Method for producing 4-cyano-2-aminomethylthiazole

Details Method for producing 4-cyano-2-aminomethylthiazole Method for producing 4-cyano-2-aminomethylthiazole

2002-04-30

2003-10-28

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

06639081

ABSTRACT:

This application is a 371 of PCT/EP00/06563 Jul. 11, 2000.
Preparation of 4-cyano-2-aminomethylthiazole
The present invention relates to a novel process for preparing 2-aminomethyl-4-cyanothiazole.
Syntheses for preparing 2-aminomethylthiazoles which are substituted in the 4 position by an electron-withdrawing group, such as a carboxylic acid or a carboxylic acid derivative, for example an ester, an amide or a thioamide, have been described in the literature.
The key step of the synthesis sequence is the construction of the thiazole ring. In the customary literature syntheses, the thiazole ring is obtained by reacting a thioamide with a bromopyruvic acid derivative (1) G. Videnov, D. Kaiser, C. Kempter, G. Jung, Angew. Chem. Int. Ed. Engl. 35 (1996), 1503; (2) Y. Nakamura, C. Shin, K. Umemura, J. Yoshimura, Chem. Lett. (1992), 1005; (3) J. A. Sowinski, P. L. Toogwood, J. Org. Chem. 61 (1996), 7671; (4) M. North, G. Pattenden, Tetrahedron 46 (1990), 8267; (5) U. Schmidt, Synthesis 1987, 233; (6) WO 98/6741.
The thioamides used for this purpose are obtained, for example, by reacting an amide with Lawessons' reagent (1), (2), (3), or by reacting an aminonitrile with H
2
S (7) K. P. Moder, F. R. Busch, D. C. Richter, Org. Prep. Proced. Int. 24 (1992), 66; G. Li, P. M. Warner, D. J. Jebaratnam, J. Org. Chem. 61 (1961), 778; T. P. Holler, F. Q. Ruan, A. Spaltenstein, P. B. Hopkins, J. Org. Chem. 54 (1989), 4570; T. P . Culbertson, J. M. Dornagala, P. Peterson, S. Bongers, J. B. Nichols, J. Heterocycl. Chem. 24 (1987), 1509; H. Moser, A. Flin, A. Steiger, A. Eschenmesser, Helv. Chim. Acta 69 (1986), 1224.
The processes described in the literature are in most cases only suitable for small batches on a laboratory scale. They employ protective groups which, when used on an industrial scale, would increase preparation costs owing to the high cost of the starting materials. Furthermore, in the case of the synthesis of the thioamides with reaction with H
2
S, industrial implementation of the process is made difficult owing to high environmental and safety requirements. The synthesis of the thioamides with Lawesson's reagent on an industrial scale is unattractive for economical reasons, owing to the high cost of the starting materials. Furthermore, it has been found that these procedures, when the reaction is conducted on a pilot plant scale, do not give the yields that have been described, and/or can only be realized with very high technical expense.
In addition to the intermolecular cyclizations mentioned, intramolecular cyclizations of an N-(hydroxyethyl)thioamide under Mitsunobo conditions have also been described in the literature (8) C. Shin, A. Ito, K. Okumura, Y. Nakamura, Chem. Left. (1995), 45. However, this method also entails the abovementioned disadvantages.
If it were easily accessible industrially, 2-aminomethyl-4-cyanothiazole would be an interesting intermediate for preparing serine protease inhibiting low-molecular-weight substances (for example thrombin inhibitors). Such thrombin inhibitors are mentioned, for example, in WO 9806741. Moreover, 2-aminomethyl-4-cyanothiazole can be used for preparing other thrombin inhibitors and their prodrugs such as, for example, N-(ethoxycarbonylmethytene)-(D)cyclohexylaianyl-3,4-dehydro-prolyl-[2-(4-hydroxyamidino)thiazole]methylamide hydrochloride.
It is an object of the present invention to provide a process for preparing 2-aminomethyl-4-cyanothiazole, thus making available this synthesis building block cost efficiently for other syntheses.
We have found that this object is achieved by a novel way of constructing the thiazole skeleton which makes the 4-cyano-2-methylthiazole building block industrially accessible.
where R
1
is branched or straight-chain C
1
-C
10
-alkyl or
where n=0, 1 or 2 and R
2
is branched or straight-chain C
1
-C
10
-alkyl or C
1
-C
4
-alkoxy or C
1
-C
4
-dialkylamino. Preferred substituents are —OCH
3
, OCH
2
CH
3
, N(CH
3
)
2
, N(C
2
H
5
)
2
, CH
3
, C
2
H
5
, C
3
H
7
.
Here, the thiazole ring is obtained by reacting an aminonitrile with L-cysteine, giving the thiazolidine, followed by its oxidative aromatization.
Thiazole syntheses by oxidation of thiazolidines or thiazolanes are known from the literature; however, they have only been described on a laboratory scale. Frequently, these oxidations are carried out using manganese dioxide. However, this variant gives only moderate yields (9) Y. Hamada, K. Kohda, T. Shioiri, Tetrahedron Lett. 25 (1984), 5303. Better yields are obtained by using perbenzoic acid esters in the presence of copper salts (10) F. X. Tavares, A. I. Meyers, Tetrahedron Lett. 35 (1994), 6803; (11) A. I. Meyers, F.X. Tavares, J. Org. Chem. 61 (1996), 8207. Almost quantitative conversion is obtained in the presence of bromochloroform and DBU (12) D. R. Williams, P. D. Lowder, Y. G. Yu, D. A. Brooks, Tetrahedron Lett. 38 (1997), 331. This reaction is characterized by particularly mild reaction conditions. However, this synthesis, too, has only been carried out on a gram scale.
The preparation of a thiazolidine or thiazolane starting from a cysteine derivative has only rarely been mentioned in the literature. Examples are known where a cysteine ester has been reacted with aminoaldehydes to give the thiazolane (3), (4), which is then converted into the thiazole via the thiazolidine intermediate. However, &agr;-aminoaldehydes are not very stable. Moreover, they are not commercially available, and they therefore have to be prepared from the corresponding amino acids by multi-step processes.
In addition, thiazolidine syntheses are known where the thiazolidine is obtained by reacting the cysteine derivative with imido esters (3), (4), (10), (13) K. Inami, T. Shiba, Bull. Chem. Soc. Jpn. 58 (1985), 352. However, imido esters are likewise not commercially available and have to be synthesized by a multi-step process, for example from an aminonitrile.
According to the invention, the thiazolidine was synthesized from an aminonitrile, with quantitative conversion. The reaction of the cysteine ester hydrochlorides, in particular the methyl and ethyl esters, with the protected aminoacetonitrile is carried out in an inert solvent, for example in cyclic or open-chain ethers, such as THF, dioxane, DME, in acetonitrile, DMF, or chlorinated hydrocarbons such as CH
2
Cl
2
, CHCl
3
or in toluene, or in an alcoholic medium (C
1
-C
6
-alcohol, preferably isopropanol, ethanol or methanol) in the presence of a base, such as, for example, NEt
3
, morpholine, pyridine, lutidine, DMAP, DBU, DBN (preferably triethylamine). The thiazolidine can then be oxidized quantitatively to the corresponding thiazole. The oxidation is likewise carried out in inert solvents, such as, for example, chlorinated hydrocarbons, toluene or cyclic and open-chain ethers.
Organic amines, such as NEt
3
, morpholine, pyridine, DMAP (dimethylaminopyridine) and lutidine serve as base.
In both steps, the crude products can be employed directly in the next step without costly purification.
The next step in the synthesis sequence according to the invention is the aminolysis of the ester to give the amide. The aminolysis can be carried out both in aqueous medium and in alcoholic ammonia solution. It is possible to use alcoholic NH
3
solutions (for example in MeOH, EtOH, iPrOH), but also aqueous NH
3
solutions (for example 25% strength).
In aqueous NH
3
solutions, higher NH
3
excesses are required; for this reason, preference is given to alcoholic NH
3
solutions, owing to the higher space-time yield. The process according to the invention is characterized in that the reaction can be carried out in highly concentrated form using the crude thiazolecarboxylic acid ester. If the process is carried out on an industrial scale, this results in a good space-time yield.
The conversion into the 2-aminomethyl-4-cyanothiazole (VIII) or (Ia) and (Ib) can then be carried out in a simple manner by dehydratization using, for example, trifluoroacetic anhydride, and subsequent gentle removal of the BOC protective group.
The process acc

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