Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-10
2003-11-04
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S202000
Reexamination Certificate
active
06642388
ABSTRACT:
This application is a 371 of PCT/EP00/06562 Jul. 11, 2000.
The present invention relates to a novel process for preparing 2-aminomethyl-4-cyanothiazole.
The synthesis of 2-aminomethylthiazoles which contain a functional group such as a carboxylic acid, a carboxylic ester, a carboxamide or a carbothioamide in the 4-position has been described in the literature; literature (1): J.-L. Bemier, R. Houssin, J.-P. Henichart, Tetrahedron 42 (1986), 2695; literature (2): U. Schmidt et al., Synthesis (1987), 233; literature (3): G. Jung et al., Angew. Chem. Int. Ed. 35 (1996), 1503; literature (4): WO 9806741; literature (5): Kenner et al., J. Chem. Soc. (1963), 2143.
The abovementioned processes known from the literature have been described for small laboratory batches and are, for some reaction steps, not particularly suitable for a preparation on an industrial scale. For example, literature (2) describes the synthesis of the 4-ethoxycarbonylthiazole derivative using a Z protective group (Z=benzyloxycarbonyl). However, the Z protective group can, after conversion of the corresponding carboxamide into the Z-protected 2-aminomethyl4-cyanothiazole, no longer be removed by methods known from the literature (for example hydrogenolytically or with HBr) on an industrial scale with the cyano group remaining intact.
The 2-benzamidomethyl-4-ethoxycarbonylthiazole, which is described in literature (5), is, after further conversion into the corresponding benzoyl-protected 4-cyanothiazole, likewise unsuitable for removing the protective group with the cyano group remaining intact.
Literature (3) describes the synthesis of the 4-hydroxycarbonylthiazole derivative using the BOC protective group (BOC=tert-butyloxycarbonyl) which can be cleaved off with the cyano group remaining intact. However, a precursor of the thiazole derivative, i.e. the N-BOC-glycinethioamide, is synthesized from the BOC-glycinamide using Lawson's reagent which, when used on an industrial scale, would involve considerably higher costs than the hydrogen sulfide method described in literature (2). Lawson's reagent is also employed in literature (1).
The authors of literature (3) describe the cyclization to the 4-carboxylic acid of the thiazole using bromopyruvic acid. This route is also possible on an industrial scale; however, it has the disadvantage that bromopyruvic acid is less stable than ethyl bromopyruvate, which is used in literature (1), (2) and (5), and that the preparation of the thiazole carboxamide via the thiazole carboxylic acid involves higher technical expense. Moreover, it was not possible to achieve the thiazole carboxylic acid yield described in literature (3) on a larger scale when using CaCO
3
.
Using the procedure described in literature (1), the preparation of ethyl thiazole carboxylate with ethyl bromopyruvate in diethyl ether was very much incomplete. Instead of the stated reaction time of 3 h, our own studies showed that even after 20 h only some of the starting material (thioamide) had reacted. The desired ethyl thiazole carboxylate had indeed been formed in addition to a number of byproducts; however, in none of the experiments was it possible to even come close to the stated yield.
Likewise, it was not possible to employ the procedure, described in literature (2), for the cyclization to the thiazole carboxylic ester successfully. The use of ethanol at 65° C. in the presence of molecular sieves resulted in rapid cleavage of the BOC protective group, owing to HBr being formed. Even at 40° C. in ethanol and with other alcohols (for example methanol or isopropanol), it was not possible to realize the procedure of literature (2) with yields >70%. Addition of basic solution did likewise not lead to higher yields.
2-Aminomethyl-4-cyanothiazole would be an interesting intermediate for preparing serine protease-inhibiting low-molecular-weight substances (for example thrombin inhibitors), if it was readily available industrially. Such thrombin inhibitors are mentioned, for example, in WO 9806741. 2-Aminomethy-4-cyanothiazole can also be employed for preparing other thrombin inhibitors and prodrugs thereof, for example N-(ethoxycarbonyl-methylene)-(D)-cyclohexylalanyl-3,4-dehydroprolyl-[2-(4-hydroxyamidino)-thiazole]methylamide hydrochloride.
It is an object of the present invention to provide a process for preparing 2-aminomethy-4-yanothiazole, thus making available this synthesis building block for further syntheses, in a cost-effective manner.
We have found that this object is achieved by cyclizing the thioamide with the bromopyruvate without addition of bases and without addition of molecular sieves in alcohol at room temperature with a yield of almost 90%. The yield depends highly on the dilution of the starting materials in alcohol and reaches its maximum after a reaction time of about 5 h. The reaction in alcoholic solution is preferably carried out in a concentration range of less than 0.75 mol/l, based on thioamide (IV). Particular preference is given to a concentration of from more than 0.25 mol/l to 0.55 mol/l, based on IV. At concentrations of 1 mol/l, the reaction no longer proceeds with satisfactory yields. According to the invention, the reaction temperature is in the range from −5° C. to 40° C., preferably in the range from 5° C. to 30° C. and in particular from 10° C. to 25° C. At 65° C., as in literature (2), little BOC-protected thiazole carboxylic ester, if any, can be isolated after less than 5 h, even at a relatively high dilution. In the series of the alcohols, it was possible to obtain higher yields with isopropanol than with methanol. Small amounts of water do not negatively affect the cyclization, so that dehydrating agents such as molecular sieves can advantageously be dispensed with.
Also unexpected was the aminolysis of the thiazole carboxylic ester with aqueous ammonia to give the thiazole carboxamide. Reaction was observed only on addition of substantially more than two molar equivalents NH
3
. Preference is given to an excess of at least 5 molar equivalents NH
3
, in particular to values of at least 10 molar equivalents NH
3
. The solubilizer used can likewise be alcohol. However, in the series of the alcohols, yields with methanol were higher than with isopropanol.
Thiazole carboxylic ester can be obtained in crystalline form. To remove the solvent, it is necessary to scavenge the HBr formed using bases. Under pH control, it is possible to use dilute aqueous sodium hydroxide solution or else ammonia for this purpose. By hydrolyzing the ester with, for example, aqueous sodium hydroxide solution and subsequently adding acid in a pH-controlled manner, it is also possible to prepare the corresponding BOC-protected thiazole carboxylic acid in a simple manner and with good yields by this route.
For a synthesis on an industrial scale, it is advantageous to prepare the thiazole carboxamide without isolating the ester in a one-pot process. Starting with the thioamide, it is then possible to achieve a yield of >60% of crystalline amide with small technical expense.
The conversion into the 2-aminomethyl-4-cyanothiazole can then easily be effected by dehydration with, for example, trifluoroacetic anhydride and subsequent gentle removal of the BOC protective group.
The present invention relates to a process for preparing 2-aminomethyl-4-cyanothiazole and its salts of the formulae Ia and Ib,
in which
n=1 or 2 and,
for n=1, X is chloride, bromide, triflate and hydrogen sulfate and,
for n=2, X is sulfate,
which can be carried out by introducing the tert-butyloxycarbonyl protective group (BOC) at the nitrogen of the aminoacetonitrile, subsequently adding hydrogen sulfide to the nitrile group, cyclizing this N-BOC-glycinethioamide with bromopyruvate according to Scheme A to give the corresponding thiazole-4-carboxylic ester and then the thiazole-4-carboxamide and finally the 4-cyanothiazole derivative.
Shown in Scheme A, an advantageous process which can easily be carried out on an industrial scale is described:
The aminoaceton
Abbott & GmbH & Co. KG
McKane Joseph K.
Shiao Robert
Wood Phillips Katz Clark & Mortimer
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