
, SO
2
OR
3
, or PO(OR
3
)(OR
4
), in which R
3
is in each case independently H, an alkali metal such as sodium or potassium, or one equivalent of an alkaline earth metal such as calcium, and R
4
is H, an alkali metal, one equivalent of an alkaline earth metal or C
1
-C
6
-alkyl.
The amine of the formula III is preferably an amino carboxylic acid, amino sulfonic acid or amino phosphonic acid or a salt thereof. Sarcosine, in particular in the form or sodium or potassium sarcosinate, and glycine, taurine or 4-aminomethylcyclohexanecarboxylic acid are particularly preferred.
According to the invention, the cyanamide of the formula II and the amine of the formula III are continuously brought into contact with one another in the presence of seed crystals of the guanidine derivative of the formula I. Thus, for example, a stream of the cyanamide derivative, preferably in the form of an aqueous solution, can be mixed with the seed crystals, and the resulting suspension can be reacted with the amine of the formula III, preferably in the form of an aqueous solution. On the other hand, the amine of the formula III can be mixed with the seed crystals, and then be mixed with the cyanamide derivative. In a further alternative, the seed crystals can be converted into a suspension, and the cyanamide derivative of the formula II and the amine of the formula III are combined with the suspended seed crystals.
The cyanamide derivative of the formula II and the amine of the formula III are preferably employed in a molar ratio of from 2:1 to 1:2, in particular from 0.8:1 to 1.1:1.
The novel reaction normally takes place in an aqueous medium such as water itself or a mixture of water with water-miscible organic solvents such as alcohols, for example methanol or ethanol; acetone or THF. The cyanamide derivative of the formula II and the amine of the formula III can be employed in the form of solutions in water or said water-miscible solvents or mixtures thereof.
The novel reaction preferably takes place at a pH of from 8 to 12, in particular 9 to 10. To maintain a pH in the stated

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