JPH0616680A - Production of carbapenem compound - Google Patents

Abstract

PURPOSE:To continuously and readily produce a carbapenem compound exhibiting an excellent antimicrobial activity by eliminating a hydroxyl- protecting group of a specified compound, converting the resultant compound through a cyclization reaction, etc., to a reactive derivative and then reacting the obtained reactive derivative with a mercapto compound. CONSTITUTION:A compound of formula I (R<1> is a carboxyl-protecting group; R<2> is an OH-protecting group) is subjected to an acidic hydrolysis reaction in the presence of an acid such as hydrochloric acid in a solvent such as methanol at 0 to 100 deg.C for 0.5 to 18hr so as to eliminate the OH-protecting group of R<2>. The resultant compound of formula II is cyclized preferably in the presence of a metallic catalyst such as rhodium octanoate in a solvent such as methanol so as to obtain a compound of formula III. Further, this compound is acylated so as to be converted to a derivative reactive at the oxo part and a compound of formula IV (X<-> is an anionic ion residue) is subsequently reacted therewith in the presence of an organic base, etc., at -40 deg.C to room temperature, thus producing the objective compound of formula V.

Description

Detailed Description of the Invention

The present invention relates to a method for producing a novel carbapenem compound, more specifically, the following formula

[0002]

[Chemical 13]

In the formula, R ¹ represents a protecting group for a carboxyl group and X ⁻ represents an anion residue, and relates to a simple and high-yield production method of a carbapenem compound.

The carbapenem compound of the above formula (I) has excellent antibacterial activity previously proposed by the present inventors by removing the carboxyl protecting group of R ¹ (see Japanese Patent Laid-Open No. 64-25779). Formula (A) useful as an antibacterial agent

[0005]

[Chemical 14]

Can be induced to a compound represented by
Therefore, it is useful as a synthetic intermediate for the compound of formula (A).

According to the present invention, the equation (a) is

[0008]

[Chemical 15]

In the formula, R ¹ represents a protecting group for a carboxyl group and R ² represents a protecting group for a hydroxyl group, and the protecting group for a hydroxyl group of R ^{2 in} the compound represented by the formula (b) is obtained.

[0010]

[Chemical 16]

In the formula, R ¹ has the above-mentioned meaning, and a compound represented by the formula (c)

[0012]

[Chemical 17]

Wherein R ¹ has the above meaning, after acylation of the compound represented by the formula to convert it into a reactive derivative at the oxo group of the compound,

[0014]

[Chemical 18]

In the formula, X ⁻ represents an anion residue, and the formula is obtained by reacting with a mercapto compound represented by

[0016]

[Chemical 19]

There is provided a process for preparing a carbapenem compound represented by the formula: wherein R ¹ and X ^- have the above meanings.

The above-mentioned method of the present invention allows the steps (a), (b) and (c) of the above-mentioned reaction to be continuously carried out without particularly isolating and purifying the intermediate product. It is particularly advantageous in industrial production, in which the compound of formula (I) is produced in large quantities.

Another advantage of the present invention is that the steps (a) to (c) of the above reaction can be carried out in the same reaction vessel (that is, in one pot).

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

The "carboxyl-protecting group" may be any carboxyl-protecting group known per se as a carboxyl-protecting group in the field of peptide chemistry, for example, an ester residue of a carboxylic acid is exemplified. You can Representative examples of such ester residues include: (a) lower alkyl ester residues: eg methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, te.
rt-butyl ester, pentyl ester, hexyl ester and the like.

(B) Lower alkyl ester residue which may have at least one suitable substituent: eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pi Valoyloxymethyl ester, hexanoyloxymethyl ester, 1- (or 2-)
Acetoxyethyl ester, 1- (or 2- or 3
-) Acetoxypropyl ester, 1- (or 2- or 3- or 4-) acetoxybutyl ester, 1-
(Or 2-) propionyloxyethyl ester, 1
-(Or 2- or 3-) propionyloxypropyl ester, 1- (or 2-) butyryloxyethyl ester, 1- (or 2-) isobutyryloxyethyl ester, 1- (or 2-) pivalo Yloxyethyl ester, 1- (or 2-) hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2
-Ethyl butyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1- (or 2
-) Lower alkanoyloxy (lower) alkyl ester residue such as pentanoyloxyethyl ester; Lower alkanesulfonyl (lower) such as 2-mesylethyl ester
Alkyl ester residue; 2-iodoethyl ester,
Mono (or di or tri) halo (lower) alkyl ester residues such as 2,2,2-trichloroethyl ester;
Methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tert-butoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester Lower alkoxycarbonyloxy (lower) such as
Alkyl ester residue; phthalidylidene (lower) alkyl ester residue; (5-methyl-2-oxo-1,3-
Dioxole-4-yl) methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-2-oxo-1,3-
(5-lower alkyl-2-oxo-1,3-dioxol-4-, such as dioxol-4-yl) ethyl ester
(Yl) (lower) alkyl ester and the like.

(C) Lower alkenyl ester residue: For example, vinyl ester, allyl ester and the like.

(D) Lower alkynyl ester residue: For example, ethynyl ester, propynyl ester and the like.

(E) Aralkyl ester residue which may have at least one suitable substituent: for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydrid. Ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditert-butylbenzyl ester and the like. (F) Aryl ester residue which may have at least one suitable substituent: for example, phenyl ester, 4-
Chlorophenyl ester, tolyl ester, tert-
Butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.

(G) Others: phthalidyl ester, etc.

Among the protecting groups for the carboxyl group, preferred examples include a phenyl-lower alkyl group which may be substituted with a nitro group, and a lower alkenyl group, more preferred is the 4-nitrobenzyl group. .

Further, the “amino-protecting group” may be any amino-protecting group known per se as an amino-protecting group in the field of peptide chemistry, and examples of the “hydroxyl-protecting group” include trimethylsilyl. , Silyl groups such as triethylsilyl, tert-butyldimethylsilyl, diphenyl-tert-butylsilyl, etc., substituted or unsubstituted benzyloxycarbonyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, etc. Included are commonly used hydroxyl protecting groups.

The method for producing the compound represented by the formula (I) provided by the present invention is shown in the following reaction scheme.

[0030]

[Chemical 20]

In the formula, R ¹ , R ² and X ⁻ have the same meaning as described above.

The above manufacturing process will be described in more detail below.

Step (a) : Step (a) is a step of eliminating the hydroxyl-protecting group represented by R ² in the compound of formula (II).

For example, removal of a protecting group in which R ² is a triorganosilyl group such as a t-butyldimethylsilyl group is accomplished by removing the compound of formula (II) in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane and the like. ,
0-10 in the presence of acids such as hydrochloric acid, sulfuric acid, acetic acid, etc.
It can be carried out by acid hydrolysis at a temperature of 0 ° C. for 0.5 to 18 hours. (The above "triorganosilyl group" more preferably includes a silyl group substituted with an organic group independently selected from a lower alkyl group, a phenyl group and a phenylalkyl group.) In the formula (II), R ^The following formula (II-a), wherein ¹ is a 4-nitrobenzyl group and R ² is a t-butyldimethylsilyl group

[0035]

[Chemical 21]

In addition, the t-butyldimethylsilyl group of the formula (II-a) is eliminated by the operation of the step (a) to obtain the following formula (III-a).

[0037]

[Chemical formula 22]

The genus compounds of the above are those which can be obtained especially in the form of morphology.

Conventionally, all of these compounds have been obtained only as an amorphous powder, and when the production on an industrial scale is considered, the compound has a high purity and is isolated and purified by crystals which are easy to handle. This can be said to be particularly preferable.

Therefore, another object of the present invention is also to provide a compound in the crystalline form represented by the above formulas (II-a) and (III-a).

Step (b) : The step (b) is represented by the formula (III)
This is a step of cyclizing the compound of formula (1) by reacting it with a metal catalyst to obtain an oxo compound of formula (IV).

The cyclization is carried out, for example, by reacting the compound of formula (III) with an inert organic solvent such as methanol, ethanol, n.
-Alcohols such as propanol, isopropanol, n-butanol; Ethers such as tetrahydrofuran, diethyl ether, dioxane; Esters such as ethyl acetate; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; Acetone, dimethylformamide , Pyridineacetonitrile and the like, in a solvent appropriately selected, preferably dichloromethane, acetone or ethyl acetate, a metal catalyst such as bis (acetylacetonato) Cu (II), copper sulfate, copper powder, rhodium acetate (II), rhodium (II) octoate, lead tetraacetate or the like, preferably in the presence of rhodium (II) octoate, at room temperature to the reflux temperature of the solvent by stirring for 1 to 7 hours. it can.

The amount of the above-mentioned metal catalyst used is not particularly critical and can be appropriately changed, but is usually 0.2 to 2.0% by weight, more preferably 0.5 to 2.0% by weight based on the compound of the formula (III). 1.0% by weight is used. This gives the formula (I
The compound of V) is produced almost quantitatively.

After completion of the reaction, the solvent can be distilled off from the reaction mixture under reduced pressure to obtain the compound of formula (IV) as a residue, but without treating the reaction mixture,
It is directly used for the next step in the same reaction vessel.

Step (c) : In the step (c), the formula (I
Acylation of a compound of V) is carried out by reacting a reaction mixture containing the compound of formula (IV) obtained in the above step (b) or a compound of formula (IV) obtained as a concentrated residue with a suitable acylating agent. Can be done by.

By this acylation, the following formula which is a reactive derivative at the oxo group of the compound of the above formula (IV)

[0047]

[Chemical formula 23]

In the formula, ^a compound represented by R a represents an acyl group and R ¹ has the same meaning as described above is produced.

Therefore, as an acylating agent that can be used in the above acylation reaction, the following formula

[0050]

Embedded image R ^a OH (VII) wherein R ^a has the same meaning as described above, or an acid or salt thereof represented by or a reactive derivative thereof, for example,

[0051]

Embedded image R ^a Hal (VII-1) In the formula, Hal represents a halogen atom, and R ^a has the same meaning as described above, and an acid halide represented by

[0052]

Embedded image R ^a ₂ O (VII-2) In the formula, R ^a has the same meaning as described above, and an acid anhydride represented by

Here, the "acyl group" represented by R ^a is, for example, an aliphatic acyl group, an aromatic acyl group, a heterocyclic acyl group and an aliphatic acyl group substituted with an aromatic group or a heterocyclic group. Acyl groups derived from various carboxylic acids, carbonic acids, sulfonic acids, phosphoric acids and carbamic acids. Representative examples of such acyl groups are listed below: (a) Aliphatic acyl groups: alkanoyl groups such as lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl; Alkylsulfonyl groups such as lower alkylsulfonyl groups such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl; N-alkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl; Alkoxy groups such as lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, etc. Sicarbonyl group; alkenyloxycarbonyl group such as lower alkenyloxycarbonyl group such as vinyloxycarbonyl, allyloxycarbonyl; alkenoyl group such as lower alkenoyl group such as acryloyl, methacryloyl, crotonoyl; eg cyclopropanecarbonyl, cyclo Cycloalkanecarbonyl groups such as cyclo (lower) alkanecarbonyl groups such as pentanecarbonyl and cyclohexanecarbonyl; di (lower) alkyl groups such as diethyl phosphate.

(B) Aromatic acyl group: an aroyl group such as benzoyl, toluoyl, xyloyl;
-Phenylcarbamoyl, N-tolylcarbamoyl, N
-N-arylcarbamoyl groups such as naphthylcarbamoyl; arenesulfonyl groups such as benzenesulfonyl and tosyl; diaryl phosphate groups such as diphenyl phosphate.

(C) Heterocyclic acyl group: for example, furoyl,
Heterocyclic carbonyl groups such as thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl and tetrazolylcarbonyl.

(D) Aliphatic acyl group substituted with an aromatic group: for example, phenylacetyl, phenylpropionyl,
Aralkanoyl groups such as phenyl (lower) alkanoyl groups such as phenylhexanoyl; Aralkoxycarbonyl groups such as phenyl (lower) alkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, etc .; For example, phenoxyacetyl Aryloxyalkanoyl groups such as phenoxy (lower) alkanoyl groups such as phenoxypropionyl and the like.

(E) Aliphatic acyl group substituted with a heterocyclic group: for example, thienylacetyl, imidazolylacetyl,
Heterocyclic alkanoyl groups such as heterocyclic (lower) alkanoyl groups such as furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl and thiadiazolylpropionyl.

These acyl groups further include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl; chlorine, bromine, and the like.
Halogen such as iodine and fluorine; lower alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy; lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio Group; may be substituted with one or more suitable substituents such as nitro group, and preferable acyl groups having such a substituent include, for example, chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc. A mono (or di or tri) haloalkanoyl group; a mono (or di or tri) haloalkoxycarbonyl group such as chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl; Nitro (or halo or lower alkoxy) aralkoxycarbonyl groups such as nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methoxybenzyloxycarbonyl and the like; such as fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, etc. A mono (or di or tri) halo (lower) alkylsulfonyl group and the like can be mentioned.

As the acylating agent, those which can introduce the above acyl group into the compound of the formula (IV) are used. Generally, the acid halide represented by the above formula (VII-1) or the formula (VII) is used. An acid anhydride represented by -2) is preferably used. Typical examples of such acid halides include arenesulfonyl halides such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride: methanesulfonyl chloride, ethanesulfonyl chloride, chloride. Examples thereof include lower alkanesulfonyl halides which may further have halogen such as trifluoromethanesulfonyl; di (lower) alkyl halophosphates such as diethyl chlorophosphate; diaryl halophosphates such as diphenyl chlorophosphate.

Typical examples of the acid anhydrides are arenesulfonic acid anhydrides such as anhydrous benzenesulfonic acid, anhydrous p-toluenesulfonic acid, and anhydrous 4-nitrobenzenesulfonic acid; for example, anhydrous methanesulfonic acid and anhydrous ethane. Examples thereof include lower alkane sulfonic acid anhydrides which may have a halogen such as sulfonic acid and trifluoromethanesulfonic anhydride.

Among such acylating agents, more preferable ones include diethyl chlorophosphate and diphenyl chlorophosphate.

In the acylation reaction of the compound of formula (IV), when a free acid represented by formula (VI) or a salt thereof is used as an acylating agent, the reaction is carried out in the presence of a conventional condensing agent. Is preferred. Representative examples of such condensing agents include: (a) carbodiimide compounds: for example, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide,
N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N-ethyl-
N '-(3-dimethylaminopropyl) carbodiimide and the like.

(B) Carbonyldiimidazole compound:
For example, N, N'-carbonyldiimidazole, N, N '
-Carbonylbis (2-methylimidazole) and the like.

(C) Ketenimine compound: For example, pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine and the like.

(D) Others: For example, ethoxyacetylene, 1-alkoxy-1-chloroethylene, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, 2-ethyl-7-.
Hydroxybenzisoxazolium salt, 2-ethyl-5
-(M-sulfophenyl) isoxazolium hydroxide inner salt, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, and N, N-dimethylformamide with thionyl chloride, phosgene or oxy. So-called Vilsmeier reagent prepared by reaction with phosphorus chloride and the like.

Further, the acylation reaction of the compound of the formula (IV) is preferably carried out by an alkali metal such as lithium, sodium or potassium; an alkaline earth metal such as calcium; an alkali metal hydrogen such as sodium hydride. Alkaline earth metal hydrides such as calcium hydride; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; Alkali metal hydrogen carbonate such as potassium hydrogen; Alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tertiary butoxide; Alkali acid alkali metal salt such as sodium acetate; Alkali such as magnesium carbonate and calcium carbonate Earth metal carbonate Such as trimethylamine, triethylamine, N, N-diisopropyl -N- tri ethylamine and the like (lower) alkylamine; for example pyridine,
Pyridine compounds such as picoline, lutidine, N, N-di (lower) alkylaminopyridines such as N, N-dimethylaminopyridine; quinoline; N-lower alkylmorpholines such as N-methylmorpholine; eg N, N-
It can be carried out in the presence of an organic or inorganic base such as N, N-di (lower) alkylbenzylamine such as dimethylbenzylamine.

The above acylation is usually from about -20 ° C to about 4 ° C.
It can be carried out at a relatively low temperature of 0 ° C.

The amounts of the acylating agent and the base used in the above reaction are not particularly critical and can be appropriately changed depending on the reaction conditions and the like, but the acylating agent and the base are usually the starting materials of the formula ( It can be used in a proportion of 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of the compound of III). This produces a compound of formula (VI) almost quantitatively.

The formula (V
The compound of I) was prepared in the same reaction vessel without isolation from the reaction mixture.

[0070]

[Chemical 27]

Wherein X ⁻ has the same meaning as defined above,
By reacting the mercaptopyrazolotriazolium represented by or the reactive derivative thereof, the carbapenem compound represented by the formula (I) as the target compound can be obtained.

The reaction of a compound of formula (VI) above with a mercapto compound of formula (V) or a reactive derivative thereof is generally carried out in the presence of an organic or inorganic base similar to those mentioned above in the acylation reaction. It can be carried out at a temperature of about -40 ° C to room temperature. The amount of the mercapto compound of the formula (V) or its reactive derivative and the above-mentioned base used is not critical, but usually the compound 1 of the formula (III) 1
It can be used in a proportion of 1 to 2 mol, preferably 1.0 to 1.5 mol, based on mol.

The compound of formula (I) thus obtained can be isolated by separation and purification methods known per se.

Next, the crystals of the compounds (II-a) and (III-a) which can be the starting materials for the synthesis of the compound (I) will be described in detail.

The compounds represented by the formulas (II-a) and (III-a) provided in the present invention are represented by the following formula

[0076]

[Chemical 28]

Where:

[0078]

[Chemical 29]

Represents a t-butyldimethylsilyl group,
It can be produced from the compound shown by the following methods, for example, in Examples 3 and 4. The produced compound (II-a) is, for example, a mixed solution of ethyl acetate and n-hexane, and the compound (III-a) is, for example, ethyl acetate
It can be recrystallized from a mixed solution of hexane or a mixed solution of ethyl acetate and isopropyl ether.

The compounds (II-a) and (III-a) of the present invention which can be produced as described above have been confirmed to be crystals by observation with a polarization microscope and powder X-ray diffraction analysis. It is identified by having a characteristic peak in the line diffraction analysis. The peak patterns are shown in Tables (I) and (II) below.

[0081]

[Table 1]

[0082]

[Table 2] The formula (II-a) and the formula (III-
The crystals of the compound represented by a) are far superior in solid stability to the amorphous form. Therefore, it can be used as an advantageous raw material having high storage stability and transportability in the industrial synthesis of compound (I).

Further, the compound (I) synthesized by the method of the present invention has the following formula (A) useful as an antibacterial agent by removing the protective group of the carboxyl group represented by R ¹ in the formula.

[0084]

[Chemical 30]

It is possible to obtain a compound represented by:

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these descriptions.

In the following description of this specification, the following abbreviations are used.

[0088]

[Chemical 31]

T-butyldimethylsilyl group PNB: 4-nitrobenzyl group

[0090]

[Example] Example 1

[0091]

[Chemical 32]

3.02 ml (29.7 mmol) of concentrated hydrochloric acid
And 50 ml of methanol in a mixed solution at 25 ° C.
-A) 5.0 g (9.9 mmol) was added and stirred. Two
After hours, sodium hydrogencarbonate 5.00 g (59.5 mmo
l), dichloromethane 50 ml and saturated saline 50 ml
It was extracted with. All the obtained organic layers were mixed, dried over anhydrous magnesium sulfate, and the solvent was distilled off.

Then, the obtained residue was mixed with dichloromethane 5
Dissolve in 1 ml, rhodium (II) octanoate 31m
g (0.0398 mmol) was added and the mixture was heated to reflux. After 7 hours, the reaction solution was cooled to −15 ° C., 2.95 g (10.8 mmol) of diphenyl chlorophosphate was added, and 2.32 ml (13.0 mmol) of diisopropylethylamine and 24 mg (0.193 m) of 4-dimethylaminopyridine.
mol) in dichloromethane (20m dichloromethane)
1) was added dropwise over 0.5 hour, and the mixture was further stirred for 0.5 hour.

After completion of the reaction, the solvent was distilled off, and acetone 12m was added.
1, 12 ml of acetonitrile and 1.2 ml of dimethylformamide were added and dissolved. Then add 7 to this mixture.
1.84 g (10.44 mmol) of 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1.2.4] triazolium chloride, 2.32 ml of diisopropylethylamine (13 .04 mmo
l) and 48 mg of the compound (I) as seed crystals were sequentially added, and the mixture was stirred at 4 to 7 ° C. for 2 hours, and dichloromethane 3
0 ml was added and stirred for 1 hour. After the reaction was completed, the precipitated crystals were quickly collected by filtration, 2 ml of dichloromethane and 2 ml of acetone.
The mixture was washed twice with a mixed solution of 4 times and once with 4 ml of dichloromethane, and then dried under vacuum.

As a result, 5.88 g of compound (I) (yield 7
0.0%) was obtained.

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

[0097]

[Chemical 33]

585 mg (1.5) of compound (III-a)
mmol) was dissolved in 14 ml of dichloromethane, and rhodium (II) octanoate (3.5 mg) (0.0398 mmo)
1) was added and the mixture was refluxed for 3 hours. The reaction solution was cooled to −15 ° C., and diphenyl chlorophosphate 443 mg (1.65 mmo
l) was added, followed by diisopropylethylamine 256
A dichloromethane solution (dichloromethane 3 ml) of mg (1.98 mmol) and 4-dimethylaminopyridine 3.7 mg (0.03 mmol) was added dropwise over 30 minutes. The reaction solution was further stirred for 30 minutes and then the solvent was distilled off,
1.9 ml of acetonitrile and 1.9 m of acetone are added to the residue.
1 and 0.2 ml of dimethylformamide were added and dissolved. Next, to this solution, under ice cooling, 6,7-dihydro-6-mercapto-5H-pyrazolo [1,2-a] [1.2.
4] Triazolium chloride 373 mg (2.1 mm
ol), 340 mg of diisopropylethylamine (2.
63 mmol) and 5 mg of compound (I) as seed crystals were added. After stirring for 2 hours, 4.8 ml of dichloromethane was added and the mixture was further stirred for 1 hour. The precipitated crystals were collected, washed successively with a small amount of a mixed solution of dichloromethane / acetone = 1/1 and dichloromethane, and then vacuum dried to give compound (I).
598 mg (76.5% yield) was obtained. The NMR data of the compound obtained here were completely in agreement with those obtained in Example 1.

Example 3 (Synthesis and Crystallization of Compound (II-a))

[0100]

[Chemical 34]

156.2 g of ethyl chlorocarbonate (1.44
mol) in 2740 ml of dry dichloromethane,
Cooled to about -20 ° C. 361.8 g of compound (VII)
(1.20 mol) and triethylamine 157.9 g
A solution of (1.56 mol) in dichloromethane (915 ml of dichloromethane) was added dropwise to the above solution while maintaining the temperature of the reaction solution at about -15 ° C, and the reaction solution was stirred at 0 ° to 5 ° C for 30 minutes. Then 114.4 g of imidazole
A solution of (1.68 mol) in 730 ml of dry dichloromethane was added to the reaction solution at 0 ° to 10 ° C,
The compound (VII
A solution of I) was obtained.

Separately, a magnesium malonate solution was prepared by the following procedure. 488.0 g (2.04 mol) of p-nitrobenzyl malonate was suspended in 2740 ml of dry dichloromethane, and 97.1 g (1.02 mol) of magnesium chloride was added under a nitrogen atmosphere. further,
A solution prepared by diluting 206.4 g (2.04 mol) of triethylamine with 183 ml of dry dichloromethane was added while keeping the temperature of the reaction solution at 0 ° to 10 ° C, and the temperature was kept at that temperature for 1 hour and further returned to room temperature. Stir for 30 minutes.

The magnesium malonate solution synthesized in this manner was added to the solution of the compound (VIII) to give 6
The reaction was carried out at 0 ° to 65 ° C for 2.5 hours.

After completion of the reaction, the reaction solution was cooled to room temperature and
It was washed successively with NH Cl, water, 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate and then filtered to obtain a solution of compound (IX).

To this solution was added 472.4 g (1.34 mol) of p-dodecylbenzenesulfonyl azide in dichloromethane (890 ml), and subsequently 31.4 g of triethylamine with stirring at 15 ° to 25 ° C. under a nitrogen atmosphere. After adding (0.31 mol),
The mixture was stirred for 1.5 hours while maintaining the temperature.

After the reaction, the reaction mixture was concentrated and n-hexane was added to the residue for crystallization. The crystals were collected by filtration and dried in vacuum to obtain 455.6 g (yield 75.3%) of crystals of compound (II-a). As a result of observing this crystal with a polarization microscope, it was confirmed that the crystal had a polarization property and was a crystal.

The compound (II-a) was recrystallized by the following method. That is, the compound (I
The crystals of Ia) (17.4 g) were dissolved in ethyl acetate (174 ml) and concentrated to about 50 ml.
After adding ml, the solution was crystallized and filtered. Crystals are n-hexane 20
After washing with ml × 2, vacuum drying was performed to obtain 11.3 g (yield 64.9%) of recrystallized crystals of compound (II-a).

Further, powder X-ray diffraction analysis was conducted on the recrystallized crystals, and it was confirmed that they had the characteristic peaks shown in Table (I) above.

Example 4 (Synthesis and Crystallization of Compound (III-a))

[0110]

[Chemical 35]

156.2 g of ethyl chlorocarbonate (1.44
mol) in 2740 ml of dry dichloromethane,
Cooled to about -20 ° C. 361.8 g of compound (VII)
(1.20 mol) and triethylamine 157.9 g
A solution of (1.56 mol) in dichloromethane (915 ml of dichloromethane) was added dropwise to the above solution while maintaining the temperature of the reaction solution at about -15 ° C, and the reaction solution was stirred at 0 ° to 5 ° C for 30 minutes. Then 114.4 g of imidazole
A solution of (1.68 mol) in 730 ml of dry dichloromethane was added to the reaction solution at 0 ° to 10 ° C,
The compound (VII
A solution of I) was obtained.

Separately, a magnesium malonate solution was prepared by the following procedure. 488.0 g (2.04 mol) of p-nitrobenzyl malonate was suspended in 2740 ml of dry dichloromethane, and 97.1 g (1.02 mol) of magnesium chloride was added under a nitrogen atmosphere. further,
A solution obtained by diluting 206.4 g (2.04 mol) of triethylamine with 183 ml of dry dichloromethane was added while maintaining the temperature of the reaction solution at 0 ° to 10 ° C, and the temperature was kept for 1 hour, and the temperature was further returned to room temperature. Stir for minutes.

The magnesium malonate solution thus synthesized was added to the solution of the compound (VIII), and
The reaction was carried out at 0 ° to 65 ° C for 2.5 hours.

After completion of the reaction, the reaction solution was cooled to room temperature and
It was washed successively with NH Cl, water, 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate and then filtered to obtain a solution of compound (IX).

A dichloromethane solution (890 ml of dichloromethane) of 472.4 g (1.34 mol) of p-dodecylbenzenesulfonyl azide was added to this solution, and 31.4 g (0) of triethylamine was stirred with stirring at 15 ° to 25 ° C. under a nitrogen atmosphere. (.31 mol) was added, and the mixture was stirred for 1.5 hours while maintaining the temperature.

After concentrating the reaction solution, 5180 ml of methanol was added to the obtained residue (compound (II-a)) to dissolve it, 267 ml (3.25 mol) of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature (20 to 25 ° C.). Stir for 1.5-2.5 hours. After completion of the reaction, sodium hydrogencarbonate powder was added to neutralize, and 5180 ml of dichloromethane and 5180 m of saturated saline solution were added.
1 was added and stirred. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Ethyl acetate was added and the mixture was concentrated under reduced pressure, and 675 ml of ethyl acetate was added to the obtained residue to dissolve it. After stirring this solution at room temperature for 1 hour, n-
Hexane was added for crystallization to obtain 339 g of a crystal of compound (III-a) (yield 72%).

As a result of observing this crystal with a polarizing microscope, it was confirmed that the crystal had a polarizing property and was a crystal. Further, an X-ray diffraction analysis was carried out, and it was confirmed that it had the characteristic peaks described in the above-mentioned Table (II). A sample purified and recrystallized by the following procedure was used for X-ray diffraction analysis. That is, the crystals of compound (III-a) 20.
After 3 g was purified using a silica gel column and activated carbon, it was dissolved in 40 ml of ethyl acetate, and 160 ml of hexane was added with stirring to crystallize. After drying in vacuum, 17.9 g of recrystallized crystals of compound (III-a) (yield 88.3).
%) Was obtained.

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[Procedure amendment]

[Submission date] June 18, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0037

[Correction method] Change

[Correction content]

[0037] Both compounds are particularly obtainable in the form of crystals.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0081

[Correction method] Change

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[0081]

[Table 1]

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0082

[Correction method] Change

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[0082]

[Table 2] The formula (II-a) and the formula (III-
The crystals of the compound represented by a) are far superior in solid stability to the amorphous form. Therefore, it can be used as an advantageous raw material having high storage stability and transportability in the industrial synthesis of compound (I).

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0091

[Correction method] Change

[Correction content]

[0091]

[Chemical 32]

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0097

[Correction method] Change

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[0097]

[Chemical 33]

Claims (6)

[Claims] 1. A formula (a): In the formula, R ¹ represents a protecting group for a carboxyl group, R ² represents a protecting group for a hydroxyl group, and the protecting group for a hydroxyl group of R ^{2 in} the compound represented by In the formula, R ¹ has the above-mentioned meaning, and a compound represented by Wherein R ¹ has the above meaning, after being acylated to convert it to a reactive derivative at the oxo group of the compound, In the formula, X ⁻ represents an anion residue, and is represented by the formula: In the method for producing a carbapenem compound represented by the formula, wherein R ¹ and X ⁻ have the above meanings, the compound (III) obtained in the step (a) and the compound (IV) obtained in the step (b) are simply used. Steps (a) and (b) without separation
And (c) are continuously carried out. 2. The formula (b): In the formula, R ¹ represents a protecting group for a carboxyl group, and a compound represented by the formula (c) is obtained. Wherein R ¹ has the above meaning, after being acylated to convert it to a reactive derivative at the oxo group of the compound, In the formula, X ⁻ represents an anion residue, and is represented by the formula: In the method for producing a carbapenem compound represented by the formula, wherein R ¹ and X ⁻ have the above meanings, the compound (IV) obtained in the step (b) can be obtained by isolating the step (b) without isolation.
And (c) are continuously carried out. 3. The following formula (II-a): In the formula, Represents a t-butyldimethylsilyl group, and PNB represents 4-
A compound having a crystal form represented by: representing a nitrobenzyl group. 4. In the powder X-ray diffraction pattern, the plane spacing (d) is 6.79, 6.63, 5.46, 5.34, 5.
12, 4.97, 4.66, 4.41, 4.37, 3.
The compound according to claim 3, which has characteristic peaks at 94, 3.80, 3.70, 3.59, 3.42 and 2.96Å. 5. The following formula (III-a): In the formula, PNB represents a 4-nitrobenzyl group. 6. In the powder X-ray diffraction pattern, the plane spacing (d) is 8.11, 6.19, 5.56, 5.22, 4.
82, 4.43, 4.06, 3.94, 3.83, 3.
74, 3.65, 3.59, 3.49, 3.40, 3.
31, 3.22, 3.13, 3.03, 2.88, 2.
78, 2.71, 2.62, 2.57, 2.50, 2.
6. The characteristic peaks at 46 and 2.22Å.
The described compound.