JP3396066B2 - Method for producing protected amino group-containing heterocyclic compound - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for reacting a compound having an amino group with an aralkyl halide or an acid halide to obtain an amino group-protected heterocyclic compound. And a method for producing the same in an advantageous manner. [0002] A compound having an amino group and a hydroxyl group in the same molecule, for example, 2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetic acid ester is useful as an intermediate in the production of pharmaceuticals. It is an important compound used as a side chain of antibiotics such as cephems and cephalosporins. [0003] The above compound is combined with a β-lactam compound such as 7-aminocephalosporanic acid (7-ACA) by an amidation reaction to form a basic skeleton of an antibiotic. At that time, the amino group and the hydroxyl group of the compound are distinguished from the amino group of the β-lactam compound,
When it is necessary to protect the amino group and the hydroxyl group of the above compound with different protecting groups depending on the reaction conditions after coupling with the β-lactam compound or the deprotection conditions, it is necessary to protect the amino group and the hydroxyl group with some protecting groups. There is. In that case, only one of the amino group and the hydroxyl group present in the same molecule must be selectively protected. When reacting a compound having an amino group and a hydroxyl group in the same molecule with an aralkyl halide or an acid halide, a reaction occurs preferentially toward the amino group or a reaction occurs between both the hydroxyl group and the amino group Is usually the case. However, the hydroxyl group of the hydroxyimino group of the compound represented by the general formula (I) is very reactive, and there is still no method of leaving this hydroxyl group unreacted and protecting only the amino group with high yield. unknown. It is known to produce a heterocyclic compound having an amino group protected by reacting a compound having an amino group and a hydroxyl group in the same molecule with an aralkyl halide or an acid halide. For example, German Offenlegungsschrift 28 31 332 discloses that 2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetic acid ethyl ester and 1.1 equivalents of triphenylmethyl chloride are converted to 1.2 equivalents of triethylamine. By reacting under cooling in the presence, 2- (2-triphenylmethylamino-4-
A method for producing (thiazolyl) -2-hydroxyiminoacetic acid ethyl ester has been proposed. [0005] However, in the above method, the target product is crystallized using a large amount of an organic solvent and water, and the obtained yield is not satisfactory at 76%. When the present inventors repeated the above reaction,
It was found that a by-product of the substitution reaction was formed not only on the amino group but also on the hydroxyl group of the hydroxyimino group, and thus the yield of the desired product was reduced. And this side reaction is
It has been found that the same occurs when other known organic bases are used. Once produced, it is difficult to separate the by-product from the target product, and a complicated purification step is required. Therefore, it has been desired to develop a method for suppressing this by-product. The inventors of the present invention have conducted intensive studies on the development of a new technique for overcoming the above-mentioned drawbacks of the prior art. In the reaction with aralkyl or acid halide, a side chain reaction as described above is suppressed by using a specific inorganic base as a base to synthesize a heterocyclic compound in which only an amino group is selectively protected in a high yield. And found that the present invention was completed. That is, the present invention provides a compound represented by the following formula (I): [0009] (wherein, X ¹ is NH, a sulfur atom or an oxygen atom, X ² is CH or nitrogen atom, R ¹ is A
Alkyl, aralkyl, aryl, or N-substituted
It is a succinimide group . Wherein the compound represented by the formula (I) is reacted with an aralkyl halide or an acid halide in the presence of an inorganic weak base. (Where X ¹ , X ² and R ¹ are the same as in the above formula (I), and R ² is a residue obtained by removing a halogen atom from an aralkyl halide or an acid halide). It is a manufacturing method of the heterocyclic compound shown. In the present invention, the compound represented by the above formula (I) is a compound in which an amino group is directly bonded to a 5-membered heterocyclic ring containing a sulfur atom, a nitrogen atom or an oxygen atom as a hetero atom. Specific examples of such a five-membered ring include a thiazole ring, an oxazole ring, an imidazole ring, and a thiadiazole ring. In the above formula (I), the organic group represented by R ¹ may be any group as long as it forms a carboxylic acid derivative which can be subjected to an amidation reaction, such as an ester or an active ester. That is , examples include an alkyl group, an aralkyl group, an optionally substituted aryl group, and an N-substituted succinimide group . To describe these groups more specifically, for example, an alkyl group is a methyl group, an ethyl group, an n-propyl group, an i-propyl group,
A lower alkyl group such as -butyl group, i-butyl group, t-butyl group and the like is preferable, an aralkyl group is preferably a benzyl group, and an optionally substituted aryl group is a phenyl group, a tolyl group, and a xylyl group. , P-nitrophenyl group and the like, and the N-substituted succinimide group is preferably an N-hydroxysuccinimide group. Among them, an alkyl group can be preferably used. In the compound represented by the formula (I), there may theoretically exist both isomers of syn and anti with respect to the oximino group, but in the present invention, both can be used similarly. Specific examples of the compound represented by the above formula (I) which can be suitably used in the present invention include, for example, methyl 2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetate, 2- ( Thiazole derivatives such as ethyl 2-amino-4-thiazolyl) -2-hydroxyiminoacetate; 2- (2-amino-4-oxazolyl) -2
-Methyl hydroxyiminoacetate, 2- (2-amino-4
Oxazole derivatives such as ethyl-oxazolyl) -2-hydroxyiminoacetate; methyl 2- (2-amino-4-imidazolyl) -2-hydroxyiminoacetate, 2- (2
Imidazole derivatives such as ethyl-amino-4-imidazolyl) -2-hydroxyiminoacetate; methyl 2- (2-amino-4-thiadiazolyl) -2-hydroxyiminoacetate, 2- (2-amino-4-thiadiazolyl)- 2-
And thiadiazole derivatives such as ethyl hydroxyiminoacetate. In the present invention, it is necessary to use an inorganic weak base. The inorganic weak base used in the present invention is an inorganic base having a small ionization constant, and examples thereof include carbonates, bicarbonates, and phosphates. In particular, an inorganic weak base in which the acid having the inorganic weak base as a conjugate base has a pKa of less than 15 is preferred, more preferably less than 13, and most preferably less than 11. More specifically, examples of the inorganic weak base that can be used in the present invention include lithium carbonate, sodium carbonate, magnesium carbonate, potassium carbonate, calcium carbonate, and barium carbonate as the carbonate, and hydrogen carbonate as the bicarbonate. Sodium and potassium bicarbonate are preferred, and phosphates include sodium tribasic phosphate and potassium tribasic phosphate. Of these, sodium and potassium carbonates and bicarbonates have a high yield of the desired product and can be suitably used. In the present invention, the above-mentioned inorganic weak base may be used in an amount equal to or more than the amount of the starting compound represented by the general formula (I). In consideration of the above, the amount is preferably in the range of 1 to 3 equivalents to the raw material, and more preferably in the range of 1 to 2 equivalents. In the present invention, known compounds can be employed as the aralkyl halide or the acid halide without any limitation. As the halogen atom in these compounds, a fluorine atom, a chlorine atom and a bromine atom are preferred. An aralkyl halide is a compound in which the above-mentioned halogen atom is bonded to an aralkyl group, and an acid halide is a compound in which the hydroxyl group of carboxylic acid and sulfonic acid is substituted with the above-mentioned halogen atom. Specific examples of these compounds include aralkyl halides such as benzyl chloride, benzyl bromide, triphenylmethyl chloride, and triphenylmethyl bromide. Acid halides include, for example, hydrofluoric acid Acetyl chloride, acetyl chloride, acetyl bromide, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, pivaloyl chloride, methoxycarbonyl chloride, trichloroethoxycarbonyl chloride, methoxyacetyl chloride, benzyloxycarbonyl chloride, p-nitrobenzyloxycarbonyl chloride 4-ethoxy-1-naphthoxycarbonyl chloride, phenylacetyl chloride, 9-fluorenylmethoxycarbonyl chloride, vinyloxycarbonyl chloride, allyloxycarbonyl chloride, phenylsulfonylethoxycarbonyl chloride , Triphenylphosphinoethoxycarbonyl chloride, benzoyl fluoride, benzoyl chloride, benzoyl bromide, p-phenylbenzoyl chloride, trimethylbenzoyl chloride, naphthoyl chloride, methanesulfonyl fluoride, methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl fluoride Benzenesulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfonyl chloride, nitrobenzenesulfonyl fluoride, nitrobenzenesulfonyl chloride and the like. The amount of the above-mentioned aralkyl halide or acid halide to be used is not particularly limited as long as it is used in an equivalent amount or more based on the compound represented by the general formula (I) as a raw material. However, it is not economically advantageous to use too much, and in view of the trouble of removing these compounds after the reaction or those compounds which have changed in the treatment step,
The range is preferably up to 3 times equivalent to the raw material, and more preferably up to 2 times equivalent. The reaction in the present invention proceeds with or without an organic solvent, but it is preferable to use an organic solvent in order to obtain a sufficient reaction rate. The solvent that can be used is not particularly limited, and aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; nitriles such as acetonitrile;
Ethers such as 4-dioxane and tetrahydrofuran;
Ketones such as acetone and methyl ethyl ketone; N, N-
Amides such as dimethylformamide and N-methylpyrrolidone; alcohols such as 2-propanol and 2-methyl-2-propanol; chloroform, dichloromethane,
Halogenated hydrocarbons such as 1,2-dichloroethane; and carbonates such as dimethyl carbonate and diethyl carbonate can be used. In particular, when an amide such as N, N-dimethylformamide and a ketone such as acetone are used, the yield of the desired product is high, and therefore it can be particularly preferably employed. These organic solvents may be used alone or in combination of two or more. The reaction temperature in the present reaction is not particularly limited. However, if the temperature is too low, the entire system solidifies or the reaction rate decreases, and if the temperature is too high, the product decomposes. ~ 80 ° C, preferably 0 ~
It is good to carry out in the range of 50 ° C. The reaction can be carried out under any of normal pressure, increased pressure and reduced pressure. The time required for the reaction depends on the reaction temperature, solvent,
Depending on the type of acid used, it is usually 0.1 to
A reaction time of 30 hours is sufficient. In this way, the compound having an amino group and a hydroxyl group is reacted with an aralkyl halide or an acid halide to obtain a heterocyclic compound represented by the formula (II) wherein only the amino group is selectively protected. Can be industrially advantageously produced. In the above formula (II), R ²
Represents a residue obtained by removing a halogen atom from the aforementioned aralkyl halide or acid halide. According to the present invention, a compound having an amino group and a hydroxyl group in the same molecule is used as a raw material, and a heterocyclic compound in which only the amino group is selectively protected while leaving the hydroxyl group as it is under mild conditions. Can be obtained in high yields. The present invention will be described below with reference to examples and comparative examples, but the present invention is not limited to these examples. Example 1 Into a 500 ml four-necked kolben, 2- (2-amino-4) was added.
-Thiazolyl) -2-hydroxyiminoacetate 1
0.76 g (0.05 mol), 15.33 g (0.055 mol) of triphenylmethyl chloride, 5.01 g (0.05 mol) of potassium hydrogen carbonate and 150 parts of acetone
Then, the mixture was stirred at 25 ° C. After stirring for 7 hours, quantitative analysis by high performance liquid chromatography revealed that 9
Ethyl ethyl 2- (triphenylmethylamino-4-thiazolyl) -2-hydroxyiminoacetate was produced in a yield of 3.0%. Examples 2 to 4 Using inorganic weak bases shown in Table 1, and using 1.1 times equivalent of triphenylmethyl chloride with respect to the compound serving as a substrate, the reaction was carried out in the same manner as in Example 1 Are shown in Table 1. [Table 1] Examples 5 to 12 The same operations as in Example 1 were carried out using aralkyl halides or acid halides shown in Table 2, and the results are shown in Table 2. [Table 2] Comparative Examples 1 to 3 The same operation as in Example 1 was performed without using an inorganic weak base or using the organic base shown in Table 3. Table 3 shows the results. [Table 3]

Continuation of the front page (51) Int.Cl. ⁷ identification symbol FI C07D 277/46 C07D 277/46 285/08 285/08 (58) Investigated field (Int.Cl. ⁷ , DB name) C07D 233/88 C07D 249/14 C07D 263/48 C07D 271/06 C07D 277/42 C07D 277/46 C07D 285/08 CA (STN)

Claims (1)

(57) [Claims] (Claim 1) The following formula (I): (Where X ¹ is NH, a sulfur atom or an oxygen atom,
X ² is CH or a nitrogen atom; R ¹ is an alkyl group;
Aralkyl, aryl, or N-substituted succinimi
Group . ) Is reacted with an aralkyl halide or an acid halide in the presence of an inorganic weak base. (However, X ¹ , X ² and R ¹ are the same as those in the above formula (I), and R ² is a residue obtained by removing a halogen atom from an aralkyl halide or an acid halide.) Method for producing ring compound.