JPH0730079B2 - 6,7-Dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1,2,4] triazolium and process for producing the same - Google Patents

Description

Detailed Description of the Invention

The present invention relates to a mercapto compound and a method for producing the same, more specifically, the following formula (I):

[0002]

[Chemical 5]

In the formula, X to represent a salt-forming anion,
6,7-dihydro-6-mercapto-5H-
The present invention relates to a pyrazolo [1,2-a] [1,2,4] triazolium and a method for producing the same.

The mercapto compound represented by the above formula (I) provided in the present invention has the following formula (IV):

[0005]

[Chemical 6]

(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-3-carboxylate or an important compound used in the preparation of a pharmaceutically acceptable salt thereof,
It is a novel compound that has not been described in the literature so far.

Thienamycin [US Pat. No. 3,953]
0,357; J. Am. Chem. Soc., 100 , 313 (198).
It is known that carbapenem compounds such as 7)] exhibit excellent antibacterial activity, and various compounds as carbapenem antibiotics have been studied for synthesis. Among them, imipenem (INN) has been developed and marketed as a practical carbapenem antibiotic, and has been clinically widely used.

The inventors of the present invention have conducted extensive research aiming at the development of an excellent carbapenem compound as an antibacterial agent, and as a result, have found that the compound represented by the above formula (IV) has a strong antibacterial activity. KAISHO 64-25779 Publication:
U.S. Pat. Nos. 4,866,171 and 4,925,8
36 and 4,295,935). That is, the compound represented by the formula (IV) is carb-2-penem-3.
Belongs to a carboxylic acid derivative, has a methyl group in the β-coordinate at the 1-position, and has the following formula at the 3-position:

[0009]

[Chemical 7]

A specific 6,7-dihydro-5 represented by
A novel compound having H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl-thio group, which has a wide range of strong antibacterial activity and chemical and physical properties. It is also a compound that is expected to be a clinically excellent drug, since it is also highly stable and stable against renal dehydropeptidase in vivo.

By the way, the previously proposed equation (I
The production method of the carbapenem compound represented by V) is represented by the following formula (V):

[0012]

[Chemical 8]

Wherein R ¹ represents a carboxy protecting group,
R ^a represents an acyl group, a compound represented by the following formula (V
I):

[0014]

[Chemical 9]

In the formula, R ^b represents an amino-protecting group,
By reacting a mercapto reagent represented by the following formula (VII):

[0016]

[Chemical 10]

In the formula, R ¹ and R ^b are as defined above, and a protecting group R ¹ and R ^b is eliminated from the compound to give the following formula (VIII):

[0018]

[Chemical 11]

It is carried out by obtaining a compound of formula (I) and reacting the resulting compound of formula (VIII) with a formimidate derivative.

The present inventors have studied to develop a more efficient production method of the carbapenem compound represented by the above formula (IV), and as a result, the following formula (I):

[0021]

[Chemical 12]

In the formula, X to are as defined above, and the yield of 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1,2,4] triazolium represented by We succeeded in synthesizing well, and succeeded in establishing a simple method for synthesizing the carbapenem compound represented by the formula (IV) using the mercapto reagent represented by the formula (I).

Therefore, the present invention provides the following formula (I):

[0024]

[Chemical 13]

In the formula, X to are as defined above, and 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1,2,4] triazolium and its crystal The present invention further provides a compound of the form:

[0026]

[Chemical 14]

A pyrimidin-4-yl-disulfide represented by the following formula or its acid addition salt is reacted with a formimidate ester derivative to give the following formula (III):

[0028]

[Chemical 15]

In the formula, X-is as defined above, and is represented by the formula 6,7-dihydro-5H-pyrazolo [1,2-
a] [1,2,4] Triazolium-6-yl-disulfide is obtained, and then the obtained compound of formula (III) is reduced. Dihydro-6-mercapto-5H-pyrazolo [1,2-
a] [1,2,4] triazolium production method is provided.

The mercapto compound of the formula (I) provided by the present invention is an important compound used in the synthesis of the carbapenem compound of the formula (IV), and is represented by the formula (IV) in comparison with the conventional method. The carbapenem compound is extremely useful in that it can be produced more easily, and can also be applied to side chain formation of other physiologically active compounds.

In the present specification, the term "lower" means that the group or compound to which this term is attached has 1 carbon atom.
It means that it is ~ 7, preferably 1-4.

The "lower alkyl group" may be linear or branched and preferably has 1 to 6 carbon atoms, for example methyl, ethyl, n-.
Propyl, isopropyl, n-butyl, isobutyl, se
C-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl groups and the like are included.
Examples of the “carboxy protecting group” include ester residues, and examples of such ester residues include methyl, ethyl, n-propyl, isopropyl, n-, iso.
Lower alkyl ester residues such as-, tert-butyl and n-hexyl ester; benzyl, p-nitrobenzyl, o
-Nitrobenzyl, p-methoxybenzyl, etc. araalkyl ester residues; acetoxymethyl, propionyloxymethyl, n-, iso-, butyryloxymethyl, pivaloyloxymethyl, etc. lower aliphatic acyloxymethyl residues, etc. Can be mentioned.

The "acyl group" includes not only the rest of the atomic groups obtained by removing OH from the carboxyl group of an organic carboxylic acid, but also, in a broad sense, an acyl group derived from an organic sulfonic acid or an organic phosphoric acid. And lower alkanoyl groups such as acetyl, propionyl and butyryl; (halo) such as methanesulfonyl and trifluoromethanesulfonyl groups
Lower alkylsulfonyl group; benzenesulfonyl, p-
Substituted or unsubstituted aryl such as nitrobenzenesulfonyl, p-bromobenzenesulfonyl, toluenesulfonyl, 2,4,6-triisopropylbenzenesulfonyl, etc.
Sulfonyl group; a diphenylphosphoryl group and the like.

The "salt-forming anion" refers to an anion corresponding to a quaternary ammonium cation, specifically, a hydroxy anion; an alkoxy anion such as methoxy anion and ethoxy anion; a chloro anion and a bromo anion. , Halogen anions such as iodine anions and fluorine anions; or “acid anions” described below. The term "acid anion" means, in a broad sense, the remaining atomic group obtained by removing a hydrogen atom from a proton donating molecule, and typical examples thereof include organic acid residues such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid, and trichloroacetic acid. Lower fatty acids such as acetic acid; substituted or unsubstituted benzoic acids such as benzoic acid and p-nitrobenzoic acid; methanesulfonic acid;
(Halo) lower alkyl sulfonic acid such as trifluoromethane sulfonic acid; substitution of benzene sulfonic acid, p-nitrobenzene sulfonic acid, p-bromobenzene sulfonic acid, toluene sulfonic acid, 2,4,6-triisopropylbenzene sulfonic acid, or the like Unsubstituted aryl sulfonic acid;
Remaining atomic groups obtained by removing hydrogen atom from organic phosphoric acid such as diphenylphosphoric acid: Inorganic acid residues such as nitrous acid, nitric acid, sulfuric acid or perchloric acid, and hydrogen halide acid such as borofluoric acid The remaining atomic groups can be exemplified.

Thus, a specific example of the 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1,2,4] triazolium represented by the formula (I) provided in the present invention is shown. Examples of the compound include 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1,2,4] triazolium chloride, bromide, iodide, acetate, propionate, trifluoro. Acetate, trichloroacetate, benzoate, p-nitrobenzoate, methanesulphonate, trifluoromethanesulphonate, benzenesulphonate, p-nitrobenzenesulphonate, p-bromobenzenesulphonate -G, p-
Toluene sulfonate etc. can be mentioned.

The present invention will be described in detail below.

The mercapto reagent represented by the above formula (I) provided in the present invention, that is, 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1,2,4]
The triazolium salt is specifically produced according to the following reaction formula.

[0038]

[Chemical 16]

In the formula, R ² represents a lower alkyl group, and X
Are as defined above.

Further, (a) and (b) show steps.

A more detailed description will be given of each step (a) and (b) in the above reaction formula.

Step (a) : In the step (a), the compound represented by the formula (II) is converted into the following formula (IX):

[0043]

Embedded image in R ² OCH = NH (IX) formula, R ² is by reacting with Horumuimido ester derivative represented in the above meaning, the compound of formula (III) is a disulphide body It is a process of obtaining.

The reaction can be carried out in an inert solvent, for example, any solvent selected from water, alcohol, tetrahydrofuran, acetone and the like.

The formimidate ester derivative and the compound represented by the formula (II) may each be an acid addition salt itself, and the compound of the formula (II) or the formimidate ester derivative (IX) is an acid addition salt. In some cases,
As the reaction solvent, water is particularly preferable, and a base such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate is added to adjust the pH to about 6.0. It is preferable to carry out the reaction near neutrality adjusted to about 8.0.

Specific examples of the formimidic acid ester derivative represented by the formula (IX) and its acid addition salt to be used include ethyl formimidate, methyl formimidate or benzyl formimidate or their hydrochlorides. .

The formimidic acid ester derivative or its acid addition salt is used in an amount of about 4 to about 20 mol, preferably about 4 to about 12 mol, per 1 mol of the compound represented by the formula (II). can do.

The reaction temperature may not be unconditionally limited, but is about -7.
It can be carried out at 8 ° C. to about room temperature, more preferably about −
It is preferable to carry out the reaction at a relatively low temperature of 20 ° C. to about 10 ° C., and generally the reaction can be completed in about 5 minutes to about 1 hour. The desired compound of formula (III) is often isolated from the reaction solution as crystals.

Step (b) : The step (b) is the above step (a)
The 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1 represented by the formula (I), which is a mercapto compound, is obtained by reducing the compound (III) that is a disulfide body obtained in 1. This is a step of obtaining [2,4] triazolium. In the reduction reaction in this step (b), reducing conditions generally used for cleaving the sulfur-sulfur bond of disulphide in a normal organic chemical reaction are applied, and specifically, trimethylphosphine, triethylphosphine,
Trialkyl phosphine such as tributyl phosphine, method using triaryl phosphine such as tolphenyl phosphine or reduction with metal, or metal hydride compound such as sodium borohydride, lithium aluminum hydride, lithium triethyl borohydride Reduction is preferable, and among them, a method using tributylphosphine or triphenylphosphine is preferable. The reaction is usually carried out in a solvent, and such a solvent can be arbitrarily selected as long as it does not directly affect the reaction, and depending on the reducing reagent used, water, methanol or ethanol can be used.
If necessary, an alcohol such as alcohol and isopropanol, an ether solvent such as ether, tetrahydrofuran, dioxane and the like can be appropriately combined and used.

The reaction temperature and the reaction time vary depending on the reducing reagent used and cannot be unconditionally limited, but may be from -20 ° C to
10 minutes at 100 ° C, preferably room temperature to about 50 ° C
It can be finished in about time. After completion of the reaction, the mercapto compound represented by the formula (I) is isolated by a method known per se, for example, by appropriately combining means such as solvent removal, extraction, washing, lyophilization, crystallization and the like. Can be taken as solid powder or crystalline form.

When the compound of formula (I) is taken out in a crystalline form, for example, the compound of formula (I) is isolated as an oily substance by a method such as extraction after the above-mentioned reaction, distillation of the solvent and the like to obtain an oily product. Is an organic solvent miscible with water, for example, alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile and propionitrile. After dissolving in 1 or 2 or more suitable solvent, the solvent is distilled off under reduced pressure to obtain an oily substance again, and if desired, the operation of dissolving and distilling off the solvent is repeated several times to obtain an oily substance. Further drying under vacuum gives a compound of formula (I) in crystalline form (see Example 3 below). Further, if the obtained crystalline form of the compound of formula (I) is used as a seed crystal, the compound of formula (I) can be crystallized from various solvents in crystalline form (see Example 4 below).

In the above case, the compound represented by the formula (III) or (I) is usually isolated as a quaternary ammonium salt. The anion moiety forming the quaternary ammonium salt corresponds to an acid residue, and the acid constituting the acid residue is a fatty acid, a substituted or unsubstituted benzoic acid, a substituted or unsubstituted aryl sulfone as described above. Acids, organic acids typified by organic phosphoric acid, nitric acid, sulfuric acid, inorganic acids typified by hydrohalic acid, among which methanesulfonic acid,
Organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, trifluoromethanesulfonic acid, etc., or inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, borofluoric acid, perchloric acid, nitrous acid, etc. Is preferably used.

Thus, the mercapto compound represented by the formula (I) exemplified below can be preferably obtained depending on the kind of the salt.

6,7-Dihydro-6-mercapto-5H
-Pyrazolo [1,2-a] [1,2,4] triazolium chloride, bromide, iodide, trifluoroacetate, methane sulfonate, p-toluene sulfonate, etc.

The pyrazolidin-4-yl-disulfide represented by the formula (II) or its acid addition salt, which is a starting compound in the production of the mercapto compound represented by the formula (I), can be prepared, for example, by the present inventors. It can be produced by the following method applied for (see Reference Examples 1 and 2 below).

[0056]

[Chemical 18]

In the formula, R ³ and R ⁴ each independently represent a hydrogen atom or an amino-protecting group (provided that R ³ and R ⁴ are not hydrogen atoms at the same time).

The "amino protecting group" may be any protecting group known per se as a protecting group for amino group in the field of peptide chemistry, and examples thereof include aromatic acyl groups such as phthaloyl. Benzoyl, or chlorobenzoyl, p-nitrobenzoyl, p-tert
-Benzoyl substituted with halogen, nitro or lower alkyl such as butylbenzoyl and toluoyl; naphthoyl; phenylacetyl; phenoxyacetyl; benzenesulfonyl, lower alkyl-substituted benzenesulfonyl such as p-tert-butylbenzenesulfonyl and toluenesulfonyl Etc., aliphatic or halogenated aliphatic carboxylic acyl groups: for example, camphorsulfonyl, methanesulfonyl, formyl, acetyl, valeryl, caprylyl, n-decanoyl, acryloyl, pivaloyl, halogenoacetyl (eg, monochloroacetyl, monobromoacetyl. , Dichloroacetyl, trichloroacetyl)
Etc. Esterified carboxy groups: for example, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc. A carbamoyl or thiocarbamoyl group: for example, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl and the like, or a thiocarbamoyl group corresponding to these.

In the above reaction scheme, the step (c) is carried out by oxidizing the 4-mercaptopyrazolidine derivative represented by the formula (X) known per se (JP-A-2-67268) to give the formula (XI). Is a process for producing a pyrazolidin-4-yl-disulfide derivative represented by. For the reaction, a suitable oxidizing agent such as hydrogen peroxide, peracid, cupric chloride, bromine, iodine, halosuccinimide, and air oxidation (in the presence of a base) are used in an inert organic solvent such as chloroform or dichloromethane. It can be carried out by a known method of oxidation reaction of thiol used per se, and particularly preferable methods include iodine oxidation, air oxidation using iron as a catalyst and the like (Reference Example 1 described later).

Step (d) is a step of removing the amino-protecting group of the compound of formula (XI) to produce the compound of formula (II). The reaction can be carried out by a deprotecting group reaction of an amino protecting group which is known per se, and specifically, a reducing reaction using a metal hydride compound such as sodium borohydride, lithium aluminum hydride, platinum oxide. , Catalytic hydrogenation using palladium-activated carbon or the like as a catalyst, or solvolysis performed under acidic conditions can be exemplified (Reference Example 2 described later). The compound of the formula (II) thus obtained can be converted into a diacid addition salt or a tetraacid addition salt, if necessary, by treating with an acid according to a conventional method.

Further, the formula (I) of the present invention produced above is also used.
The method for producing the carbapenem compound represented by the formula (IV) using the mercapto compound represented by the following can be specifically represented by the following reaction formula.

[0062]

[Chemical 19]

In the formula, R ¹ , R ^a and X-are as defined above.

That is, a compound represented by the formula (V):
6,7-Dihydro-6-mercapto-5H-pyrazolo [1,2-, represented by the formula (I), which is a mercapto compound.
a] [1,2,4] triazolium salt is reacted to give a compound of formula (XI
I) and the resulting compound of formula (XII)
By removing the carboxy protecting group R ¹ in the compound of formula (IV), the compound of formula (IV) (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-3-carboxylate is produced.

In this case, the reaction between the compound represented by the formula (V) and the mercapto compound represented by the formula (I) is carried out, for example, by reacting the compound represented by the formula (V) with tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, In a suitable solvent such as dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, etc., an excess amount of formula (I) is about equimolar to about 5 times, preferably about 1.5 to about 3 times. In the presence of the indicated mercapto compound and preferably a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine at about -40 to about 25 ° C at a temperature within the range of about 3
It can be carried out by reacting for 0 minutes to about 24 hours.

By the above reaction, the compound represented by the formula (XII) is obtained. In the compound of the formula (XII), the carboxylic acid at the 3-position is protected with a carboxy protecting group. The removal of the protecting group can be carried out by a deprotecting group reaction known per se such as solvolysis, reduction by treatment with zinc, or hydrogenolysis. Typically, a compound of formula (XII) is added, for example, to an acetate buffer of pH 5.5, a morpholinopropanesulfonic acid-sodium hydroxide buffer of pH 5.5,
Tetrahydrofuran-water containing pH 5.5 phosphate buffer, dipotassium phosphate, sodium bicarbonate, etc., tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol -In a mixed solvent such as water, using hydrogen at 1 to 4 atm, in the presence of a hydrogenation catalyst such as platinum oxide, palladium-activated carbon, palladium hydroxide-activated carbon, in the range of about 0 to about 50 ° C. It can be carried out by treating at the internal temperature for about 0.25 to about 5 hours (see Production Examples 1 and 2 below).

Thus, the target compound (1R, 5S, 6S) -2-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] represented by the formula (IV) is obtained. ] Triazolium-6-yl)] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylate is prepared. As described above, the carbapenem compound represented by the formula (IV) is a dehydropeptidase.
It is extremely stable against attack by a renal enzyme known as ze (DHP) and has excellent antibacterial activity.
Further, it has high chemical and physical stability and can be a clinically excellent drug, and the present invention is considered to have high practical value in providing a more efficient production method of such a compound. It

The present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited to these descriptions.

The symbols in each description have the following meanings.

Z: benzyloxycarbonyl group PNB: para-nitrobenzyloxycarbonyl group Reference Example 1

[0071]

[Chemical 20]

0.56 ml of triethylamine and 508 mg of iodine were added to 20 ml of a dichloromethane solution containing 1.14 g of the compound (1), and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the reaction solution is washed with aqueous sodium thiosulfate and saturated saline, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1),
Compound (2) as a pale yellow solid, 939 mg (85.2
%)Obtained.

¹ H-NMR (CDCl ₃ , δppm): 3.25 (m, 2H), 3.40
(m, 2H), 3.70 (m, 2H), 4.10 (m, 4H), 5.16 (s, 8H), 7.30
(s, 20H) Reference example 2

[0074]

[Chemical 21]

742 mg of the compound (2) obtained in Reference Example 1
Is dissolved in 3.1 g of a 25% acetic acid solution of hydrobromic acid, and the mixture is stirred at room temperature for 4 hours. After completion of the reaction, the compound (3) obtained as a precipitate is collected by filtration and washed with 10 ml of ethyl acetate. The obtained precipitate was dissolved in methanol and the solvent was evaporated under reduced pressure to give compound (3) as a brown solid (420 mg, 7).
9%) was obtained.

¹ H-NMR (D ₂ O, δppm): 3.50 (m, 4H), 3.53 to 3.85 (m, 6H)

[0077]

[Example] Example 1

[0078]

[Chemical formula 22]

568 mg of the compound (3) obtained in Reference Example 2 was dissolved in 30 ml of water, and under ice cooling, 858.2 mg of potassium hydrogen carbonate.
Is gradually added to adjust the pH of the aqueous solution to 7.10. Then, 2.112 g of ethyl formimidate hydrochloride was added, and the mixture was stirred under the same conditions for 10 minutes. After completion of the reaction, the pH of the aqueous solution is adjusted to 5.5 with 1N-hydrochloric acid, and then the reaction solution is washed with 50 ml of ethyl acetate. The aqueous layer is concentrated under reduced pressure to dryness, 30 ml of methanol is added and the precipitate is filtered off. The residue obtained by distilling off the methanol under reduced pressure is purified by SP-207 column chromatography (SP-207, 100 ml, water) to obtain the compound (4). The obtained compound (4) was lyophilized, 10 ml of methanol and 1 ml of trifluoroacetic acid were added, and after completion of the reaction, the solvent was distilled off under reduced pressure to give compound (5) as white crystals.
Obtained 17.2 mg (58.3%).

¹ H-NMR (D ₂ O, δ ppm): 4.80 to 5.00 (m, 4H),
5.00 to 5.16 (m, 6H), 9.05 (s, 4H) Example 2

[0081]

[Chemical formula 23]

112 mg of the compound (5) is dissolved in a mixed solution of 3 ml of water and 3 ml of tetrahydrofuran, 0.082 ml of tri-n-butyl phosphorus is added under ice cooling, and the mixture is stirred for 1 hour under the same conditions. After the reaction was completed, 10 ml of water was added and 2 ml of 10 ml of dichloromethane was added.
The reaction solution was washed once with ethyl acetate (10 ml), and the obtained aqueous layer was freeze-dried to give compound (6) (102.2 mg).
(90.9%) was obtained.

¹ H-NMR (D ₂ O, δppm): 4.50 to 4.70 (m, 2H),
5.00 to 5.20 (m, 3H), 9.00 (s, 2H) Example 3

[0084]

[Chemical formula 24]

9 g of the compound (4) obtained in Example 1 was dissolved in a mixed solution of 45 ml of water and 45 ml of tetrahydrofuran, 8 g of triphenylphosphine was added under ice cooling, and 1
Stir for hours. After completion of the reaction, tetrahydrofuran was distilled off under reduced pressure, the obtained aqueous layer was washed 3 times with 45 ml of ethyl acetate, and then water was distilled off under reduced pressure to obtain an oily compound (7). The obtained oily substance was dissolved in a mixed solvent of 9 ml of methanol and 9 ml of acetonitrile, the solvent was distilled off under reduced pressure, and the resulting residue was further dried under vacuum to give compound (7) in a crystalline form as a compound (7). 0.4 g (yield 90%) was obtained.

¹ H-NMR (D ₂ O, δ ppm): 4.58-4.69 (m, 2H),
5.12~5.21 (m, 3H), 9.05 (s, 2H) Elemental _{analysis: C 5 H 8 N 3 SCl} · 1/2 H 2 O Calculated C; 32.97, H; 4.70, N; 23 0.07 measured value C; 33.21, H; 4.56, N; 22.95 It was confirmed by observation with a polarizing microscope that this product was a crystal. Also, in the powder X-ray diffraction pattern, the plane spacing (d)
7.17, 6.10, 5.09, 5.08, 5.05, 4.9
8, 4.96, 4.93, 4.24, 4.06, 3.67,
3.65, 3.46, 3.45, 3.33, 3.22, 2.9
5, 2.74, 2.62, 2.53, 2.21, 2.03
Characteristic peaks were shown at 9, 2.038 and 2.036Å.

Example 4 To a solution of 90 g of the compound (4) obtained in Example 1 in 450 ml of water was added a solution of 67 g of triphenylphosphine in 450 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, tetrahydrofuran was distilled off under reduced pressure,
It is washed three times with 450 ml of ethyl acetate, and water is distilled off from the obtained aqueous layer under reduced pressure. Methanol 90 was added to the obtained oily substance.
ml was added and the mixture was stirred at room temperature for 15 minutes, the precipitated insoluble material was filtered off, and the solvent was evaporated under reduced pressure. Isopropyl alcohol 2 was added to the oily substance obtained by repeating the above operation two more times.
70 ml are added and the solvent is distilled off under reduced pressure. 180 ml of methanol is added to the obtained oily substance, and the solvent is distilled off under reduced pressure. After adding 45 ml of isopropyl alcohol to the obtained oil and mixing, 100 mg of the crystalline compound (7) obtained in Example 3 is added. To this solution, 135 ml of isopropyl alcohol was added with stirring, and the mixture was stirred at room temperature for 40 minutes. 540 ml of isopropyl ether was added dropwise to the obtained solution over 1 hour, and the precipitated solid was collected by filtration and dried under vacuum to obtain 66 g of compound (7) in crystalline form.

This product is the compound (7) obtained in Example 3.
And their NMR spectra were in perfect agreement, and it was confirmed by observation with a polarizing microscope that they had a crystalline form.

Production Example 1

[0090]

[Chemical 25]

Compound (6) obtained in Example 2 (85.5 m)
g and 199.6 mg of compound (8) with anhydrous acetonitrile 3
Dissolve in ml and chill on ice. Diisopropylethylamine (0.06 ml) was added, and the mixture was stirred under ice cooling for 1 hour. After completion of the reaction, the reaction solution is concentrated under reduced pressure, 20 ml of ethyl acetate is added, and after centrifugation (3000 rpm, 5 minutes), the supernatant is removed by decanting.
The above centrifuge operation is repeated 3 times, the supernatant removed by decanting is collected and concentrated, and 20 ml of chloroform is added, followed by centrifugation to remove the supernatant. The centrifugal precipitates obtained by each treatment were dissolved in methanol and collected, and the methanol was distilled off under reduced pressure to obtain 134.8 mg (67%) of compound (9) as a pale yellow oily substance.

¹ H-NMR (CD ₃ OD, δppm): 1.32 (d, 6H, J = 6.0H
z), 3.35 (m, 1H), 3.65 (m, 1H), 4.20 (m, 1H), 4.42 (m, 1
H), 4.60-4.90 (m, 2H), 5.1 to 5.3 (m, 3H), 5.36 (ABq, 2H, J
= 13.7Hz), 7.67 (d, 2H, J = 8.5Hz), 8.21 (d, 2H, J = 8.5Hz),
9.07 (s, 1H), 9.08 (s, 1H) Production example 2

[0093]

[Chemical formula 26]

84.9 m of compound (9) obtained in Preparation Example 1
g was dissolved in 2.5 ml of 0.1 M acetate buffer (pH 5.5),
-Butanol 2.5 ml, 10% palladium-carbon 25 mg
Was added, and the mixture was stirred under a hydrogen atmosphere (4 atm) at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered through Celite, and 20 ml of water was added.
After the celite was washed with, the pH of the aqueous layer was adjusted to 4.8-5.6 with 1N sodium hydroxide, and washed with 20 ml of butanol. The aqueous layer was concentrated under reduced pressure to 5 ml, and the resulting residue was subjected to SP-207 column chromatography (SP-
207, 10 ml), the fraction of compound (10) is concentrated to 10 ml, and then freeze-dried. Water (0.1 ml) and ethanol (2 ml) were added to the obtained solid for crystallization to give compound (10) (1R, 5S, 6S) -2-
[(6,7-Dihydro-5H-pyrazolo [1,2-a]
[1,2,4] Triazolium-6-yl)] thio-6-
30 mg (60%) of [(R) -1-hydroxyethyl] -1-methyl-carboxylate was obtained as white crystals.

¹ H-NMR (D ₂ O, δ ppm): 1.29 (d, 3 H, J = 7.3 H)
z), 1.33 (d, 3H, J = 6.3Hz), 3.44 (dq, 1H, J = 7.3,9.5Hz),
3.56 (dd, 1H, J = 2.9,6.2Hz), 4.30 (quintet, 1H, J = 6.2H
z), 4.34 (dd, 1H, J = 2.9,9.5Hz), 4.75-4.84 (m, 2H), 5.
08 ~ 5.17 (m, 2H), 4.98 ~ 5.04 (m, 1H), 9.06 (s, 1H), 9.
07 (s, 1H)

Claims (4)

[Claims] 1. The following formula (I): In the formula, 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1,2,4] triazolium represented by the formula, wherein X ~ represents a salt-forming anion. 2. The 6,7-dihydro-6-mercapto-of the formula (I) according to claim 1, which has a crystalline form.
5H-Pyrazolo [1,2-a] [1,2,4] triazolium. 3. The following formula (II): A pyrimidin-4-yl-disulfide represented by or an acid addition salt thereof is reacted with a formimidate ester derivative to obtain a compound represented by the following formula (III): In the formula, X to represent a salt-forming anion, and 6,7-dihydro-5H-pyrazolo [1,2-a] [1,
2,4] triazolium-6-yl-disulfide is obtained, and the resulting compound of formula (III) is then reduced, 6,7-indicated by formula (I) according to claim 1.
Dihydro-6-mercapto-5H-pyrazolo [1,2-
a] A method for producing [1,2,4] triazolium. 4. The following formula (III): In the formula, X-represents a salt-forming anion, which reduces a compound represented by the formula (I): 6,7-dihydro-6-mercapto-
Process for producing 5H-pyrazolo [1,2-a] [1,2,4] triazolium.