JPH0776585A - Production of 6,7-dihydro-5h-pyrazolo(1,2-a)(1,2,4)triazoliums - Google Patents

Abstract

PURPOSE:To simply and readily obtain the compounds extremely useful as a modifying group for a carbapenem-based compound using a stable and readily available reactional reagent by reacting a pyrazolidine derivative with a syn- triazine. CONSTITUTION:This method for producing 6,7-dihydro-5H-pyrazolo[1,2- a][1,2,4]triazoliums is to react a compound expressed by formula I (R is mercapto or an acid residue) (e.g. 4-mercapto-1,2-pyrazolidine) or an acid addition salt thereof with syn-triazine preferably in an amount of 1-10 equiv. based on the compound expressed by formula I and afford the compounds expressed by formula II (X<-> is a salt-forming anion). The reaction is usually carried out in the presence of a solvent such as water or acetone and the reactional temperature is preferably -30 to +40 deg.C. Furthermore, the starting raw material expressed by formula I is obtained by protecting, e.g. hydrazine hydrate, then reacting the protected hydrazine hydrate with epichlorohydrin, providing an alcoholic derivative expressed by formula III (R0<1> and R0<2> are each a protecting group) and subsequently reacting the resultant compound with an acid chloride.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazoliums useful as synthetic intermediates for carbapenem antibiotics. .

[0002]

2. Description of the Related Art In recent years, carbapenem compounds have been clinically used as antibiotics having a strong and wide range of antibacterial activities. One of such carbapenem compounds is the chemical formula [V] described in JP-B-4-38756.

[Chemical 5] (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4]
Triazolium-6-yl)]-thio-6-[(R)-
1-hydroxyethyl] -1-methyl-carbapenem-
There is 3-carboxylate. The compound has a wide range of strong antibacterial activity, is excellent in chemical and physical stability, and is highly expected as a carbapenem antibiotic that is stable against renal dehydropeptidase in vivo.

General formula [II]

[Chemical 6] (In the formula, R represents an optionally protected mercapto group or an acid residue, and X ⁻ represents a salt-forming anion.) (Hereinafter, abbreviated as compound [II]). It is described in JP-A-4-230286 that the compound is extremely useful as a modifying group at the 2-position of the carbapenem compound [V].

Further, the general formula [IV]

[Chemical 7] The compound represented by the formula (wherein X ⁻ is the same as above) (hereinafter abbreviated as compound [IV]) is an extremely precursor substance of the compound in which R is a mercapto group in the general formula [II]. Usefulness is described in JP-A-4-230267.

The method disclosed in JP-A-4-230286 and JP-A-4-230267 is a method for producing compound [IV] and a compound in which R in the general formula [II] is a mercaptomethyl group. In general, the method is represented by the following reaction scheme [A].

[Formula 1] That is, compound [III] is reacted with formimidate esters to give compound [IV], and then the disulfide bond of compound [IV] is reductively cleaved to give compound [II] (where R is a mercapto group). It is a manufacturing method.

However, the formimidic acid esters used in this production method are easily decomposed by moisture and the like, so that they cannot be stored for a long period of time and need to be prepared before use. Further, they are not commercially available, and therefore difficult to obtain. There are various problems such as these, and their improvement has been desired.

[0007]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and is a method for easily and easily producing compound [II] or compound [IV] using a stable and easily available reaction reagent. The purpose is to provide.

[0008]

To achieve the above object, the present invention comprises the following configurations. “(1) General formula [I]

[Chemical 8] (In the formula, R represents an optionally protected mercapto group or an acid residue.) (Hereinafter abbreviated as compound [I]) or an acid addition salt thereof is reacted with syn-triazine. General formula [II] characterized by

[Chemical 9] (In the formula, X ⁻ represents a salt-forming anion, and R is the same as the above.).

(2) Chemical formula [III]

[Chemical 10] A compound represented by the formula or an acid addition salt thereof is reacted with syn-triazine, represented by the general formula [IV]

[Chemical 11] (In the formula, X ⁻ is the same as the above). "

That is, the present inventors have conducted various studies on the triazole cyclization reaction of the compound [I] or the compound [III] or an acid addition salt thereof with various commercially available reagents. It was found that the desired compound [II] or compound [IV] can be easily and easily obtained by reacting with syn-triazine, and has completed the present invention which solves all the problems of the conventional methods described above. .

In the general formulas [I] and [II], R represents an optionally protected mercapto group or an acid residue. The acid residue as used herein means, in a broad sense, a proton donating molecule to the proton. Means the rest of the atomic groups except. Examples of the proton donating molecule include lower fatty acids such as acetic acid, propionic acid, butyric acid, and trifluoroacetic acid; and benzo which may have a substituent such as a halogen atom, a nitro group, a lower alkyl group, and a lower alkoxy group. Acid; halo-lower alkylsulfonic acid such as methanesulfonic acid and trifluoromethanesulfonic acid; benzenesulfonic acid which may have a substituent such as halogen atom, nitro group, lower alkyl group and lower alkoxy group; dimethylphosphoric acid , Organic phosphoric acid such as diethylphosphoric acid, diphenylphosphoric acid, etc., or sulfuric acid, nitrous acid, nitric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, borofluoride Examples thereof include inorganic acids such as hydrogen acid.

The mercapto group-protecting group can be used as a mercapto group-protecting group of a sulfur-containing amino acid such as methionine in the field of peptide chemistry, and includes any known protecting group per se. To be Specific examples include a halogen atom, a nitro group,
Aromatic carboxylic acid acyl groups such as benzoyl group, phthaloyl group or phenoxyacetyl group which may have a substituent such as lower alkyl group and lower alkoxy group; eg formyl group, acetyl group, propionyl group, chloroacetyl group Groups, aliphatic carboxylic acid acyl groups such as bromoacetyl group; eg, having substituents such as methanesulfonyl group, trifluoromethanesulfonyl group, camphorsulfonyl group, such as halogen atom, nitro group, lower alkyl group, lower alkoxy group Sulfonic acid acyl group such as benzenesulfonyl group; substituents such as methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl group such as halogen atom, nitro group, lower alkyl group, lower alkoxy group Have Benzyloxycarbonyl group or phenoxycarbonyl group or other esterified carboxyl group; for example, benzyl group or phenethyl group which may have a substituent such as halogen atom, nitro group, lower alkyl group or lower alkoxy group And aralkyl groups such as groups; for example, carbamoyl groups such as methylcarbamoyl group, ethylcarbamoyl group and phenylcarbamoyl group; thiosulfate groups and salts thereof; for example, thioalkyl groups such as thioethyl group and thiotert-butyl group.

In the general formulas [II] and [IV], X ⁻ represents a salt-forming anion, and the salt-forming anion referred to here is an anion corresponding to a quaternary ammonium cation. Specifically, for example, a halogen anion such as a fluorine anion, a chlorine anion, a bromine anion, an iodine anion, and a hydroxy anion, a methoxy anion,
Examples thereof include alkoxy anion such as ethoxy anion and acid anion. Here, the acid anion broadly means an atomic group remaining after removing the proton from the proton donating molecule. Examples of the proton donating molecule include lower fatty acids such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid and trichloroacetic acid; substituted or unsubstituted benzoic acid such as benzoic acid and p-nitrobenzoic acid; methanesulfonic acid and trifluoroacetic acid. Lower alkyl sulfonic acid such as methane sulfonic acid; substituted or unsubstituted aryl sulfonic acid such as toluene sulfonic acid and benzene sulfonic acid; organic phosphoric acid such as dimethyl phosphoric acid and diphenyl phosphoric acid; Inorganic acids such as nitric acid, nitric acid, sulfuric acid, perchloric acid, and hydrofluoric acid can be used.

In the production method of the present invention, sy is reacted with compound [I] or compound [III] or an acid addition salt thereof.
As n-triazine, a commercially available product can be used as it is, and the amount thereof is usually about 1 to about 20 equivalents relative to the raw material compound [I] or compound [III] or an acid addition salt thereof. And preferably in the range of about 1 equivalent to about 10 equivalents. The compound [I] or the compound [III] may be used as it is, or may be used in the form of an acid addition salt, but when used as it is, it is necessary to add an acid for forming a salt after completion of the reaction. . The acid may be any acid as long as it can generate the desired salt-forming anion.

The reaction is usually carried out in the presence of a solvent. Examples of the reaction solvent include water, alcohols such as methanol, ethanol, propanol and butanol, ethers such as tetrahydrofuran and dioxane, acetonitrile, propionitrile and the like. Nitriles, acetone,
Examples thereof include ketones such as methyl ethyl ketone, amides such as formamide, dimethylformamide, acetamide, esters such as ethyl acetate and methyl acetate, halogenated hydrocarbons such as chloroform and methylene chloride, etc., which may be used alone or in appropriate two kinds. The above are combined and used as a mixed solvent. The reaction temperature is not particularly limited, but is usually about −
The temperature is from 80 ° C to about 50 ° C, preferably from about -30 ° C to about 40 ° C. Although the reaction time varies slightly depending on the reaction temperature, the reaction solvent and other conditions, the reaction is usually completed in a few minutes to a few hours, so it may be followed by HPLC or the like to determine the reaction end point. After the reaction, post-treatment may be carried out according to a conventional method, and if necessary, purification can be carried out by column chromatography, recrystallization or the like to obtain a highly pure compound [II] or compound [IV].

When R is a mercapto group, the compound [II] thus obtained can be used as it is as a modifying group of a carbapenem compound, and the modifying group can be obtained from Compound [I] in one step. Simplification of manufacturing process,
It can be said that this is an extremely excellent method in terms of reduction of manufacturing cost. When the mercapto group is protected, the protecting group may be removed according to a conventional method before use. As a method of removing the protecting group, for example, an ester protecting group such as an acetyl group or a benzoyl group can be removed by acid hydrolysis using hydrochloric acid, sulfuric acid or the like or alkaline hydrolysis using sodium hydroxide, potassium hydroxide or the like. The benzyl group, the benzyloxycarbonyl group and the like can be removed by a catalytic reduction reaction, and thus it is sufficient to follow the known deprotection method of the corresponding protecting group. When R is an acid residue, sulfur or sulfur compounds such as hydrogen sulfide, sulfides such as sodium sulfide, hydrosulfides such as sodium hydrosulfide, potassium hydrosulfide, sodium disulfide, lithium disulfide, etc. Disulfide,
The compound [II] in which R is a mercapto group can be easily converted by reacting thioacetates, thiourea and the like. Furthermore, the compound [IV] can be easily converted to the compound [II] in which R is a mercapto group by reducing the disulfide bond.

The compound [I] as a starting material used in the present invention can be easily produced by the following method according to the reaction scheme [B] below according to the method described in JP-A-4-230267. Therefore, it is sufficient to use the product thus produced.

[Formula 2]

That is, for example, commercially available hydrazine hydrate is protected with a suitable protecting group (R ₀ ¹ ) and then reacted with acetone to obtain a hydrazone (a). This is reacted with an allyl halide in the presence of a base, deprotected, and then protected again with a suitable protecting group (R ₀ ¹ , R ₀ ² ) to give an allyl hydrazine (b). When a halogen such as bromine or chlorine is added to the allyl hydrazine (b) to form a dihalogenated compound (c), which is treated with a base such as potassium carbonate, a compound [I ₀ ] in which R is halogen is obtained. . On the other hand, after protecting the hydrazine hydrate with an appropriate protecting group, it is reacted with epichlorohydrin to form the alcohol compound (d), and if an acid chloride such as methane sulfonic acid chloride is allowed to act on this hydroxyl group, R is an acid residue. The compound [I ₀ ] is obtained. The compound [I] can be easily obtained by removing the amino protecting groups R ₀ ¹ and R ₀ ² of the compound [I ₀ ] thus obtained by a conventional method.

Further, the compound [III] is the same as in JP-A-4-4-2.
According to the method described in 30267, etc., and according to the following reaction scheme [C], compound [I ₀ ] (where R = B
It can also be produced by subjecting r) to thioacetylation → hydrolysis → oxidation → deprotection.

[Formula 3] Alternatively, the compound [I ₀ ] or the compound [I] is directly reacted with a disulfide such as an alkali metal disulfide, an alkaline earth metal disulfide, ammonium disulfide, and a trialkylammonium disulfide to give a monosulfide. It is also possible to manufacture it in a process.

When the compound [III] is produced by the latter method using the compound [I ₀ ] as a starting material, the amino protecting group (R ₀ ¹ , R ₀ ² ) is, as a matter of course, used after the completion of the reaction. Need to be desorbed by. In addition, these starting materials may be used in an isolated state, or may be used as they are in the reaction solution of the final step of producing them. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

[0021]

【Example】

Example 1 0.7 g of 4-mercapto-1,2-pyrazolidine (5 mmo
l-) in water (40 ml) 2.70 g (3
3.3 mol) was added, and the mixture was stirred and reacted at room temperature for 2 hours while adjusting the pH to 5 to 8 with 10% hydrochloric acid. After the reaction is complete, 10
The residue obtained by adjusting the pH to 1 or less with% hydrochloric acid and concentrating under reduced pressure was dissolved in 10 ml of methanol, and the insoluble material was filtered off.
After repeating this operation twice, the mother liquor was concentrated under reduced pressure, and the resulting residue was subjected to SP-207 column chromatography (SP-207 100 ml,
Water). The eluate is concentrated under reduced pressure and freeze-dried to obtain the target compound 6,7-dihydro-6-mercapto-5H.
1.05 g of -pyrazolo [1,2-a] [1,2,4] triazolium chloride was obtained as white crystals (yield 59.1
%). ¹ H-NMR (D ₂ O) δppm: 4.55-4.67 (3H, m), 5.08-5.15 (2H,
m), 9.01 (2H, s)

Example 2 1,2-pyrazolidin-4-yl-disulfide dihydrochloride 1.40 g (5 mmol) of water (40 ml) in a solution of water (40 ml) was stirred at room temperature with 10% hydrochloric acid to maintain the pH of 5-8. A solution of 1.35 g (16.67 mmol) of triazine in ethanol (32 ml) was added dropwise, and the mixture was stirred and reacted at room temperature for 1.5 hours. After completion of the reaction, the pH was adjusted to 1 or less with 10% hydrochloric acid, the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in 10 ml of methanol, and the insoluble material was filtered off. After repeating this operation twice, the mother liquor was concentrated under reduced pressure, 6 ml of methanol and 6 ml of n-propanol were added to the obtained residue to dissolve it, and the mixture was allowed to stand at room temperature for crystallization. The precipitated crystals were collected by filtration and dried in vacuum to obtain the target compound 6,7-dihydro-5H-pyrazolo [1,2-a].
1.07 g of [1,2,4] triazolium-6-yl-disulfide dichloride was obtained as slightly yellow prism crystals (yield 60.6%). ¹ H-NMR (D ₂ O) δppm: 4.89-4.96 (6H, m), 5.04-5.17 (4H,
m), 9.05 (4H, s)

Example 3 1.87 g (10 mmol) of 4-bromo-1,2-pyrazolidine
S-triazine (0.54 g, 6.67 mmol) in ethanol (2 ml) while maintaining pH 5-8 with 10% hydrochloric acid in water (25 ml).
(5 ml) solution was added dropwise, and the mixture was stirred and reacted at room temperature for 1 hour.
After the reaction was completed, the pH was adjusted to 1 or less with 10% hydrochloric acid, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 20 ml of methanol.
The insoluble material was filtered off. After repeating this operation twice,
Methanol was concentrated under reduced pressure, and the obtained residue was dissolved in 10 ml of n-propanol. 10 ml of acetone was poured into this solution, and the crystallized crystals were collected by filtration under a nitrogen stream and dried to give the desired compound 6,7-dihydro-6-bromo-5H-pyrazolo [1,2-a] [1,2, 4] Triazolium chloride
1.31 g was obtained as white crystals (yield 58.5%). ¹ H-NMR (D ₂ O) δppm: 5.13-5.17 (4H, t like), 5.50-5.60 (1
H, m), 9.10 (2H, s)

[0024]

INDUSTRIAL APPLICABILITY According to the present invention, 6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium compounds useful as a modifying group for carbapenem antibiotics can be stably In addition, it has a remarkable effect in that it can be produced more easily and easily than the conventional method by using a reaction reagent which is easily available.

Front page continuation (72) Inventor Tani Riki 1633 Matoba, Kawagoe City, Saitama Prefecture Wako Pure Chemical Industries, Ltd. Tokyo Research Laboratory

Claims (2)

[Claims] 1. A compound represented by the general formula [I]: (Wherein R represents a mercapto group or an acid residue which may be protected) or an acid addition salt thereof is reacted with syn-triazine. Chemical 2] (In the formula, X ⁻ represents a salt-forming anion, and R is the same as the above.). 2. A chemical formula [III]: The compound represented by the formula or an acid addition salt thereof is reacted with syn-triazine, represented by the general formula [IV]: (In the formula, X ⁻ represents a salt-forming anion).