JPH04230290A - Production of carbapenem compound - Google Patents

Abstract

PURPOSE:To profitably produce the compound of a carbapenem antibiotic useful used as an antibacterial agent by reacting a specific carbapenem compound with a pyrazolo-triazolium compound and subsequently removing the protecting group from the reaction product to form an intramolecular salt. CONSTITUTION:A carbapenem compound of formula I (R<1> is carboxy-protecting group; R<3> is acyl) is reacted with 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a][1,2,4] triazolium to produce a compound of formula III. If necessary, the protecting group is removed from the compound of formula III to provide the objective carbapenem compound of formula IV consisting of (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 (salt).

Description

[Detailed description of the invention]

[0001] The present invention relates to a method for producing carbapenem compounds, more specifically, the following formula (I):

0002

[C5]

(1R,5S,6S)-2-[
(6,7-dihydro-5H-pyrazolo[1,2-a][
1,2,4]triazolium-6-yl)]thio-6-
The present invention relates to a method for producing [(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate or a pharmacologically acceptable salt thereof.

Thienamycin [US Patent No. 3,95]
No. 0,357; J. Am. Chem. Soc. ,100
, 313 (1987)] are known to exhibit excellent antibacterial activity, and studies have been conducted to synthesize various compounds as carbapenem antibiotics. Among these, imipenem (INN) has been developed and marketed as a practical carbapenem antibiotic, and has come to be widely used clinically.

[0005] As a result of extensive research aimed at developing carbapenem compounds excellent as antibacterial agents, the present inventors have discovered that the compound represented by the above formula (I) has strong antibacterial activity (particularly Publication No. 64-25779;
U.S. Patent No. 4,866,171, U.S. Patent No. 4,925
, 836 and 4,295,935; European Patent No. 289801). That is, the compound represented by the formula (I) is carba-2-penem-3
- Belongs to carboxylic acid derivatives and has a methyl group in β coordination at the 1st position, and the following formula at the 3rd position:

[0006]

[C6]

A specific 6,7-dihydro-5 represented by
A novel compound having an H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl-thio group,
This compound has a wide range of strong antibacterial activities, has good chemical and physical stability, and is stable against renal dehydropeptidase in vivo, making it a compound that is expected to be an excellent clinical drug. It is.

By the way, the previously proposed formula (I
) The method for producing the carbapenem compound represented by the following formula (
II)

[0009]

[C7]

In the formula, R1 represents a carboxy protecting group,
Ra represents an acyl group, and the compound represented by the following formula (V
II)

[0011]

[Chemical formula 8]

In the formula, Rb represents a protecting group for an amino group,
It is reacted with a mercapto reagent represented by the following formula (VIII
)

[0013]

[Chemical formula 9]

##STR2## where R1 and Rb are as defined above, and then the protecting groups R1 and Rb are removed from the compound to form the following formula (IX)

0
015]

[Chemical formula 10]

This is carried out by obtaining a compound represented by the formula (IX) and reacting the obtained compound of formula (IX) with a formimidate ester derivative.

[0017] As a result of our studies to develop a more efficient method for producing the carbapenem compound represented by the above formula (I), we have now developed the carbapenem compound represented by the following formula (III).

[0018]

[Chemical formula 11]

In the formula, X- represents a salt-forming anion,
6,7-dihydro-6-mercapto-5H-
We succeeded in synthesizing pyrazolo[1,2-a][1,2,4]triazolium in good yield, and synthesized a carbapenem compound represented by formula (I) using a mercapto reagent represented by formula (III). We succeeded in establishing a simple synthesis method.

[0020] Therefore, the present invention provides the following formula (II)

00
21]

[Chemical formula 12]

In the formula, R1 represents a carboxy protecting group,
Ra represents an acyl group, and the compound represented by the following formula (I
II)

[0023]

[Chemical formula 13]

In the formula, X- is as defined above. , the following formula (IV)

[0025]

[Chemical formula 14]

[0026] In the formula, R1 and

[
0027

[Chemical formula 15]

(1R,5S,6S)-2-[
(6,7-dihydro-5H-pyrazolo[1,2-a][
1,2,4]triazolium-6-yl)]thio-6-
A carbapenem compound of the above formula (IV) or (I), characterized in that it is [(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate or a pharmacologically acceptable salt thereof. The present invention provides a method for manufacturing.

Another aspect of the present invention is a mercapto reagent used in the above production method, that is, a mercapto reagent of the following formula (III).

[
0030

[Chemical formula 16]

6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a][1,2,4]triazolium and its production law, that is, the following equation (V)

[0032]

[Chemical formula 17]

Pyrazolidin-4-yl-disulfide or its acid addition salt represented by the formula (VI) is reacted with a formimidic acid ester derivative.

[0034]

[Chemical formula 18]

In the formula, X- represents a salt-forming anion,
6,7-dihydro-5H-pyrazolo[1,2
-a] [1,2,4]triazolium-6-yl-disulfide is obtained, and then the obtained compound of formula (VI) is reduced. A method for producing a mercapto reagent represented by the above formula (III) It provides:

Formula (IV) or (
The method I) for producing a carbapenem compound is simpler than conventional methods and can be said to be particularly useful.

[0037] In this specification, the term "lower" means that the group or compound to which this term is attached has 1 carbon atom.
~7 pieces, preferably 1 to 4 pieces.

The "lower alkyl group" may be linear or branched and preferably have 1 to 6 carbon atoms, such as methyl, ethyl, n-
propyl, isopropyl, n-butyl, isobutyl, s
Included are ec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl groups, and the like.

Examples of the "carboxyl protecting group" include ester residues, such as methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, n- Lower alkyl ester residues such as hexyl ester; benzyl, p
-Aralkyl ester residues such as nitrobenzyl, o-nitrobenzyl, m-nitrobenzyl, 2,4-dinitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-methoxybenzyl; acetoxymethyl, acetoxyethyl, propionyl Oxymethyl, n-, iso-
, butyryloxymethyl, pivaloyloxymethyl, and other lower aliphatic acyloxymethyl residues.

[0040] Furthermore, the term "acyl group" does not simply include the atomic group remaining after removing OH from the carboxyl group of an organic carboxylic acid, but also includes, in a broad sense, an acyl group derived from an organic sulfonic acid or an organic phosphoric acid. For example, lower alkanoyl groups such as acetyl, propionyl, butyryl; (halo) such as methanesulfonyl and trifluoromethanesulfonyl groups;
Lower alkylsulfonyl group; benzenesulfonyl, p-
Examples include substituted or unsubstituted arylsulfonyl groups such as nitrobenzenesulfonyl, p-bromobenzenesulfonyl, toluenesulfonyl, and 2,4,6-triisopropylbenzenesulfonyl; diphenylphosphoryl groups, and the like.

[0041] Furthermore, the term "salt-forming anion" refers to an anion corresponding to a quaternary ammonium cation, specifically, for example, an alkoxy anion such as a hydroxy anion, a methoxy anion, an ethoxy anion; a chlor anion; , bromo anion, iodo anion, fluorine anion, and other halogen anions; or "acid anions" described below. The term "acid anion" broadly refers to the atomic group remaining after 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, trichloroacetic acid, etc. Lower fatty acids such as acetic acid; substituted or unsubstituted benzoic acids such as benzoic acid and p-nitrobenzoic acid; (halo) such as methanesulfonic acid and trifluoromethanesulfonic acid
Lower alkylsulfonic acids; substituted or unsubstituted arylsulfonic acids such as benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6-triisopropylbenzenesulfonic acid; diphenyl phosphoric acid; Remaining atomic group after hydrogen atoms are removed from organic phosphoric acids such as acids: Hydrogen atoms are removed from inorganic acid residues, such as nitrous acid, nitric acid, sulfuric acid, or hydrohalic acids such as perchloric acid and hydrofluoroboric acid. The remaining atomic groups can be exemplified.

The present invention will be explained in more detail below.

A: Production of mercapto reagent: The above formula (I
II), i.e. 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a
][1,2,4]triazolium salt is specifically produced according to the following reaction formula.

[0044]

[Chemical formula 19]

In the formula, R2 represents a lower alkyl group, and
- is as defined above.

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

Each step (a) and (b) of the above reaction formula will be explained in more detail.

Step (a): In step (a), the following formula (X) is added to the compound represented by the formula (V).

[0049]

[Chemical formula 20] R2OCH=NH
This is a step of obtaining a disulfide compound represented by formula (VI) by reacting with a formimidic acid ester derivative represented by formula (X), in which R2 represents the above meaning.

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

Formimidic acid ester derivative and formula (
Each of the compounds represented by V) may itself be an acid addition salt, and when the compound of formula (V) or the above-mentioned formimidic acid ester derivative (X) is an acid addition salt, particularly as a reaction solvent, Water is preferred, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate,
Sodium hydroxide, potassium hydroxide, sodium acetate,
By adding chlorine such as potassium acetate, the pH is about 6.0 to about 8.
．． It is preferable to carry out the reaction near neutrality adjusted to zero.

[0052] Specific examples of the formimidate ester derivative represented by formula (X) and its acid addition salt include ethyl formimidate, methyl formimidate, benzyl formimidate, or their hydrochlorides. .

The amount of these formimidic acid ester derivatives or acid addition salts thereof to be used is about 4 to about 20 mol, preferably about 4 to about 12 mol, per 1 mol of the compound represented by formula (V). can do.

[0054] Although the reaction temperature cannot be absolutely limited, it is about -7
It can be carried out at 8°C to about room temperature, more preferably at about -
It is preferable to carry out the reaction at a relatively low temperature of 20° C. to about 10° C., and the reaction can generally be completed in about 5 minutes to about 1 hour. The target compound represented by formula (VI) is often isolated from the reaction solution in the form of crystals.

Step (b): Step (b) is the step (a) described above.
) by reducing the disulfide compound (VI) obtained in 6,7-dihydro-6-mercapto-5H-pyrazolo[1,2-a][ represented by formula (III), which is a mercapto reagent. 1,2,4] triazolium.

For the reduction reaction in step (b), reduction conditions commonly used to cleave the sulfur-sulfur bond of disulfide in ordinary organic chemical reactions are applied, and specifically, trimethylphosphine, triethylphosphine, etc. ,
A method using a trialkylsulfine such as tributylphosphine, a triarylphosphine such as tolphenylphosphine, or reduction with a metal, or reduction with sodium borohydride, lithium aluminum hydride, or lithium triethylborohydride is preferred, and among these, tributylphosphine is preferred. It is preferable to use The reaction is usually carried out in a solvent, and any solvent can be selected as long as it does not directly affect the reaction. Depending on the reducing reagent used, water, alcohols such as methanol, ethanol, isopropanol, etc. Ether solvents such as ether, tetrahydrofuran, and dioxane can be used in appropriate combinations as required.

The reaction temperature and reaction time vary depending on the reducing reagent used and cannot be absolutely limited, but range from -20°C to
10 minutes to 10 minutes at 100°C, preferably room temperature to about 50°C.
It can be completed in about an hour. After the reaction is completed, the formula (I
Isolation of the mercapto reagent shown in II) is carried out by a method known per se, for example, by appropriately combining means such as solvent distillation, extraction, washing, and freeze-drying, and the target product can be taken out as a solid powder. .

In this case, the compound represented by formula (VI) or (III) is usually isolated as a quaternary ammonium salt. The anion moiety forming the quaternary ammonium salt corresponds to an acid residue, and the acids constituting the acid residue include fatty acids, substituted or unsubstituted benzoic acid, substituted or unsubstituted arylsulfonic acid, and organic phosphorus. Examples include organic acids such as nitric acid, sulfuric acid, and inorganic acids such as hydrohalic acid, including methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid,
Organic acids such as trifluoromethanesulfonic acid, or inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, fluoroboric acid, perchloric acid, and nitrous acid are preferably used.

In this way, depending on the type of salt, specifically, a mercapto reagent represented by the formula (III) shown below can be obtained.

6,7-dihydro-6-mercapto-5H
-Pyrazolo[1,2-a][1,2,4]triazolium chloride, bromide, iodide, trifluoroacetate, methanesulfonate, p-toluenesulfonate, etc.

[0061] The pyrazolidin-4-yl-disulfide represented by formula (V) or its acid addition salt, which is a starting compound in the production of the mercapto reagent represented by formula (III), is used by the present inventors in the present application. It can be produced by the method described in the specification filed on the same date (see Reference Examples below).

B: Production of the carbapenem compound represented by formula (I): The method for producing the carbapenem compound represented by formula (I) using the mercapto reagent represented by formula (III) produced above is specifically described. can be expressed by the following reaction formula.

[0063]

[C21]

In the formula, R1, Ra and X- are as defined above.

That is, the production of the carbapenem compound of the present invention involves the use of a compound represented by formula (II) and a mercapto reagent, a compound represented by formula (III), 6,7-dihydro-6-mercapto-5H-pyrazolo. [1,2-a]
[1,2,4]triazolium salt is reacted to form the formula (IV
), and then, if necessary, by removing the carboxy protecting group R1 in the obtained compound of formula (IV), the compound represented by formula (I), (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 formula (II) and the mercapto compound represented by formula (III) can be carried out, for example, by reacting the compound represented by formula (II) with tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, In a suitable solvent such as dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, etc.
Approximately equimolar amount to about 5 times the molar amount, preferably about 1.5 to about 5 times the molar amount
in the presence of about a 3-fold molar excess of a mercapto reagent of formula (III) and preferably a base such as sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine at a temperature of about -40 to about 25°C. This can be carried out by reacting at a temperature of about 30 minutes to about 24 hours.

The above reaction yields a compound represented by formula (IV), in which the carboxylic acid at the 3-position is protected with a carboxy protecting group. Removal of the protecting group can be carried out by deprotecting group reactions known per se, such as solvolysis or hydrogenolysis. Typically, a compound of formula (IV) is added to a compound of formula (IV), e.g.
Acetate buffer at pH 5.5, morpholinopropanesulfonic acid-sodium hydroxide buffer at pH 5.5, phosphate buffer at pH 5.5, dipotassium phosphate, sodium bicarbonate, etc. in tetrahydrofuran-water, tetrahydrofuran- Using hydrogen at 1 to 4 atmospheres in a mixed solvent such as ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water, etc., platinum oxide, palladium-activated carbon, palladium hydroxide-activated carbon, etc. in the presence of a hydrogenation catalyst of about 0.25°C at a temperature within the range of about 0°C to about 50°C.
This can be done by treating for ~5 hours.

[0068] The protective group can also be removed by treatment with zinc in a buffer solution. For example, the compound represented by formula (IV) may be added to zinc in a buffer having a pH of 5 to 7, such as phosphate buffer, acetate buffer, citrate buffer, morpholinopropanesulfonic acid buffer, N-methylmorphophosphate buffer. This can be done by processing. Examples of the zinc used include zinc powder, zinc flakes, zinc granules, etc., and the amount used is not particularly limited, but generally 1 to 10 parts by weight per 1 part by weight of the compound of formula (IV), Preferably it is within the range of 1 to 5 parts by weight. In addition, in order to ensure a homogeneous reaction system in this elimination reaction, an organic solvent may be used in combination as necessary. Examples of solvents that can be used in this case include alcohols such as ethanol, propanol, and n-butanol. Ether solvents such as diethylethanol and tetrahydrofuran; examples include acetonitrile, dimethylformamide, and dimethylacetamide. The reaction is -20 to about 50
C., preferably room temperature to about 30.degree. C., for 0.1 to 5 hours.

Thus, the object compound of the present invention, the formula (
I) (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.

As mentioned above, the carbapenem compound represented by the formula (I) provided by the present invention is extremely stable against attack by a renal enzyme known as dehydropeptidase (DHP), and has antibacterial properties. It also has excellent activity. Furthermore, it has high chemical and physical stability and can be a clinically excellent drug, and the present invention is judged to have high practical value in providing a more efficient manufacturing method for such compounds. . Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples, but the present invention is not limited by these descriptions.

[0071] The symbols in each description have the following meanings.

Z: benzyloxycarbonyl group PNB:
Paranitrobenzyloxycarbonyl group

[0073]

[Reference example 1]

[0074]

[C22]

Add 0.56 ml of triethylamine to 20 ml of dichloromethane solution in which 1.14 g of compound (1) is dissolved.
, 508 mg of iodine is added, and the mixture is stirred at room temperature for 10 minutes. After the reaction is completed, the reaction solution is washed with aqueous sodium thiosulfate and saturated brine, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1:1) to give 939 mg (8
5.2%) was obtained.

1H-NMR (CDCl3, δppm):
3.25 (m, 2H), 3.40 (m, 2H), 3.7
0 (m, 2H), 4.10 (m, 4H), 5.16 (s
, 8H), 7.30(s, 20H)

[0077]

[Reference example 2]

[0078]

[C23]

Compound (2) 742m obtained in Reference Example 1
g was dissolved in 3.1 g of a 25% acetic acid solution of hydrobromic acid, and stirred at room temperature for 4 hours. After completion of the reaction, compound (3) obtained as a precipitate is collected by filtration and washed with 10 ml of ethyl acetate. After dissolving the obtained precipitate in methanol, the solvent was distilled off under reduced pressure to obtain 420 mg of compound (3) as a brown solid.
(70%) obtained.

1H-NMR (D2O, δppm): 3.
50 (m, 4H), 3.53-3.85 (m, 6H)

[
0081

[Example 1]

[0082]

[C24]

568 mg of compound (3) obtained in Reference Example 2 was dissolved in 30 ml of water, and 858 mg of potassium hydrogen carbonate was added under ice cooling.
Add 2 mg slowly and adjust the pH of the aqueous solution to 7.10. Next, 2.112g of ethyl formimide hydrochloride
In addition, stir for 10 minutes under the same conditions. 1N after completion of reaction
-Adjust the pH of the aqueous solution to 5.5 with hydrochloric acid, and then wash the reaction solution with 50 ml of ethyl acetate. The aqueous layer is concentrated to dryness under reduced pressure, 30 ml of methanol is added, and the precipitate is filtered off. The residue obtained by distilling off methanol under reduced pressure is SP-20
Purification is performed using 7 column chromatography (SP-207, 100 ml, water) to obtain compound (4). Obtained compound (4)
was freeze-dried, 10 ml of methanol and 1 ml of trifluoroacetic acid were added, and after the reaction was completed, the solvent was distilled off under reduced pressure to obtain the compound (5
) was obtained as white crystals in an amount of 317.2 mg (58.3%).

1H-NMR (D2O, δppm): 4.
80-5.00 (m, 4H), 5.00-5.16 (m
, 6H), 9.05 (s, 4H)

[0085]

[Example 2]

[0086]

[C25]

[0087] 112 mg of compound (5) was dissolved in a mixture of 3 ml of water and 3 ml of tetrahydrofuran, and stirred under ice cooling.
Add 0.082 ml of butyl phosphorus and stir for 1 hour under the same conditions. After the reaction is complete, add 10 ml of water and add 1 ml of dichloromethane.
The reaction solution was washed twice with 0 ml and then once with 10 ml of ethyl acetate, and the resulting aqueous layer was lyophilized to give compound (6) 1
02.2 mg (90.9%) was obtained.

1H-NMR (D2O, δppm): 4.
50-4.70 (m, 2H), 5.00-5.20 (m
, 3H), 9.00 (s, 2H)

[0089]

[Example 3]

[0090]

[C26]

Compound (6) obtained in Example 2: 85.5
mg and 199.6 mg of compound (7) were dissolved in 3 ml of anhydrous acetonitrile and cooled. Add 0.06 ml of diisopropylethylamine and stir for 1 hour under ice cooling. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and 20ml of ethyl acetate was added.
After centrifugation (3000 rpm, 5 minutes), remove the supernatant by decantation. Repeat the above centrifugation three times, collect and concentrate the supernatant removed by decantation, add 20 ml of chloroform, and centrifuge to remove the supernatant. The centrifuged precipitate obtained in each treatment was dissolved in methanol and collected, and the methanol was distilled off under reduced pressure to obtain compound (8) as a pale yellow oil with a concentration of 134.8
mg (67%) was obtained.

1H-NMR (CD3OD, δppm):
1.32 (d, 6H, J=6.0Hz), 3.35 (m
, 1H), 3.65 (m, 1H), 4.20 (m, 1H)
), 4.42 (m, 1H), 4.60-4.90 (m,
2H), 5.1-5.3 (m, 3H), 5.36 (A
Bq, 2H, J=13.7Hz), 7.67(d, 2H
, J=8.5Hz), 8.21(d,2H, J=8.5
Hz), 9.07 (s, 1H), 9.08 (s, 1H)

[0093]

[Example 4]

[0094]

[C27]

Compound (8) obtained in Example 3: 84.9
mg was dissolved in 2.5 ml of 0.1 M acetate buffer (pH 5.5), 2.5 ml of n-butanol and 25 mg of 10% palladium-carbon were added, and the mixture was stirred at room temperature under a hydrogen atmosphere (4 atm) for 1 hour. Ivy. After the reaction was completed, the reaction solution was filtered through Celite, and the Celite was washed with 20 ml of water, and the pH of the aqueous layer was adjusted to 4.8-5.6 with 1N sodium hydroxide.
Wash with 20 ml of butanol. The aqueous layer was concentrated under reduced pressure to 5 ml, the resulting residue was purified by SP-207 column chromatography (SP-207, 10 ml), the fraction of compound (9) was concentrated to 10 ml, and then frozen. dry. 0.1 ml of water and 2 ml of ethanol were added to the obtained solid to perform crystallization, and compound (9) was obtained as (1R,5S,6S)-2-[(6,7-dihydro-5
30 mg of H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carboxylate as white crystals (60%) obtained.

1H-NMR (D2O, δppm): 1.
29 (d, 3H, J = 7.3Hz), 1.33 (d, 3H
H, 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=6.2Hz), 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)
H)

[0097]

[Example 5]

[0098]

[C28]

Compound obtained according to the method described in Reference Example 2 (
3) Dissolve 568 mg in 30 ml of water, gradually add 858.2 mg of potassium hydrogen carbonate under ice cooling, and adjust the pH of the aqueous solution to 7.10. Next, 2.1 g of ethyl formimidate hydrochloride was added and stirred for 10 minutes under the same conditions. After the reaction is completed, the pH of the aqueous solution is adjusted to 3.5 with 1N hydrochloric acid, and then the reaction solution is washed with 50 ml of ethyl acetate. The aqueous layer is concentrated to dryness under reduced pressure, 30 ml of methanol is added, and the precipitate is filtered off. The residue obtained by distilling off methanol under reduced pressure was subjected to column chromatography (DOWEX-X4, 11 ml, 5
After purification with 0% methanol water, 50% 6N hydrochloric acid-methanol), add a small amount of methanol and leave overnight. The precipitated crystals were collected and dried under vacuum to obtain 337 mg (56%) of compound (4) [Compound (4) is a 10% hydrated salt].

1H-NMR (D2O, δppm): 4.
80-5.00 (m, 4H), 5.00-5.16 (m
, 6H), 9.05 (s, 4H)

[0101]

[Example 6]

[0102]

[C29]

353 mg of the compound (4) obtained in Example 5 was dissolved in a mixture of 10 ml of water and 10 ml of tetrahydrofuran, and 340 mg of triphenylphosphine was added under ice cooling, followed by stirring for 1 hour under the same conditions. After the reaction was completed, tetrahydrofuran was distilled off, 10 ml of water was added, and the resulting water layer was washed three times with 10 ml of ethyl acetate, and the resulting aqueous layer was freeze-dried to obtain compound (10).
160 mg (90%) was obtained.

1H-NMR (D2O, δppm): 4.
50-4.70 (m, 2H), 5.00-5.20 (m
, 3H), 9.00 (s, 2H)

[0105]

[Example 7]

[0106]

[C30]

Compound (10) 177 obtained in Example 6
mg and 594 mg of compound (7) were suspended in 6 ml of anhydrous acetonitrile and cooled on ice. Add 0.2 ml of diisopropylethylamine and stir for 1 hour under ice cooling. After the reaction is complete, add 6 ml of dichloromethane and collect the precipitated crystals. Dissolve the crystals in a small amount of acetonitrile and dichloromethane.
After sequentially washing with acetonitrile (1:1) and dichloromethane and drying under vacuum, 365 mg (70 mg) of compound (11) was obtained.
%)Obtained.

1H-NMR (CD3OD, δppm):
1.32 (d, 6H, J=6.0Hz), 3.35 (m
, 1H), 3.65 (m, 1H), 4.20 (m, 1H)
), 4.42 (m, 1H), 4.60-4.90 (m,
2H), 5.1-5.3 (m, 3H), 5.36 (AB
q, 2H, J=13.7Hz), 7.67(d, 2H,
J=8.5Hz), 8.21(d,2H, J=8.5H
z), 9.07 (s, 1H), 9.08 (s, 1H)

[0109]

[Example 8]

[0110]

[Chemical formula 31]

Compound (11) obtained in Example 7 250
mg to 8.6ml of 0.3M phosphate buffer (pH 5.6)
8.6 ml of n-butanol and 2 g of zinc powder were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction is completed, the reaction solution is filtered through Celite, and after washing the Celite with 20 ml of water, the pH of the aqueous layer is adjusted to 5.5 with 1N sodium hydroxide, and 20 ml of n-butanol is added to separate the layers. The aqueous layer was concentrated under reduced pressure to 10 ml, and the resulting residue was
207 column chromatography (SP-207, 10
ml), and the fraction of compound (9) is concentrated to 5 ml and then freeze-dried. 0.5 of water to the obtained solid
ml and 3.7 ml of ethanol were added to perform crystallization, and compound (9) was obtained as (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-carboxylate was obtained as white crystals in an amount of 132 mg (79%).

The NMR spectrum of this product completely matched that of Example 4.

[0113]

Example 9 The following compounds were obtained according to the method described in Example 7.

Ethyl (1R,5S,6S)-2-[(6
,7-dihydro-5H-pyrazolo[1,2-a][1,
2,4]triazolium-6-yl)thio]-6-[(
1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride (12
)

[0115]

[C32]

1H-NMR (CDCl3-CD3OD)
δ: 1.23-1.34 (9H, m), 3.28-3.
31 (1H, m), 3.55-3.65 (1H, m),
4.18-4.27 (3H, m), 4.39-4.43
(1H, m), 4.56-4.69 (2H, m), 5.
10-5.22 (1H, m), 5.22-5.31 (2
H, m), 8.97 (2H, bs) IR (KBr) cm
-1:1770, 17051-acetoxyethyl (1R
,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-
6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride (13)

[0117]

[Chemical formula 33]

1H-NMR (D2O) δ: 1.30 (3
H, d, J = 7.2 Hz), 1.53 (1.5 H, d,
J=5.3Hz), 1.54 (1.5H, d, J=5.
3Hz), 2.09 (3H, s), 3.55-3.64
(2H, m), 4.25 (1H, quintet, J=
6.2Hz), 4.63 (1H, dd, J=2.7Hz
, 9.4Hz), 4.91-5.22 (5H, m), 6
．． 89 (1H, q, J = 5.3Hz), 9.04 (1H
,s), 9.07(1H,s)IR(KBr)cm-1
:1760, 3400

Claims (3)

[Claims] Claim 1: A compound represented by the following formula (II) [Formula 1], in which R1 represents a carboxy protecting group and Ra represents an acyl group, is a compound represented by the following formula (III) [Formula 2]
] In the formula, X- represents a salt-forming anion;
,7-dihydro-6-mercapto-5H-pyrazolo[1
,2-a][1,2,4]triazolium,
A compound represented by the following formula (IV) is prepared, where R1 and X- are as defined above, and then, if necessary, the protecting group R1 is removed from the compound to form the following formula ( I) (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
- A method for producing a carbapenem compound of the above formula (IV) or (I), characterized in that it is a carboxylate or a pharmacologically acceptable salt thereof. 2. A carbapenem compound represented by formula (I) according to claim 1, or a pharmacologically acceptable carbapenem compound thereof, characterized in that the protecting group R1 is removed from compound (IV) according to claim 1. Salt manufacturing method. 3. The production method according to claim 1, wherein the protective group R1 is removed by any one of solvolysis, hydrogenolysis, or treatment with zinc in a buffer solution.