NO163366B - NEW 2-AMINOTIAZOLD DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF. - Google Patents

Description

The present invention relates to a new compound which

is suitable for the production of a 2-(2-(aminothiazol-4-yl)-glyoxylic acid derivative or a salt thereof, and a process

method for producing this compound.

Derivatives of 2-(2-aminothiazol-4-yl)glyoxylic acid of the general form1:

where R<1> is an, optionally protected, amino group, are useful starting materials for the preparation of various cephalo-

trace antibiotics. For the production of these starting materials, there is up to now known (1) a method in which an ester of 2-[2-(protected or unprotected)aminothiazol-4-yl]acetic acid is oxidized with selenium dioxide or potassium permanganate (exposed Japanese patent application Kokai no. 125,190/77 or 5,193/78) and (2) a method in which an ester of acetylglyoxylic acid is halogenated and the resulting halogenation product, after reaction with thiourea, is hydrolyzed (issued Japanese patent

application Kokai no. 112.895/78 and 154.785/79).

To arrive at a new method of manufacture

of a compound of formula (I), it is of the applicants through-

conducted an extensive research program. This has resulted in a new manufacturing process which is the subject of a standard application

patent 832178 (patent 161114).

According to the parent application, 2-(2-aminothiazol-4-yl)glyoxylic acid derivatives with the general formula (I) or salts thereof can be prepared by using the following synthesis steps:

in 1 2 where R is as indicated above; X is a halogen atom and R an alkyl or aralkyl group.

Protecting groups for the amino group in R include all groups that are usually used as amino-protecting groups such as e.g. easily cleavable acyl groups such as trichloroethoxycarbonyl, tribromomethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, formyl, tert.-amyloxycarbonyl, tert. -butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-methoxybenzyloxycarbonyl, 4-(phenylazo)-benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, (pyridine-1-oxide-2-y1)methoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1 ,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like. Furthermore, other easily cleavable groups such as trityl, o-nitrophenylsulfenyl1, 2,4-dinitrophenylsulfenyl, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4 -pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1^ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1-[N-(2 -methoxypheny1)carbamoyl]-2-propylidene, 1_rn_(4-methoxypheny1)carbamoyl]-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene, (di-, tri-)alkylsilyl groups and the like.

The halogen atom can be fluorine, chlorine, bromine or iodine.

As an alkyl group for R 2, it can e.g. lower alkyl groups such as methyl, ethyl, n-propyl and the like are used, and as an aralkyl group for R 2, e.g. ar lower alkyl groups such as a benzyl group and the like.

The salts of the compound of formula (I) include salts

in the amino group or the carboxyl group. As amino group salts, salts with a mineral acid can be used, for example

such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid or the like; salts with an organic carboxylic acid such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, or salts with a sulphonic acid such as methanesulphonic acid, p-toluenesulphonic acid, 1- or 2-naphthalenesulphonic acid or the like. As carboxylic acid salts, salts with an alkali metal such as e.g. sodium or potassium or with alkaline earth metals such as calcium, magnesium or the like.

The expression "salt of the compound of the general formula (II) or (III)" means a salt with the amino group in formula (II) or (III) and includes those salts referred to as amino group salts of the compound of formula (I).

According to the invention, a 2-aminothiazole derivative with the general formula is provided:

where R<1> is an amino group which is optionally protected with a formyl group and R<3> is a monohalomethyl or a c^_^~ alkylthiocarbonyl group.

The compound of formula (VIII) includes to a certain extent

degree the previously mentioned compounds of formula (II) and (III).

The monohalomethyl group in R"^ can, for example, be a chloromethyl group, a bromomethyl group, an iodomethyl group and the like. The C1-4-alkylthiocarbonyl group can, for example, be a methylthiocarbonyl group, an ethylthiocarbonyl group, an n-propylthiocarbonyl group and the like.

Among compounds of the general formula (VIII), compounds where R 3 is a chloromethyl or methylthiocarbonyl group are particularly preferred.

When it

-group in each of the above-mentioned general formulas, these occur in the form of the tautomers shown below, which are also covered by the invention: where R"<*>"<9> is an imino group which is optionally protected with a formyl group, and R ^" is as indicated above. According to the invention, the compound of formula VIII where R1 is an amino group is prepared by a 1,4-dihalobutane-2,3-dione of the general formula 1 2a where X and X, which are different, are halogen atoms , is reacted with thiourea with the formula:

and the reaction product, if necessary, is reacted with a di-C^_^-alkyl sulfoxide, the reaction with a thiourea being preferably carried out at -50°C to 10°C,

Preparation of the compound of formula VIII where R 1 is monohalomethyl is illustrated in the following reaction scheme.

where X1 and X2a, which are different, are halogen atoms and

R<1> has the above meaning.

X<2a> in the general formula (Via) means a halogen atom such as fluorine, chlorine, bromine or iodine.

The halogenation to obtain a 1-halo-butane-2,3-dione

with the general formula (V) from butane-2,3-dione of formula (IV) and a 1,4-dihalobutane-2,3-dione of formula (Via) from a 1-halobutane-2,3-dione ( V) is carried out under the same conditions. The halogenation can, for example, be carried out with or without the presence of a reaction-inert solvent, e.g. an aromatic hydrocarbon such as benzene, toluene, xylene or the like, an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or the like, a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or the like, a carboxylic acid such as acetic acid or the like or a mixture of these solvents. As a halogenating agent, commonly used agents for halogenating paraffins can be used. As a chlorinating agent, e.g. chlorine, sulphoryl chloride, N-chlorosuccinimide, N-chlorophthalimide and the like in speech. Bromine, sulfuryl bromide, N-bromosuccinimide, N-bromophthalimide and the like can be used as brominating agents. The halogenating agent is used

preferably in n\entjders which are approximately equinolar with compound (IV), resp. connection (V). The reaction conditions will, among other things, a. depend on the halogenating agent used, but the reaction is usually carried out at a temperature of from 10°C up to the boiling point of the solvent within 30 minutes to 10 hours.

The halogenation is preferably carried out in such a way that compound (IV) is first chlorinated with sulfuryl chloride to a compound of formula (V), where X<1> is a chlorine atom, which is then reacted with bromine to a compound of formula (Via) where X<2a >is a bromine atom.

In order to then obtain a compound of the general formula (II) where R 3 is monohalomethyl, by reacting a 1,4-dihalobutane-2,3-dione, e.g. 1-bromo-4-chlorobutane-2,3-dione, with a thiourea derivative of the general formula (VII), the reaction is carried out in the presence of a reaction-inert solvent, e.g. an alcohol such as methanol, ethanol, isopropanol or the like, an ether such as tetrahydrofuran, dioxane or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric acid amide or the like, or a mixture of one or more of these, possibly also in a mixture with water. The amount of the thiourea derivative (VII) may amount to 0.90 mol or more, preferably 0.95-1.00 mol, per mol of compound (Via). This ring closure reaction usually takes from 5 minutes to 20 hours at a reaction temperature of -50° to 10°C.

Preparation of the compounds of formula VIII is illustrated in the following examples. The further transformation is illustrated in the original application.

Example 1

(1) To an unstirred solution of 172 g of butane-2,3-dione in 172 ml of benzene, 163 ml of sulfuryl chloride was added dropwise at 60°C over the course of 3 hours. After the addition was complete, stirring was continued for 1 hour at the same temperature and then 1 hour under reflux conditions. After fractional distillation under reduced pressure, 124 g (51.5% yield) of 1-chlorobutane-2,3-dione with a boiling point of 53.5-55.0°C/14 mm Hg were obtained.

IR (unmixed) cm"<1>: \ IQ = QM20

NMR (CDCl 3 ) 6 values:

(2) To a stirred solution of 120.5 g of 1-chlorobutane-2,3-dione and 120 ml of dichloroethane, 160 g of bromine were added dropwise under reflux treatment for 2 hours. After the addition was complete, the reaction mixture was stirred further under reflux conditions for 30 minutes and then cooled to 20°C. The precipitated crystals were filtered off, washed with dichloroethane and then dried, whereby 109 g (54.6% yield) of 1-bromo-4-chlorobutane-2,3-dione with a melting point of 120-121.5°C were obtained.

IR (KBr) cm"<1>: VQ = Q 1 760, 1735

NMR (CD3OD) 6 values:

3.70 (1H, s), 3.83 (1H, s), 4.63 (1H, s), 4.81 (1H, s) (3) A suspension of 20.0 g of 1-bromo-4 -chlorobutane-2,3-dione in 140 ml of ethanol was cooled to -35°C and, with stirring, 7.3 g of thiourea was added. The resulting solution was stirred at the aforementioned temperature for 4 hours, after which the temperature was raised to -20°C over a period of 30 minutes, and the solution was then further stirred for 2 hours. The temperature was then raised to 10°C over the course of 1.5 hours for deposition of white crystals. The crystals were filtered off, washed with ethanol and then dried, whereby 24.9 g (81.8% yield) of a 1:1 solvate of ethanol and the hydrobromide salt of 2-amino-4-chloro-acetylthiazole, m.p. 191°C (decomp.) was obtained.

IR (KBr) cm <1:>^ C=Q<16>95

NMR (dO,-DMSO) 6 values:

1.09 (3H, t, J=7.5Hz CH3CH2OH), 3.54 (2H, q, J=7.5Hz CHjCf^OH) ,

Example 2

A stirred solution of 30.4 g of the 1:1 solvate of ethanol and the hydrobromide salt of 2-amino-4-chloroacetylthiazole, 91 ml of dimethyl sulfoxide and 11.9 g of potassium bromide was heated to 30°C and 8.9 ml of dimethyl disulfide was added . The resulting reaction mixture was stirred at 30-35°C for 2 hours and then poured into 300 ml of ice water.

The pH of the mixture was then adjusted to 5.5 with sodium bicarbonate. The deposited solid was filtered off and dissolved in 80 ml of 1N hydrochloric acid, and small amounts of undissolved material removed from the solution by filtration, after which the filtrate was adjusted to pH 5.5 with sodium bicarbonate. The precipitated crystals were filtered off, washed with water and dried, where-

at 11.7 g (61.4% yield) of 2-(2-aminothiazol-4-yl)thio-glyoxy-1-S-acid methyl ester with a melting point of 130°C (decomp.), was obtained.

IR (KBr) cm~1:V'c = 0 1675, 1650

NMR (d b -DMSO) 6 values:

Example 3

A mixture of 40.8 g of acetic anhydride and 18.4 g of formic acid was stirred at 40-45°C for 1 hour. To the resulting mixture was added 20.2 g of 2-(2-aminothiazol-4-yl)thioglyoxyl-S-acid methyl ester under water cooling, whereupon the resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was then added dropwise to 160 ml of water under cooling with ice, after which the mixture was stirred under water cooling for 30 minutes and the precipitated crystals were filtered off. The crystals were washed successively with water and acetone and then dried, whereby 21.9 g (94.4% yield) of 2-(2-formylaminothiazol-4-yl)thioglyoxyl-S-acid methyl ester with a melting point of above 230°C.

IR (KBr) cm"1:VC=0 1960, 1970, 16<50>

Example 4

7.8 g of a 1:1 solvate of ethanol and hydrobromide salt of 2-amino-4-chloroacetylthiazole were suspended in 50 ml of water, and 2.3 g of sodium hydrogencarbonate were added portionwise to the suspension while stirring at 20°C during 15 minutes. The precipitated crystals were filtered off, washed with 10 ml

water and then dried, whereby 4.5 g (98.8% yield) of 2-amino-4-chloroacetylthiazole with a melting point of 147°C (decomp.) was obtained.

IR (KBr) cm"<1>: VQ=0 1675, 1600

NMR (d.-DMSO) 6 values:

Claims (8)

1. 2-aminothiazole derivative, characterized by the general formula where R<1> is an amino group which is optionally protected with a formyl group, and R<3> is a monohalomethyl or a C 4 alkylthiocarbonyl group, or a salt thereof. 2. 2-aminothiazole derivative as stated in claim 1, characterized in that R<3> is a chloromethyl group. 3. 2-aminothiazole derivative as stated in claim 2, characterized in that R<1> is an amino group. 4. 2-aminothiazole derivative as stated in claim 1, characterized in that R<3> is a methylthiocarbonyl group. 5. 2-aminothiazole derivative as stated in claim 4, characterized in that R<1> is an amino group. 6. 2-aminothiazole derivative as stated in claim 4, characterized in that R<1> is a formylamino group. 7. Process for the preparation of a 2-aminothiazole derivative with the general formula, resp. salt thereof: where R<3> is a monohalomethyl or C-^-q alkylthiocarbonyl group, characterized in that a 1, 4-dihalobutane-2,3-dione with the general formula where X<1> and X<2a>, which are different, are halogen atoms, is reacted with thiourea with the formula: °g the reaction product, if necessary, is reacted with a di-C1-4-alkylsulfoxide. 8. Method as stated in claim 7, characterized in that the reaction with thiourea is carried out at -50°C to 10°C.