JP3396065B2 - Method for producing heterocyclic compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention industrially provides a heterocyclic compound in which a compound having an amino group and a hydroxyl group in the same molecule is reacted with dicarbonate to protect both the amino group and the hydroxyl group. To the manufacturing method.

[0002]

2. Description of the Related Art Compounds having an amino group and a hydroxyl group in the same molecule, such as 2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetic acid ester, are useful as intermediates for the production of pharmaceuticals. For example, it is an important compound used as a side chain of antibiotics such as cephems and cephalosporins.

The above compounds are combined with a β-lactam compound such as 7-aminocephalosporanic acid (7-ACA) by an amidation reaction to form a basic skeleton of antibiotics. At that time, the amino group and the hydroxyl group of the above compound, in order to distinguish from the amino group of the β-lactam compound,
It must be protected with some kind of protecting group.

Dicarbonates, such as di-t-butyl dicarbonate, are very excellent protective agents because they can be easily protected and easily deprotected, and are used as protective agents for amino groups and the like. There is. For example, JP-A-61-2
Japanese Patent No. 4580 discloses that as a compound having an amino group,
A method for producing a compound in which an amino group is protected by heating 2- (2-amino-4-thiazolyl) acetic acid ethyl ester and 2.25 times equivalent amount of dialkyl dicarbonate has been proposed.

Further, in Japanese Patent Laid-Open No. 5-59066,
0.2 times equivalent of 4- (2-amino-4-thiazolyl) -2-hydroxyiminoacetic acid ethyl ester
There is known a method of producing a compound in which both an amino group and a hydroxyl group are protected by reacting 2.6 times equivalent amount of dialkyl dicarbonate in a dichloromethane solvent in the presence of N, N-dimethylaminopyridine.

[0006]

However, in the former method by heating, since a decomposition reaction of dialkyl dicarbonate by heat occurs during the reaction, an excess amount of dialkyl which is more than twice the necessary amount relative to the compound as a substrate is required. The problem was that dicarbonate had to be used, and therefore more than the equivalent amount of dialkyl dicarbonate was wasted.

Further, when the inventors of the present invention additionally tried the latter method of reacting in the presence of 4-N, N-dimethylaminopyridine, a heterocyclic ring in which the corresponding amino group and hydroxyl group were both protected by an alkoxycarbonyl group. In addition to the compound, a compound in which another alkoxycarbonyl group was introduced into such a heterocyclic compound was by-produced, and the yield of the target heterocyclic compound was as low as 56%, which was not satisfactory.

[0008]

Means for Solving the Problems As a result of intensive studies on the development of a new technique for compensating for the above-mentioned drawbacks of the prior art, the present inventors have found that a reaction between a compound having an amino group and a hydroxyl group in the same molecule and a dicarbonate. In the above, it was found that a heterocyclic compound in which both an amino group and a hydroxyl group are protected can be synthesized in good yield by using a combination of two or more specific amines as a catalyst, thus completing the present invention.

That is, the present invention provides the following formula (I)

[0010]

[Chemical 9]

[0011] (wherein, X ¹ is NH, a sulfur atom or an oxygen atom, X ² is CH or nitrogen atom, R ¹ is A
An alkyl group, an alkenyl group, an aralkyl group, an aryl group,
Alternatively, it is an N-substituted succinimide group . ) And a compound represented by the following formula (II)

[0012]

[Chemical 10]

(Wherein R ² is an alkyl group, an alkenyl group or an aralkyl group) and a dicarbonate represented by the following formulas (a) and (b) (a):

[0014]

[Chemical 11]

(Provided that R ³ and R ⁴ are an alkyl group, an aryl group, or these may together form a ring), and (b)
The following formula (IV) is characterized in that the reaction is carried out in the presence of an aromatic tertiary amine in which an aromatic ring is bound to a nitrogen atom via an aliphatic tertiary amine or an alkylene group.

[0016]

[Chemical 12]

(However, X ¹ , X ² , R ¹ and R ² are the same as those in the above formulas (I) and (II)).

In the present invention, the above formula (I) and the dicarbonate represented by the above formula (II) are reacted in the presence of (a) the amine represented by the above formula (III), and then (a) b) reacting with a dicarbonate represented by the above formula (II) in the presence of an aliphatic tertiary amine or an aromatic tertiary amine having an aromatic ring bound to a nitrogen atom via an alkylene group. It also provides a method for producing a heterocyclic compound represented by the formula (IV).

The compound represented by the above formula (I) in the present invention is a compound in which an amino group is directly bonded to a hetero 5-membered ring containing a sulfur atom, a nitrogen atom or an oxygen atom as a hetero atom. Specific examples of such a 5-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 thereof include an alkyl group, an alkenyl group, an aralkyl group, an optionally substituted aryl group, and an N-substituted succinimide group . Explaining these groups more specifically, for example, an alkyl group is a methyl group, an ethyl group, an n-propyl group, an i- group.
Lower alkyl groups such as propyl group, n-butyl group, i-butyl group and t-butyl group are preferable, alkenyl group is preferably allyl group, propenyl group, i-propenyl group and the like, and aralkyl group is benzyl. A group is preferable, an optionally substituted aryl group is preferably a phenyl group, a tolyl group, a xylyl group, a p-nitrophenyl group, etc., and an N-substituted succinimide group is preferably an N-hydroxysuccinimide group. . Among them, an alkyl group can be preferably used.

In the compound represented by (I) above, both syn and anti isomers can theoretically exist with respect to the oxyimino group, but both can be similarly used in the present invention.

Specific examples of the compound represented by the above formula (I) which can be preferably used in the present invention include, for example, methyl 2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetate and 2- ( 2-Amino-4-thiazolyl) -2-hydroxyiminoethyl acetate and other thiazole derivatives; 2- (2-amino-4-oxazolyl) -2
-Methyl hydroxyiminoacetate, 2- (2-amino-4)
-Oxazolyl) -2-hydroxyiminoethyl acetate and other oxazole derivatives; methyl 2- (2-amino-4-imidazolyl) -2-hydroxyiminoacetate, 2- (2
-Amino-4-imidazolyl) -2-hydroxyiminoethyl acetate and other imidazole derivatives; methyl 2- (2-amino-4-thiadiazolyl) -2-hydroxyiminoacetate, 2- (2-amino-4-thiadiazolyl)- 2-
Examples thereof include thiadiazole derivatives such as ethyl hydroxyiminoacetate.

On the other hand, the dicarbonate used in the present invention is a compound represented by the above formula (II). In the formula, the alkyl group represented by R ² is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group,
A lower alkyl group such as i-butyl group and t-butyl group is preferable, an alkenyl group is preferably an allyl group, and an aralkyl group is preferably a benzyl group. Among them, a t-butyl group can be preferably used.

Specific examples of the dicarbonate represented by the general formula (II) include dimethyl dicarbonate, diethyl dicarbonate, di-i-propyl dicarbonate,
Examples thereof include di-t-butyl dicarbonate, diallyl dicarbonate and dibenzyl dicarbonate.

The amount of dicarbonate to be used is theoretically twice as much as the amount of the compound as the substrate in order to protect both the amino group and the hydroxyl group, but is not particularly limited. However, if it is used too much, the amount of by-products increases, and it cannot be said that it is an economically advantageous method.
It is preferably in the range of 1.8 to 3.0 times equivalent, further 2.0 to 2.5 times equivalent, and further preferably 2.0 to 2.3 times equivalent to the compound which is the substrate.

In the amine represented by the above formula (III) of (a), R ³ and R ⁴ may be an alkyl group, an aryl group, or these may be taken together to form a ring. Examples of the alkyl group include a methyl group, an ethyl group,
n-propyl group, i-propyl group, n-butyl group, i-
An alkyl group having 1 to 4 carbon atoms such as a butyl group and a t-butyl group is preferable, and an aryl group having 6 to 8 carbon atoms such as a phenyl group, a tolyl group and a xylyl group is preferable. Examples of the ring formed by R ³ and R ⁴ together include a 5- or 6-membered saturated heterocycle such as a piperidine ring and a pyrrolidine ring.

Specific examples of the amine (a) which can be preferably used in the present invention include 4-N, N-dimethylaminopyridine, 4-N, N-diethylaminopyridine,
4-N, N-dipropylamino pyridine, 4-piperidino pyridine, 4-pyrrolidino pyridine etc. can be mentioned.

In the present invention, the amount of the amine (a) used is not particularly limited, but in consideration of the yield of the target product and the removal of the amine after the reaction, the general formula as a raw material is used. 0.0001 to the compound represented by (I)
It is preferably in the range of 0.3 times equivalent, and more preferably 0.
It is preferably in the range of 0005 to 0.2 times equivalent, more preferably 0.001 to 0.1 times equivalent. In the present invention,
As the aliphatic tertiary amine (b) or the aromatic tertiary amine having an aromatic ring bonded to a nitrogen atom via an alkylene group, known compounds can be used without any limitation. In particular, in the present invention, the following formula

[0029]

[Chemical 13]

[Wherein R ⁵ and R ⁶ are the same or different alkyl groups, R ⁷ is an alkylene group, Y is a hydrogen atom, an alkoxy group, an alkylthio group, an aryl group or-{Z (CH ₂ ) _m } _n -NR ⁸ R ⁹ {however, R ⁸ and R
⁹ is a hydrogen atom or an alkyl group, at least one is an alkyl group, Z is an oxygen atom, a sulfur atom or NR ¹⁰
(However, R ¹⁰ is a hydrogen atom or an alkyl group.), M is an integer of 1 or more, and n is 0 or 1. }. ] The compound represented by the following can be particularly preferably adopted.

Specific examples of the amine (b) that can be preferably used in the present invention include N, N-dimethylbenzylamine, N, N-diethylbenzylamine, N, N,
N ', N'-tetramethylethylenediamine, N, N,
N ', N'-tetramethyl-1,3-propanediamine, N, N, N', N'-tetramethyl-1,6-hexanediamine, N, N, N ', N'-tetraethylethylenediamine, N , N, N ', N'-tetraethyl-
1,3-propanediamine, N, N, N ', N'-tetraethyl-1,6-hexanediamine, N, N, N',
N'-tetramethyl-1,3-butanediamine, N,
N, N ', N'-tetramethyl-1,4-butanediamine, bis- [2- (N, N-dimethylamino) ethyl]
Ether, bis- [2- (N, N-dimethylamino) propyl] ether, bis- [2- (N, N-dimethylamino) ethyl] sulfide, bis- [2- (N, N-dimethylamino) propyl ] Sulfide, 2- (N, N-
Dimethylamino) ethyl ethyl ether, 2- (N, N
-Dimethylamino) ethyl ethyl sulfide, bis-
[2- (N, N-dimethylamino) ethyl] methylamine and the like can be mentioned.

Among the amines represented by the above general formula (b), the use of a compound in which Y is an aryl group or —NR ⁸ R ⁹ is preferable in the present invention because the yield of the desired product is high. .

The amount of the amine used in the above (b) is 0.0001 to 0.3 times that of the above compound as a substrate in consideration of the yield of the target product and the trouble of removing the amine after the reaction. Equivalent or more 0.0005 to 0.2 times Equivalent or even 0.001
It is preferably in the range of 0.1 times equivalent.

The greatest feature of the present invention is that the two kinds of amines (a) and (b) are used together as a catalyst. That is, when both the amino group and the hydroxyl group of the compound represented by the above formula (I) are protected with dicarbonate, the reaction is carried out in the coexistence of two kinds of amines (a) and (b). A heterocyclic compound in which both the group and the hydroxyl group are protected can be synthesized in good yield.

In the reaction of the present invention, when either of the above two kinds of amines is used alone, a side reaction occurs and the yield of the target compound decreases, which is not preferable. That is, the use of the above two types of amines together makes it possible to obtain a heterocyclic compound in which both the amino group and the hydroxyl group are protected, as shown in the above formula (IV), without side reactions. Can be well synthesized.

When a compound having an amino group and a hydroxyl group in the same molecule is reacted with dicarbonate, it is usual that the amino group selectively reacts and the hydroxyl group remains unreacted. However, the hydroxyl group of the hydroxyimino group of the compound represented by the above formula (I) is very reactive, and on the contrary, the hydroxyl group reacts before the amino group.

In the reaction of the compound represented by the above formula (I) with dicarbonate, the hydroxyl group is first selectively protected in the system, and the following general formula

[0038]

[Chemical 14]

[0039] (wherein, X ¹ is NH, a sulfur atom or an oxygen atom, X ² is CH or nitrogen atom, R ¹ is A
An alkyl group, an alkenyl group, an aralkyl group, an aryl group,
Alternatively, it is an N-substituted succinimide group . ) Is produced. Then, the heterocyclic compound represented by the above formula (IV) is produced by reacting the compound represented by the above general formula with dicarbonate. As described above, the main by-product is a compound obtained by further reacting the heterocyclic ring of the heterocyclic compound represented by the above formula (IV) with dicarbonate.

In this reaction, the amine of (a) of the above two catalysts effectively acts in the reaction of the first stage, and the amine of (b) acts effectively in the reaction of the second stage. ing. Therefore, the amine of (a) is necessary for the reaction in the first stage, but there is no problem even if the amine of (b) coexists. That is, these two amines do not interfere with each other in their catalytic activity.

Therefore, these two kinds of amines may be allowed to coexist from the beginning of the reaction in the preceding stage, or
The reaction of the first stage may be carried out in the presence of the amine of (a) and then the amine of (b) may be added to the reaction of the second stage.
Of course, the amine of (b) may be added during the reaction of the first stage.

The reaction in the present invention proceeds in an organic solvent or without solvent, but it is preferable to use an organic solvent in order to obtain a sufficient reaction rate. The organic 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; or carbonates such as dimethyl carbonate and diethyl carbonate can be used. These organic solvents may be used alone, or may be used as a mixed solvent of two or more kinds at all. Among the above-mentioned solvents, particularly when the reaction is carried out with ethers such as 1,4-dioxane or carbonates such as dimethyl carbonate, the yield of the desired product is high, which is preferable in the present invention.

The amount of the organic solvent used is not particularly limited, but if an amount sufficient to dissolve the entire heterocyclic compound formed is used, the reaction state changes to a homogeneous solution when the initial reaction is a slurry state. The end point of the reaction is easy to understand and is preferable.

The reaction temperature in this reaction is not particularly limited, but if the temperature is too low, the entire system solidifies or the reaction rate decreases, and if the temperature is high, the product decomposes. In the range of -80 ° C, preferably 0
It is preferable that the temperature is within the range of 50 ° C.

The reaction can be carried out under any conditions of normal pressure, increased pressure and reduced pressure, and the time required for the reaction varies depending on the reaction temperature and the type of solvent, but is usually 0.1 to 30 hours. It is enough.

In this manner, a compound having an amino group and a hydroxyl group in the same molecule is reacted with dicarbonate to produce a heterocyclic compound represented by the above formula (IV) in which both the amino group and the hydroxyl group are protected. It can be manufactured in an advantageous manner.

[0047]

INDUSTRIAL APPLICABILITY According to the present invention, a heterocyclic ring in which both the amino group and the hydroxyl group are protected by suppressing the formation of a side reaction product under mild conditions without wasting the raw material dicarbonate. The compound can be obtained in high yield.

[0048]

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 In a 200 ml eggplant-shaped flask, 2- (2-amino-4) was added.
-Thiazolyl) -2-hydroxyiminoethyl acetate 5.
19 g (24.10 mmol), di-t-butyl dicarbonate 11.05 g (50.63 mmol), 4-
0.0147 g of N, N-dimethylaminopyridine (0.
12 mmol), 0.028 g (0.24 mmol) of N, N, N ', N'-tetramethylethylenediamine and 50 ml of 1,4-dioxane were added, and the mixture was stirred at 25 ° C. After stirring for 24 hours, quantification by high performance liquid chromatography (hereinafter referred to as HPLC) gave 94.
Ethyl 2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-t-butoxycarbonyloxyiminoacetate was obtained with a yield of 9%. At this time, the by-product having three t-butoxycarbonyl groups was 1.9%.

Example 2 In a 200 ml eggplant type flask, 2- (2-amino-4) was added.
-Thiazolyl) -2-hydroxyiminoethyl acetate 5.
19 g (24.10 mmol), di-t-butyl dicarbonate 11.05 g (50.63 mmol), 4-
N, N-dimethylaminopyridine 0.0059 g (0.
05 mmol) and 50 ml of 1,4-dioxane,
Stirring was carried out at 25 ° C. After stirring for 1.5 hours, the reaction solution became a clear homogeneous solution. When quantified by HPLC, ethyl 2- (2-amino-4-thiazolyl) -2-t-butoxycarbonyloxyiminoacetate was produced in a yield of 96.1%. N, N, N ',
N'-Tetramethylethylenediamine 0.028g
(0.24 mmol) was added, and the mixture was further stirred for 20 hours, and then quantified by HPLC. As a result, 2- (2-t-butoxycarbonylamino-4-thiazolyl) -2 was obtained at a yield of 95.5%. Ethyl -t-butoxycarbonyloxyiminoacetate was obtained. At this time, the by-product having three t-butoxycarbonyl groups was 1.7%.

Examples 3 to 5 Example 3 was repeated except that the amounts of 4-N, N-dimethylaminopyridine and N, N, N ', N'-tetramethylethylenediamine shown in Table 1 were used. Example 1
The same operation was performed, and the results are shown in Table 1.

[0052]

[Table 1]

Examples 6 to 10 Using the amines shown in Table 2 as a catalyst, a two-step reaction consisting of a front stage and a rear stage was carried out in the same manner as in Example 2, and the results are shown in Table 2.

[0054]

[Table 2]

Examples 11 to 19 Reactions were carried out in the same manner as in Example 2 using various dicarbonates and raw materials shown in Table 3. The results are shown in Table 3.

[0056]

[Table 3]

Comparative Examples 1 to 8 The same reaction as in Example 1 was carried out without using the amine or using the amine shown in Table 4 alone as the catalyst. The results are shown in Table 4.

[0058]

[Table 4]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI C07D 291/04 C07D 277/40 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 233/90 C07D 249/14 C07D 263/48 C07D 277/593 C07D 285/08 C07D 291/04 CA (STN)

Claims (2)

(57) [Claims] 1. The following formula (I): (However, 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,
Lucenyl group, aralkyl group, aryl group, or N-position
It is a substituted succinimide group . ) And a compound represented by the following formula (II): (However, R ² is an alkyl group, an alkenyl group or an aralkyl group.) The following (a) and (b) (a) the following formula (III) (However, R ³ and R ⁴ are an alkyl group, an aryl group, or these may together form a ring.) The amine (b) an aliphatic tertiary amine or an alkylene group represented by The reaction is carried out in the presence of an aromatic tertiary amine having an aromatic ring bonded to the nitrogen atom via the following formula (IV): (However, X ¹ , X ² , R ¹ and R ² are the same as those in the above formulas (I) and (II).). 2. The following formula (I): (However, 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,
Lucenyl group, aralkyl group, aryl group, or N-position
It is a substituted succinimide group . ) And a compound represented by the following formula (II): (Provided that R ² is an alkyl group, an alkenyl group or an aralkyl group), and (a) the following formula (III): (However, R ³ and R ⁴ may be an alkyl group, an aryl group, or these may form a ring together.), And then react in the presence of an amine represented by )
A compound represented by the following formula (II) characterized by reacting with a dicarbonate represented by the above formula (II) in the presence of an aromatic tertiary amine or an aromatic tertiary amine having an aromatic ring bonded to a nitrogen atom via an alkylene group. IV) [Chemical 8] (However, X ¹ , X ² , R ¹ and R ² are the same as those in the above formulas (I) and (II).).