JP2008044847A - Carbapenem synthesized product and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially useful manufacturing method of carbapenem derivatives. <P>SOLUTION: A compound (I) obtained by the reaction scheme represented by formulae (wherein R<SP>1</SP>is a hydroxy-protecting group; R<SP>2</SP>is a carboxy-protecting group; and X is a halogen) and an amine salt thereof are provided. The manufacturing method of carbapenem derivatives comprises using these compounds. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a synthesis intermediate of carbapenem having antibacterial activity and a method for producing the same. Specifically, the present invention relates to the intermediate, its amine salt, its crystal, and a method for producing carbapenem using them.

また特許文献２（実施例１３）には、化合物５からドリペネムの製法が記載されている。

（式中、ＴＭＳ：トリメチルシリル）

非特許文献１には、上記化合物５のヒドロキシ保護体の製法として以下の反応が記載されている。

a: 1) TBS-Cl, NaH, THF, 0℃, 1h 2) BrCH2CO2Allyl, NaH(TMS)2, THF, −50℃, 30min 3) K2CO3, H2O, 25℃, 10min 4) aq. HCl

特開平１−７９１８０ 特開平５−２９４９７０ Synlett, 315-316, 1995 As a method for producing a synthetic intermediate of 1-alkylcarbapenem, Patent Document 1 (Reference Examples 1 and 2) discloses compounds 5 and 6 shown below as intermediates for utilizing the Dieckmann condensation reaction.

Patent Document 2 (Example 13) describes a method for producing doripenem from Compound 5.

(Where TMS: trimethylsilyl)

Non-Patent Document 1 describes the following reaction as a method for producing the hydroxy-protected form of Compound 5 above.

a: 1) TBS-Cl, NaH, THF, 0 ℃, 1h 2) BrCH2CO2Allyl, NaH (TMS) 2, THF, −50 ℃, 30min 3) K2CO3, H2O, 25 ℃, 10min 4) aq. HCl

JP-A-1-79180 JP-A-5-294970 Synlett, 315-316, 1995

  When compound 5 is produced by a conventional method, it is not easy to sufficiently control the side reaction, and as a result, it is extremely difficult to produce the target carbapenem industrially and efficiently. For example, it was found that when carboxy at the 4-position of the β-lactam ring was converted to a thioester and the N atom at the 1-position was alkylated, a part of the thioester group was removed. Further, depending on the kind of the hydroxy protecting group of the starting material, a by-product derived from the hydroxy protecting group is mixed into the compound 5 and it is difficult to completely remove it.

で示される化合物（Ｉ）またはそのアミン塩。
（２）アミンが１級アミンまたは２級アミンである、上記１記載のアミン塩。
（３）アミンが、メチルアミン、エチルアミン、イソプロピルアミン、ｔ−ブチルアミン、（−）−α−メチルベンジルアミン、ジイソプロピルアミン、またはジシクロヘキシルアミンである、上記１記載のアミン塩。
（４）ジイソプロピルアミン塩である、上記１記載のアミン塩。
（５）結晶である、上記１〜４のいずれかに記載のアミン塩。
（６）粉末Ｘ線回折パターンにおいて、２θ＝8.7, 9.7, 15.7, 22.4度に主ピークを示す結晶である、上記４記載のジイソプロピルアミン塩。
（７）以下の反応スキーム：

（式中、Ｒ¹はヒドロキシ保護基；Ｒ²はカルボキシ保護基；Ｘはハロゲン）で示され、以下の工程：
（第１工程）化合物（II）のカルボキシを保護して化合物（III）を製造する工程、
（第２工程）化合物（III）を化合物（IV）と反応させて化合物（V）を製造する工程、および
（第３工程）化合物（V）を脱保護反応に付した後、所望によりアミンと反応させる工程、
を包含することを特徴とする、上記１記載の化合物（I）またはそのアミン塩の製造方法。
（８）Ｒ¹はアルキルシリルおよび／またはＲ²はアルコキシアルキルである、上記７記載の製造方法。
（９）Ｒ¹はｔ−ブチルジメチルシリルおよび／またはＲ²は１−イソブトキシエチルである、上記７記載の製造方法。
（１０）上記１に記載の化合物（I）またはそのアミン塩のカルボキシ部分を活性エステル化、活性酸無水物化、チオールエステル化、アリールエステル化またはヘテロアリールエステル化する工程を包含する、式：

（式中、ＣＯＺは、カルボキシル基の活性エステルもしくは活性酸無水物、保護基で保護されたチオールカルボキシル基、置換アリールオキシカルボニル基、またはヘテロアリールオキシカルボニル基）で示される化合物（VI）の製造方法。
（１１）上記１に記載の化合物（I）またはそのアミン塩のカルボキシ部分を、縮合剤存在下、チオールエステル化することにより、ＣＯＺがＣＯＳＰｈ（Ｐｈはフェニル）である化合物（VI）を製造する、上記１０記載の製造方法。
（１２）縮合剤が、Ｐｈ₂Ｐ(Ｏ)Ｃｌ、（ＰｈＯ）₂Ｐ(Ｏ)Ｃｌ（Ｐｈはフェニル）または2-クロロ-4,6-ジメトキシトリアジンである、上記１１記載の製造方法。
（１３）上記１０記載の方法により化合物（VI）を製造した後、これをヒドロキシの保護反応に付すことにより、式：

（式中、ＣＯＺは、カルボキシル基の活性エステルもしくは活性酸無水物、チオールカルボキシル基の保護基で保護されたチオールカルボキシル基、置換アリールオキシカルボニル基、またはヘテロアリールオキシカルボニル基；Ｒ³はヒドロキシ保護基）で示される化合物（VII）を製造した後、これを塩基で処理し、さらに水酸基の活性エステル化剤で処理する工程を包含する、式：

（式中、Ｒ³はヒドロキシ保護基；Ｌはエステル化されたヒドロキシ基）で示される化合物（VIII）の製造方法。
（１４）Ｒ³はアルキルシリル、Ｚは−ＳＰｈ、および／またはＬは−ＯＰ(Ｏ)(ＯＰｈ)₂（Ｐｈはフェニル）である、上記１３記載の製造方法。
（１５）上記１４記載の方法により化合物（VIII）を製造した後、式：Ｒ⁴−ＳＨ（Ｒ⁴はカルバペネム誘導体の２位に結合し得るチオエーテル型側鎖の残基）で示される化合物（IX）またはその塩と反応させ、得られた化合物を脱保護する工程を包含する、式

（式中、Ｒ⁴は前記と同意義）で示される化合物（Ｘ）、その製薬上許容される塩またはそれらの溶媒和物の製造方法。 As a result of intensive studies, the present inventors have found that the compound of interest can be produced industrially efficiently through the compound (I) or its amine salt, which is a novel intermediate, as a method for producing Compound 5 and its derivatives. . In addition, the reaction conditions (for example, the type of condensing agent) for efficiently producing compound 5 were also examined, and the present invention shown below was completed.
(1) Formula:

Or an amine salt thereof.
(2) The amine salt as described in 1 above, wherein the amine is a primary amine or a secondary amine.
(3) The amine salt according to 1 above, wherein the amine is methylamine, ethylamine, isopropylamine, t-butylamine, (−)-α-methylbenzylamine, diisopropylamine, or dicyclohexylamine.
(4) The amine salt as described in 1 above, which is a diisopropylamine salt.
(5) The amine salt according to any one of the above 1 to 4, which is a crystal.
(6) The diisopropylamine salt according to 4 above, which is a crystal having a main peak at 2θ = 8.7, 9.7, 15.7, 22.4 degrees in a powder X-ray diffraction pattern.
(7) The following reaction scheme:

Wherein R ¹ is a hydroxy protecting group; R ² is a carboxy protecting group; X is a halogen, and the following steps:
(Step 1) Step of producing Compound (III) by protecting carboxy of Compound (II),
(Step 2) A step of producing compound (V) by reacting compound (III) with compound (IV), and (Step 3) After subjecting compound (V) to a deprotection reaction, if desired, an amine and Reacting,
A process for producing the compound (I) or the amine salt thereof according to the above 1, characterized by comprising:
(8) The production method according to 7 above, wherein R ¹ is alkylsilyl and / or R ² is alkoxyalkyl.
(9) The production method according to 7 above, wherein R ¹ is t-butyldimethylsilyl and / or R ² is 1-isobutoxyethyl.
(10) A step comprising active esterification, active acid anhydride formation, thiol esterification, aryl esterification or heteroaryl esterification of the carboxy moiety of the compound (I) or the amine salt thereof according to 1 above:

(Wherein COZ is an active ester or active acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group) Method.
(11) Compound (VI) in which COZ is COSph (Ph is phenyl) is produced by thiol esterifying the carboxy moiety of compound (I) or amine salt thereof according to 1 above in the presence of a condensing agent. The method according to 10 above.
(12) The process according to the above item 11, wherein the condensing agent is Ph ₂ P (O) Cl, (PhO) ₂ P (O) Cl (Ph is phenyl) or 2-chloro-4,6-dimethoxytriazine.
(13) After the compound (VI) is produced by the method described in the above 10, it is subjected to a hydroxy protection reaction to obtain a compound represented by the formula:

(Wherein COZ is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group for a thiol carboxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group; R ³ is a hydroxy protected group A compound (VII) represented by the following formula), which is treated with a base and further treated with an active esterifying agent for a hydroxyl group:

(Wherein R ³ is a hydroxy protecting group; L is an esterified hydroxy group).
(14) The production method according to the above 13, wherein R ³ is alkylsilyl, Z is —SPh, and / or L is —OP (O) (OPh) ₂ (Ph is phenyl).
(15) Compound (VIII) produced by the method described in 14 above, and then represented by the formula: R ⁴ -SH (R ⁴ is a residue of a thioether-type side chain capable of binding to the 2-position of the carbapenem derivative) IX) or a salt thereof, comprising the step of deprotecting the resulting compound

(Wherein R ⁴ is as defined above), a method for producing a compound (X), a pharmaceutically acceptable salt thereof, or a solvate thereof.

  The present invention provides a novel synthetic intermediate of a carbapenem derivative, a method for producing the same, and a method for producing a carbapenem derivative using the same. The target carbapenem derivative can be efficiently synthesized in a high yield by the production method of the present invention.

In the present invention, each term has the following meanings singly or in combination unless otherwise specified.
Examples of hydroxy protecting groups include trialkylsilyl (eg, trimethylsilyl, t-butyldimethylsilyl), acyl (eg, acetyl, pivaloyl), lower alkyl (eg, methyl, ethyl), lower alkoxy lower alkyl (eg, methoxymethyl). , Methoxyethyl), lower alkylsulfonyl (eg methanesulfonyl), lower alkoxycarbonyl (eg methoxycarbonyl, t-butyloxycarbonyl), aralkyloxycarbonyl (eg benzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p- Examples thereof include nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl), substituted methyl (eg methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl), tetrahydropyranyl and the like.
Carboxy protecting groups include lower alkyl (eg, methyl, ethyl, n-propoxy, isopropyl, t-butyl), substituted lower alkyl (substituent examples: lower alkoxy (eg, methoxy, ethoxy, n-propoxy). , Isopropoxy, n-butoxy, isobutoxy, t-butoxy)), substituted or unsubstituted aralkyl (eg benzyl, phenethyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl) , P-chlorobenzyl), C3 to C8 cycloalkyl optionally substituted with heteroatoms (eg O, S, N), alkylsilyl (eg trimethylsilyl, t-butyldimethylsilyl), lower alkoxymethyl (eg : Methoxymethyl, ethoxymethyl, isobutoxymethyl), lower aliphatic acylo Cymethyl (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl), lower alkoxycarbonyloxyethyl (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl), substituted or unsubstituted 2-lower alkenyl group having 3 to 10 carbon atoms (eg: allyl, 2-methylallyl, 3-methylallyl, 3-phenylallyl), substituted or unsubstituted diarylalkyl group (eg: diphenylmethyl, di-p-anisylmethyl) ), Substituted or unsubstituted aryl groups (eg, phenyl, p-chlorophenyl, 2,4,5-trichlorophenyl, p-nitrophenyl, o-nitrophenyl, p-methoxyphenyl), heteroaryl (eg, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2 Pyrimidyl, 2- (4,6-dimethyl) pyrimidyl) are exemplified.
“Lower” preferably means C1 to C6, more preferably C1 to C4.
Halogen represents F, Cl, Br, or I.

Amines of the amine salts of compound (I) include primary amines, secondary amines, and tertiary amines.
Primary amines include methylamine, ethylamine, isopropylamine, sec-butylamine, tert-butylamine, isoamylamine, n-decylamine, 3-methoxypropylamine, benzylamine, phenethylamine, 4-methoxyphenethylamine, 2,2-dimethoxy Ethylamine, 3,3-dimethoxypropylamine, p-chloroaniline, 2- (p-chlorophenyl) ethylamine, (-)-α-methylbenzylamine, 3,4-dimethoxyphenethylamine, benzhydrylamine, 2- (4- (Aminophenyl) ethylamine, 2-aminobenzylamine, (+)-dihydroabiethylamine, 4-methoxybenzylamine, 3-methoxyphenethylamine, 4-tert-butylbenzylamine, aniline, 4-bromo-2-fluoroaniline, 4 , 4'-dithioaniline, 2,2'-dithiodianiline , Methylamine, ethylamine, isopropylamine, tert- butylamine, (-) - a α- methylbenzylamine.
Examples of secondary amines include dimethylamine, diethylamine, diisopropylamine, dicyclohexylamine, 3,5-dichloro-4,4′-dihydroxydiphenylamine, and benzyl-N-methylethanolamine, preferably diisopropylamine, dicyclohexylamine. It is.
Examples of the tertiary amine include N-methylmorpholine, triethylamine, tributylamine, triallylamine, N-ethyldiisopropylamine, and N, N-dimethylbutylamine.
The amine salt of compound (I) is preferably a crystal. Of the above amines, those having good crystallinity with respect to compound (I) are primary or secondary amines, preferably methylamine, ethylamine, isopropylamine, tert-butylamine, (−)-α-methylbenzylamine, diisopropyl. Amine and dicyclohexylamine are preferred, and methylamine and diisopropylamine are more preferred. Of these, diisopropylamine is particularly preferred because it has advantages such as good crystallinity, non-toxicity, and low reactivity with the β-lactam ring. Moreover, it can utilize also as a base (acid trap agent) in the case of next process condensation.
The amine salt or the crystal thereof may be a solvate. Examples of the solvent include water and alcohol.
As a result of the study by the present inventors, the crystallinity was improved by converting the compound (I) into an amine salt, and the compound was successfully isolated as a high-purity crystal. As a result, various by-products (eg, TBS-OH, TBS-Cl, (TBS) ₂ O) mixed during the synthesis of compound (I) can be easily removed (TBS = t-butyldimethylsilyl). ). As a result, there are advantages such as no column treatment and increased reaction efficiency in the subsequent steps. Therefore, in the production method of the present invention, various carbapenem derivatives can be synthesized industrially efficiently, particularly via an amine salt of compound (I), preferably a crystal thereof.
The above-mentioned amine salt crystal shows the X-ray diffraction pattern shown in the examples described later by powder X-ray analysis (X-ray diffraction measurement conditions: tube CuKα ray, tube voltage 40 Kv, tube current 15 mA, dsin θ = nλ (n is an integer) , D is a surface interval (unit: angstrom), θ is a diffraction angle (unit: degree))).
These crystals are characterized by a value of each diffraction angle or spacing.

（式中、Ｒ¹はヒドロキシ保護基；Ｒ²はカルボキシ保護基；Ｘはハロゲン）

（第１工程）
化合物（II）のカルボキシを保護することにより化合物（III）を得る。当該反応は、通常のカルボキシの保護反応に準じて行えば良い。
Ｒ¹としては前記のヒドロキシ保護基が例示されるが、好ましくは、トリアルキルシリル、特にｔ−ブチルジメチルシリル（ＴＢＳ）である。
Ｒ²としては前記のカルボキシの保護基が例示されるが、好ましくは、低級アルコキシで置換された低級アルキルであり、例えば、１−メトキシエチル、１−エトキシエチル、１−イソプロポキシエチル、１−ｎ−プロポキシエチル、１−ｎ−ブトキシエチル、１−イソブトキシエチル、１−ｔ−ブトキシエチルであり、特に好ましくは、１−イソブトキシエチルである。これらの保護基は、反応中で１位Ｎ原子への転位等の副反応が起こりにくい。
所望により酸等の反応促進剤を使用してもよい。酸としては、メタンスルホン酸、ｐ−トルエンスルホン酸、塩酸、硫酸、リン酸などが例示される。
反応溶媒としては、炭化水素（例：ペンタン、ヘキサン、ヘプタン、シクロヘキサン、石油エーテル、トルエン、キシレン）、ハロゲン化炭化水素（例：ジクロロメタン、クロロホルム、四塩化炭素）、アルコール（例：メタノール、エタノール）、ギ酸、酢酸、プロピオン酸、酢酸エチル、アセトン、ホルムアミド、ニトロメタン、アセトニトリル、エーテル（例：テトラヒドロフラン、ジエチルエーテル）、水それらの混合溶媒等が例示されるが、好ましくは、トルエン、アセトニトリル、またはその混合溶媒である。
反応温度は、通常、０〜１００℃、好ましくは０〜５０℃、より好ましくは１０〜３０℃である。
反応時間は数時間から数十時間である。
得られる化合物（III）は、単離せずに次工程の反応に付してもよい。
（第２工程）
化合物（III）を化合物（IV）と反応させて化合物（V）を製造する。
Ｘで示されるハロゲンは好ましくは、ＣｌまたはＢｒである。
所望により塩基等の反応促進剤を使用してもよい。塩基としては、ＮａＨ、ソジウム tert-ブトキサイド、ポタシウム tert-ブトキサイド、ソジウム tert-ペントキサイド、n-ブチルリチウム、リチウムジイソプロピルアミド、リチウムビス（トリメチルシリル）アミド、ソジウムビス（トリメチルシリル）アミドが例示される。また所望により層間移動触媒を併用してもよい。層間移動触媒としては、4級アンモニウム塩（例：テトラn-ブチルアンモニウムクロライド、テトラn-ブチルアンモニウムブロマイド等が使用できる。
反応溶媒としては、炭化水素（例：ペンタン、ヘキサン、ヘプタン、シクロヘキサン、石油エーテル、トルエン、キシレン）、ハロゲン化炭化水素（例：ジクロロメタン、クロロホルム、四塩化炭素）、アルコール（例：メタノール、エタノール）、ギ酸、酢酸、プロピオン酸、酢酸エチル、アセトン、ホルムアミド、ニトロメタン、アセトニトリル、エーテル（例：テトラヒドロフラン、ジエチルエーテル）、水それらの混合溶媒等が例示されるが、好ましくは、トルエン、アセトニトリル、テトラヒドロフランまたはその混合溶媒である。
反応温度は、通常−７０〜０℃、好ましくは−５０〜−３０℃である。
反応時間は数時間から数十時間である。
得られる化合物（V）は、単離せずに次工程の反応に付してもよい。 The production method of compound (I) and its amine salt will be described.

(Wherein R ¹ is a hydroxy protecting group; R ² is a carboxy protecting group; X is a halogen)

(First step)
Compound (III) is obtained by protecting carboxy of compound (II). The reaction may be performed in accordance with a normal carboxy protection reaction.
Examples of R ¹ include the hydroxy protecting groups described above, and trialkylsilyl, particularly t-butyldimethylsilyl (TBS) is preferable.
R ² is exemplified by the above-mentioned carboxy protecting group, preferably lower alkyl substituted by lower alkoxy, such as 1-methoxyethyl, 1-ethoxyethyl, 1-isopropoxyethyl, 1- n-propoxyethyl, 1-n-butoxyethyl, 1-isobutoxyethyl and 1-t-butoxyethyl are preferable, and 1-isobutoxyethyl is particularly preferable. These protecting groups are unlikely to cause side reactions such as rearrangement to the 1-position N atom during the reaction.
If desired, a reaction accelerator such as an acid may be used. Examples of the acid include methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like.
Reaction solvents include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), alcohols (eg, methanol, ethanol) , Formic acid, acetic acid, propionic acid, ethyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg, tetrahydrofuran, diethyl ether), water or a mixed solvent thereof. It is a mixed solvent.
The reaction temperature is usually 0 to 100 ° C, preferably 0 to 50 ° C, more preferably 10 to 30 ° C.
The reaction time is several hours to several tens of hours.
The resulting compound (III) may be subjected to the next step without isolation.
(Second step)
Compound (V) is produced by reacting compound (III) with compound (IV).
The halogen represented by X is preferably Cl or Br.
If desired, a reaction accelerator such as a base may be used. Examples of the base include NaH, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and sodium bis (trimethylsilyl) amide. Further, an interlayer transfer catalyst may be used in combination as desired. As the interlayer transfer catalyst, a quaternary ammonium salt (eg, tetra n-butylammonium chloride, tetra n-butylammonium bromide, etc.) can be used.
Reaction solvents include hydrocarbons (eg, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), alcohols (eg, methanol, ethanol) , Formic acid, acetic acid, propionic acid, ethyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (e.g., tetrahydrofuran, diethyl ether), water, a mixed solvent thereof, and the like, preferably toluene, acetonitrile, tetrahydrofuran or The mixed solvent.
The reaction temperature is generally −70 to 0 ° C., preferably −50 to −30 ° C.
The reaction time is several hours to several tens of hours.
The resulting compound (V) may be subjected to the next step without isolation.

(Third step)
After subjecting compound (V) to a deprotection reaction, compound (I) or an amine salt thereof is obtained by optionally reacting with an amine.
The deprotection reaction may be carried out in accordance with the conditions for a normal carboxy deprotection reaction. Preferably, compound (V) may be treated with an acid. Examples of the acid include hydrochloric acid, sulfuric acid, potassium hydrogen sulfate, sodium hydrogen sulfate, nitric acid, phosphoric acid, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. The reaction time is usually several minutes to several tens of hours.
The reaction with the amine is usually performed under ice cooling to room temperature. When crystallizing as an amine salt, a seed crystal may be added if desired. Solvents used for crystallization include hydrocarbons (eg: pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, xylene), halogenated hydrocarbons (eg: dichloromethane, chloroform, carbon tetrachloride), alcohols (eg: Methanol, ethanol), formic acid, acetic acid, propionic acid, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, acetone, formamide, nitromethane, acetonitrile, ether (eg, tetrahydrofuran, diethyl ether), water and mixed solvents thereof Is done. In crystallization, heat treatment, ultrasonic treatment, stirring, or the like may be performed as desired.

（式中、ＣＯＺは、カルボキシル基の活性エステルもしくは活性酸無水物、保護基で保護されたチオールカルボキシル基、置換アリールオキシカルボニル基、またはヘテロアリールオキシカルボニル基）
ＣＯＺがカルボキシル基の活性エステルまたは活性酸無水物である場合には、Ｚ基としては例えば塩素、臭素、ヨウ素のようなハロゲン原子；例えばエトキシカルボニルオキシ、イソプロピルオキシカルボルオキシ、sec−ブチルオキシカルボニルオキシのような炭素数１〜５の低級アルキルオキシカルボニルオキシ基；例えばメタンスルホニルオキシのような炭素数１〜４の低級アルカンスルホニルオキシ基；例えばｐ−トルエンスルホニルオキシのようなアリールスルホニルオキシ基；例えばジメチルホスホリルオキシ、ジエチルホスホリルオキシのようなジ（炭素数１〜４の低級アルキル）ホスホリルオキシ基；例えばジ（フェニル）ホスホリルオキシのようなジアリールホスホリルオキシ基；例えばＮ−サクシイミドオキシ、Ｎ−フタルイミドオキシのような環状イミドオキシ基；イミダゾール、トリアゾールのようなヘテロアリール基；例えば３−（２−チオキソ）−チアゾリジニルのようなヘテロシクロアルキル基等を挙げることができる。
ＣＯＺが保護されたカルボキシル基またはチオールカルボキシル基である場合に用いられるカルボキシル基の保護基およびチオールカルボキシル基の保護基は前述と同様のものを好適なものとして挙げることができる。さらに置換アリールオキシ基としては好適なものとしてｐ−ニトロフェニルオキシ、ｏ−ニトロフェニルオキシ、２，４，５−トリクロロフェニルオキシ等を挙げることができ、ヘテロアリールオキシ基としてはｏ−ピリジルオキシ、ｐ−ピリジルオキシ等を挙げることができる。
上記の化合物（I）から（VI）への変換は、好ましくは縮合剤存在下で行われる。より好ましくは、化合物（I）またはそのアミン塩のカルボキシ部分を、縮合剤存在下、チオールエステル化することにより、ＣＯＺがＣＯＳＰｈ（Ｐｈはフェニル）である化合物（VI）を製造できる。
縮合剤としては、種々のものが使用可能であるが、好ましくは、ＣｌＣＯＯｉＢｕ、ｔＢｕＣＯＣｌ、ＣＤＩ（カルボキシジイミダゾール）、Ｐｈ₂Ｐ（Ｏ）Ｃｌ、（ＰｈＯ）₂Ｐ（Ｏ）Ｃｌ，（ＰｈＯ）Ｐ（Ｏ）Ｃｌ₂、２−クロロ−４，６−ジメトキシトリアジンが例示され、より好ましくはＰｈ₂Ｐ(Ｏ)Ｃｌ、（ＰｈＯ）₂Ｐ（Ｏ）Ｃｌまたは２−クロロ−４，６−ジメトキシトリアジンである。縮合剤の選択に応じて、上記反応は、好ましくは７０％以上、より好ましくは８０％以上、さらに好ましくは９０％以上の高収率で反応する。
また上記反応は所望により酸捕捉剤を併用してもよい。酸捕捉剤としては前記アミンが使用可能である。 Further, compound (I) or its amine salt is obtained by subjecting the carboxy moiety at the 4-position to active esterification, active acid anhydride formation, thiol esterification, aryl esterification or heteroaryl esterification according to the method described in JP-A-6-316559. By doing so, it can be converted to the known compound (VI) shown below.

(Wherein COZ is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group)
When COZ is an active ester of a carboxyl group or an active acid anhydride, examples of the Z group include halogen atoms such as chlorine, bromine and iodine; for example, ethoxycarbonyloxy, isopropyloxycarboxy, sec-butyloxycarbonyl A lower alkyloxycarbonyloxy group having 1 to 5 carbon atoms such as oxy; a lower alkanesulfonyloxy group having 1 to 4 carbon atoms such as methanesulfonyloxy; an arylsulfonyloxy group such as p-toluenesulfonyloxy; For example, di (lower alkyl having 1 to 4 carbons) phosphoryloxy groups such as dimethylphosphoryloxy and diethylphosphoryloxy; diarylphosphoryloxy groups such as di (phenyl) phosphoryloxy; for example N-succinimideoxy, N- lid Cyclic Imidookishi group such as Imidookishi; imidazole, heteroaryl groups such as triazole; such as 3- (2-thioxo) - can be exemplified a heterocycloalkyl group such as thiazolidinyl and the like.
Suitable examples of the protective group for the carboxyl group and the protective group for the thiol carboxyl group used when COZ is a protected carboxyl group or thiol carboxyl group are the same as those described above. Furthermore, preferred examples of the substituted aryloxy group include p-nitrophenyloxy, o-nitrophenyloxy, 2,4,5-trichlorophenyloxy and the like, and examples of the heteroaryloxy group include o-pyridyloxy, p-pyridyloxy and the like can be mentioned.
The conversion from compound (I) to (VI) is preferably carried out in the presence of a condensing agent. More preferably, compound (VI) in which COZ is COSph (Ph is phenyl) can be produced by thiol esterifying the carboxy moiety of compound (I) or its amine salt in the presence of a condensing agent.
Various condensing agents can be used, but preferably ClCOOiBu, tBuCOCl, CDI (carboxydiimidazole), Ph ₂ P (O) Cl, (PhO) ₂ P (O) Cl, (PhO) P (O) Cl ₂ , 2-chloro-4,6-dimethoxytriazine is exemplified, and more preferably Ph ₂ P (O) Cl, (PhO) ₂ P (O) Cl or 2-chloro-4,6- Dimethoxytriazine. Depending on the selection of the condensing agent, the above reaction is preferably performed in a high yield of 70% or more, more preferably 80% or more, and even more preferably 90% or more.
Further, the above reaction may be used in combination with an acid scavenger if desired. The amine can be used as the acid scavenger.

（式中、ＣＯＺは、カルボキシル基の活性エステルもしくは活性酸無水物、チオールカルボキシル基の保護基で保護されたチオールカルボキシル基、置換アリールオキシカルボニル基、またはヘテロアリールオキシカルボニル基；Ｒ³はヒドロキシ保護基）で示される化合物（VII）を製造した後、特開平６−３１６５５９号に記載の方法に従い、これを塩基で処理し、さらに水酸基の活性エステル化剤で処理することにより、式：

（式中、Ｒ³はヒドロキシ保護基；Ｌはエステル化されたヒドロキシ基）で示される化合物（VIII）を製造できる。
Ｒ³としては前記のヒドロキシ保護基が例示されるが、好ましくは、トリアルキルシリル、特にトリメチルシリル（ＴＭＳ）である。特に化合物（VIII）を使用してドリペネムを製造する場合には、脱保護のしやすさの点でＴＭＳが好ましく使用される。
詳しくは、化合物（VII）を不活性溶媒中、塩基で処理後、中間体を単離せず反応液中の活性エステルもしくは活性酸無水物の残基または保護されたチオールカルボキシル基のチオール残基（Ｚ-）をヨードメタン、ヨードプロパン、臭化アリル、臭化ベンジル、ｐ−トルエンスルホン酸メチルエステル等のアルキル化剤、ｐ−トルエンスルホニルクロリド、メタンスルホニルクロリド等のアシル化剤によって捕捉した後、水酸基の活性エステル化剤と処理すればよい。
Ｌで示される水酸基の活性エステルとは、例えば置換もしくは無置換アリールスルホン酸エステル基（置換もしくは無置換アリールスルホニルオキシ基）、低級アルカンスルホン酸エステル基（低級アルカンスルホニルオキシ基）、ハロゲノ低級アルカンスルホン酸エステル基（ハロゲノ低級アルカンスルホニルオキシ基）またはジアリールホスホリックアシッドエステル基（ジアリールホスホリルオキシ基）を示すか、またはハロゲン化水素とのエステルであるハロゲン化物原子を示す。したがって、水酸基の活性エステル化剤とは、上述のような活性エステルを生成する試剤である。さらに、置換もしくは無置換アリールスルホン酸エステルとしては、例えばベンゼンスルホン酸エステル、ｐ−トルエンスルホン酸エステル、ｐ−ニトロベンゼンスルホン酸エステル、ｐ−ブロモベンゼンスルホン酸エステルなどを、低級アルカンスルホン酸エステルとしては、例えばメタンスルホン酸エステル、エタンスルホン酸エステルなどを、ハロゲノ低級アルカンスルホン酸エステルとしては、例えばトリフルオロメタンスルホン酸エステルなどを、ジアリールホスホリックアシッドエステルとしては、例えばジフェニルホスホリックアシッドエステルなどを、またハロゲン化物としては、例えば塩素、臭素、ヨウ素化物などを挙げることができる。このようなアルコールの活性エステルの中で好適なものとしては、ｐ−トルエンスルホン酸エステル、メタンスルホン酸エステル、ジフェニルホスホリック酸エステルを挙げることができ、好ましくは、ジフェニルホスホリック酸エステルである。よって活性エステル化剤として好ましくは、ジフェニルホスホリック酸クロライド（例：ジフェニルホスホリック酸クロライド）である。
化合物（VII）を不活性溶媒中で処理する際の塩基としては、リチウムジイソプロピルアミド、リチウムビス（トリメチルシリル）アミド、ソジウムアミド等のアミン類の金属塩、ポタシウムｔ−ブトキサイド等のアルコール類の金属塩、水素化ナトリウム、水素化カリウム等の水素化アルカリ金属類およびソジウムメチルスルフィニルメチド等を挙げることができる。塩基の使用量は、通常、1.5〜３当量である。好適な反応温度は−７５℃〜５０℃である。
上記反応において好ましくは、Ｒ³はアルキルシリル、Ｚは−ＳＰｈ、および／またはＬは−ＯＰ(Ｏ)(ＯＰｈ)₂（Ｐｈはフェニル）である。 Further, by subjecting compound (VI) to a hydroxy protection reaction, the formula:

(Wherein COZ is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group for a thiol carboxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group; R ³ is a hydroxy protected group After the compound (VII) represented by the formula (III) is produced, it is treated with a base according to the method described in JP-A-6-316559, and further treated with an active esterifying agent for a hydroxyl group to obtain a compound represented by the formula:

(Wherein R ³ is a hydroxy protecting group; L is an esterified hydroxy group).
Examples of R ³ include the hydroxy protecting groups described above, and trialkylsilyl, particularly trimethylsilyl (TMS) is preferable. In particular, when producing doripenem using compound (VIII), TMS is preferably used from the viewpoint of easy deprotection.
Specifically, after treating compound (VII) with an inert solvent with a base, the intermediate is not isolated and the residue of the active ester or active acid anhydride or the thiol residue of the protected thiol carboxyl group in the reaction solution ( Z-) is captured by an alkylating agent such as iodomethane, iodopropane, allyl bromide, benzyl bromide, p-toluenesulfonic acid methyl ester, an acylating agent such as p-toluenesulfonyl chloride, methanesulfonyl chloride, and then a hydroxyl group. What is necessary is just to process with the active esterifying agent.
The active ester of a hydroxyl group represented by L is, for example, a substituted or unsubstituted arylsulfonic acid ester group (substituted or unsubstituted arylsulfonyloxy group), a lower alkanesulfonic acid ester group (lower alkanesulfonyloxy group), a halogeno lower alkanesulfone. It represents an acid ester group (halogeno lower alkanesulfonyloxy group) or a diarylphosphoric acid ester group (diarylphosphoryloxy group) or a halide atom that is an ester with a hydrogen halide. Therefore, the active esterifying agent of a hydroxyl group is a reagent that generates the active ester as described above. Furthermore, examples of the substituted or unsubstituted aryl sulfonic acid ester include benzene sulfonic acid ester, p-toluene sulfonic acid ester, p-nitrobenzene sulfonic acid ester, p-bromobenzene sulfonic acid ester, and the like. For example, methanesulfonic acid ester, ethanesulfonic acid ester, etc., halogeno lower alkanesulfonic acid ester, for example, trifluoromethanesulfonic acid ester, etc., diaryl phosphoric acid ester, for example, diphenylphosphoric acid ester, etc. Examples of the halide include chlorine, bromine, and iodide. Preferable examples of the active ester of alcohol include p-toluenesulfonic acid ester, methanesulfonic acid ester, and diphenylphosphoric acid ester, and diphenylphosphoric acid ester is preferable. Accordingly, diphenylphosphoric acid chloride (eg, diphenylphosphoric acid chloride) is preferable as the active esterifying agent.
Examples of the base for treating compound (VII) in an inert solvent include metal salts of amines such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide, metal salts of alcohols such as potassium t-butoxide, Examples thereof include alkali metal hydrides such as sodium hydride and potassium hydride, and sodium methylsulfinylmethide. The amount of base used is usually 1.5 to 3 equivalents. The preferred reaction temperature is -75 ° C to 50 ° C.
In the above reaction, preferably R ³ is alkylsilyl, Z is —SPh, and / or L is —OP (O) (OPh) ₂ (Ph is phenyl).

（式中、Ｒ⁴は前記と同意義）で示される化合物（Ｘ）、その製薬上許容される塩またはそれらの溶媒和物が製造できる。
製薬上許容される塩としては、塩基性塩として、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；アンモニウム塩；トリメチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、エタノールアミン塩、ジエタノールアミン塩、トリエタノールアミン塩、ブロカイン塩、メグルミン塩、ジエタノールアミン塩またはエチレンジアミン塩等の脂肪族アミン塩；N,N-ジベンジルエチレンジアミン、ベネタミン塩等のアラルキルアミン塩；ピリジン塩、ピコリン塩、キノリン塩、イソキノリン塩等のヘテロ環芳香族アミン塩；テトラメチルアンモニウム塩、テトラエチルアモニウム塩、ベンジルトリメチルアンモニウム塩、ベンジルトリエチルアンモニウム塩、ベンジルトリブチルアンモニウム塩、メチルトリオクチルアンモニウム塩、テトラブチルアンモニウム塩等の第４級アンモニウム塩；アルギニン塩、リジン塩等の塩基性アミノ酸塩等が挙げられる。酸性塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩、炭酸塩、炭酸水素塩、過塩素酸塩等の無機酸塩；酢酸塩、プロピオン酸塩、乳酸塩、マレイン酸塩、フマール酸塩、酒石酸塩、リンゴ酸塩、クエン酸塩、アスコルビン酸塩等の有機酸塩；メタンスルホン酸塩、イセチオン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のスルホン酸塩；アスパラギン酸塩、グルタミン酸塩等の酸性アミノ酸等が挙げられる。溶媒和物としては、水和物やアルコール和物が例示される。
化合物（Ｘ）としては、（１）チエナマイシン、（２）イミペネム、（３）メロペネム、（４）ビアペネム、（５）パニペネム、（６）ＢＱ−２７２７、（７）Ｓ−４６６１（ドリペネム）などが例示される（各“−ＳＲ⁴”を以下に示す）。

Compound (VIII) is prepared according to the method described in JP-A-1-79180, JP-A-6-316559, JP-A-5-294970, USP 5,317,016 and the like: R ⁴ —SH (R ⁴ is By reacting with the compound (IX) or a salt thereof represented by (thioether-type side chain residue which can be bonded to the 2-position of the carbapenem derivative) and optionally deprotecting the resulting compound,

(Wherein, R ⁴ is as defined above), a pharmaceutically acceptable salt thereof, or a solvate thereof can be produced.
Examples of the pharmaceutically acceptable salt include basic salts such as alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt and dicyclohexyl. Aliphatic amine salts such as amine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, brocaine salts, meglumine salts, diethanolamine salts or ethylenediamine salts; aralkylamine salts such as N, N-dibenzylethylenediamine and venetamine salts; pyridine Heterocyclic aromatic amine salts such as salt, picoline salt, quinoline salt, isoquinoline salt; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltri Examples include quaternary ammonium salts such as butylammonium salt, methyltrioctylammonium salt, and tetrabutylammonium salt; basic amino acid salts such as arginine salt and lysine salt. Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate. Examples of solvates include hydrates and alcohol solvates.
Examples of the compound (X) include (1) thienamycin, (2) imipenem, (3) meropenem, (4) biapenem, (5) panipenem, (6) BQ-2727, (7) S-4661 (dripenem), and the like. Exemplified (each “-SR ⁴ ” is shown below).

Examples are shown below.
(Abbreviation)
TBS: t-butyldimethylsilyl TMS: trimethylsilyl tBu: t-butyl iPr: isopropyl Ph: phenyl _{Allyl: CH 2 CH = CH 2} Alloc: CO 2 CH 2 CH = CH 2
DMF: Dimethylformamide THF: Tetrahydrofuran

Example 1 (1 → 4)
(1) Sodium hydride (purity: 60%) A suspension of 12.21 g (1.15 eq), toluene 120 ml, acetonitrile 40 ml, heated at 40 ° C, 40 ml of tert-amyl alcohol 34.9 ml (1.2 eq) in toluene The solution was added dropwise and stirred as it was for 20 minutes, and then cooled to room temperature (hereinafter referred to as a toluene-acetonitrile solution of sodium tert-pentoxide).
To compound 1 (80.00 g, 0.2654 mol), 91 mg (0.002 eq) of paratoluenesulfonic acid and 400 ml of anhydrous toluene were added, and 44.99 g (1.3 eq) of isobutyl vinyl ether was added while stirring at room temperature, followed by stirring for 2.5 hours.
(2) The reaction solvent was changed from toluene to d ₈ -THF, and the same reaction as in the above (1) was performed. A part of the reaction solution was taken out over time and subjected to NMR measurement to confirm the disappearance of the peak of the raw material compound 1. The NMR value in that case is shown below. From the NMR value, it can be confirmed that the compound 2 is produced, and it can be seen from this that the compound 2 is also produced in the case of the above (1).
¹ H-NMR (d ₈ -THF): 0.08 (6H, s), 0.89 (9H, s), 0.90 (6H, m), 1.18 (3H, d, J = 7.2 Hz), 1.19 (3H, d, J = 7.2 Hz), 1.34 (3H, m), 1.78 (1H, m), 2.64 (1H, m), 2.91 (1H, m), 3.22 (1H, m), 3.42 (1H, m), 3.76 ( 1H, m), 4.15 (1H, m), 5.87 (1H, q, J = 5.4 Hz) ppm

(3) The reaction solution obtained in the above (1) was cooled to −45 ° C., 61.76 g (1.3 eq) of allyl bromoacetate was added, and the sodium tert-pentoxy prepared previously at −40 to −45 ° C. Side toluene-acetonitrile solution was added dropwise. After stirring at the same temperature for 1.5 hours, the solution was poured into 200 ml of water in which 4.26 g (0.3 eq) of ammonium chloride was dissolved, followed by liquid separation. The toluene layer was washed twice with 200 ml of water, and the aqueous layer was extracted with 200 ml of toluene. The toluene layers were combined and concentrated under reduced pressure to obtain 170.97 g of 3 candy-like residue.
Compound 3
¹ H-NMR (CDCl ₃ ): 0.07 (6H, s), 0.89 (9H, s), 0.90 (6H, m), 1.25 (6H, m), 1.38 (3H, m), 1.83 (3H, m) , 2.87 (1H, m), 2.99 (1H, m), 3.21 (1H, m), 3.40 (1H, m), 3.83 (1H, d, J = 18.0 Hz), 4.15 (1H, m), 4.16 ( 1H, m), 4.29 (1H, dd, J = 1.5, 18.0 Hz), 4.62 (2H, m), 5.30 (2H, m), 5.89 (1H, q, J = 5.1 Hz), 5.90 (1H, m ) ppm
(4) 170.97 g of the extraction residue of (3) above was dissolved in 400 ml of acetonitrile, and 44.2 ml (0.5 eq) of 3N-hydrochloric acid was added with stirring under ice cooling, followed by stirring for 16 hours. After adding sodium bicarbonate 35.67 g (1.6 eq) and water 160 ml, acetonitrile was distilled off by concentration under reduced pressure, and toluene 200 ml was added for liquid separation. The toluene layer was washed with 100 ml of water, the aqueous layer was extracted with 100 ml of toluene, the aqueous layers were combined, and with ice-cooling, the pH was adjusted to 3.0 with concentrated hydrochloric acid. did. The ethyl acetate layer was washed with 50 ml of saturated brine, and the aqueous layer was extracted with 100 ml of ethyl acetate. The ethyl acetate layers were combined and concentrated under reduced pressure to obtain 74.84 g of 4 free-form candy-like residue.
1.38 g of a free residue of 4 was dissolved in 5 ml of butyl acetate, and 0.75 ml (1.5 eq) of diisopropylamine was added dropwise over 1.5 hours with stirring under ice cooling. The mixture was stirred for 2 hours as it was, and the precipitated crystals were filtered and washed with 3 ml of ice-cooled butyl acetate to obtain 1.23 g (yield: 65%) of diisopropylamine salt 4.
Anal.Calcd for C ₁₉ H ₃₄ N ₂ O ₆・ 0.2H ₂ O: C, 58.50; H, 8.89; N, 7.18; H ₂ O, 0.92. Found: C, 58.74; H, 8.72; N, 7.25, H ₂ O, 0.97. ¹ H-NMR (CDCl ₃ ): 1.23 (3H, d, J = 7.2 Hz), 1.29 (6H, d, J = 6.3 Hz), 1.32 (3H, d, J = 6.3 Hz) , 2.51 (1H, m), 2.89 (1H, dd, J = 2.1, 9.3 Hz), 3.34 (1H, m), 3.82 (1H, dd, J = 1.8, 8.7 Hz), 3.87 (1H, d, 18.6 Hz), 4.11 (1H, m), 4.31 (1H, d, 18 Hz), 4.63 (2H, d, J = 5.7 Hz), 5.31 (2H, m), 5.90 (1H, m), 7.0 (4H, br) ppm
The powder X-ray diffraction pattern of diisopropylamine salt 4 is shown in FIG. In particular, main peaks were shown at 2θ = 8.7, 9.7, 15.7, 22.4 degrees.

Example 2 (4 → 6)
311 ml of ethyl acetate was added to 80.00 g (purity: 97.2%, 0.201 mol) of Compound 4, and 64.80 g (1.2 eq) of diphenyl phosphate chloride was added dropwise with stirring under ice cooling, followed by stirring at room temperature for 1 hour. The mixture was ice-cooled again, 78 ml of DMF and 22.7 ml (1.1 eq) of thiophenol were added, and 37.1 ml (1.3 eq) of diisopropylamine was added dropwise, followed by stirring for 1.5 hours. At this point, it was confirmed by HPLC (high performance liquid chromatography) that Compound 5 was produced. Further, at the same temperature, 33.2 ml (1.3 eq) of trimethylsilyl chloride and 42.8 ml (1.5 eq) of diisopropylamine were successively added dropwise and stirred for 1.5 hours. After adding 367 ml (1.3 eq) of 6% sodium bicarbonate water and stirring at room temperature for 10 minutes, 1.2 L of water was added to separate the layers. The ethyl acetate layer was washed twice with 389 ml of water, the aqueous layer was extracted with 311 ml of ethyl acetate, the ethyl acetate layers were combined, concentrated under reduced pressure, 200 ml of toluene was added, and the mixture was concentrated under reduced pressure to give 108.16 g (Quantitative value: 85.0 g, yield: 94%) was obtained.
¹ H-NMR (CDCl ₃ ): 0.15 (9H, s), 1.29 (6H, d, J = 6.9 Hz), 3.08 (1H, dd, J = 2.7, 8.1 Hz), 3.15 (1H, qd, J = 6.9, 3.0 Hz), 2.85 (1H, dd, J = 0.6, 18.0 Hz), 4.12 (1H, dd, J = 2.4, 3.0 Hz), 4.32 (1H, d, 18.0 Hz), 4.60 (2H, m) , 5.27 (2H, m), 6.87 (1H, m), 7.40 (5H, m) ppm

Example 3 (6 → 7)
Sodium hydride (purity: 60%) 9.86 g (2.3 eq), toluene-acetonitrile (85-15) To a suspension of 160 ml heated at 35 ° C, 28.2 ml (1.2 eq) toluene-acetonitrile in tert-amyl alcohol (85-15) 37 ml solution was added dropwise and stirred for 15 minutes. Under cooling at −45 ° C., a 95 ml toluene-acetonitrile (85-15) solution of 6 (purity: 78.6%, 0.107 mol) obtained in Example 2 was added dropwise at −40 ° C. or lower, and the mixture was stirred as it was for 1.5 hours. Then, 8.67 ml (1.2 eq) of methyl iodide was added dropwise at the same temperature, and the mixture was stirred for 1.5 hours, and then a solution of 30.22 g (1.05 eq) of diphenyl phosphate in 27 ml of toluene-acetonitrile (85-15) was added dropwise and cooled on ice And stirred for 2 hours and 40 minutes. To this was added a solution of 13.5 g (1.5 eq) of sodium bicarbonate in 270 ml of water, followed by liquid separation. The toluene layer was washed sequentially with 270 ml of water and 270 ml of saturated saline. The aqueous layer was extracted with 160 ml of toluene, and the toluene layers were combined and concentrated under reduced pressure to give 92.70 g of candy-like residue (quantitative value: 53.36 g, yield) : 87%).
¹ H-NMR (CDCl ₃ ): 0.12 (9H, s), 1.19 (3H, d, J = 7.2 Hz), 1.25 (3H, d, J = 6.0 Hz), 3.25 (1H, dd, J = 3.0, 6.9 Hz), 3.46 (1H, m), 4.11 (1H, dd, J = 3.0, 9.9 Hz), 4.19 (1H, qu, J = 6.6 Hz), 4.66 (1H, m), 5.29 (2H, m) , 5.87 (1H, m), 7.31 (15H, m) ppm

Example 4 (7 → 9)
The compound 7 obtained in Example 3 is subjected to a condensation reaction for forming a 2-position side chain according to the method described in Example 13 of JP-A-5-294970 to synthesize Compound 8, and further deprotection By subjecting to reaction, compound 9 (dripenem) is obtained.

Example 5
According to the method of Example 1, the corresponding amine salt was obtained by reacting the above-mentioned various amines other than diisopropylamine with the free form of Compound 4. Dicyclohexylamine salt, methylamine salt, ethylamine salt, isopropylamine salt, t-butylamine salt, and (−)-α-methylbenzylamine salt were obtained as crystals. In particular, dicyclohexylamine salt, methylamine salt, t-butylamine salt, and (−)-α-methylbenzylamine salt showed good crystallinity. The powder X-ray diffraction patterns are shown in FIGS. 2 to 5, and the diffraction angles of main peaks are shown below.
Dicyclohexylamine salt 2θ = 8.5, 15.0, 18.1, 19.3, 21.7, 22.6, 24.5 degrees methylamine salt 2θ = 9.5, 11.3, 17.6, 18.0, 21.6, 22.3, 23.8, 26.0, 30.5, 33.6 degrees t-butylamine salt 2θ = 6.7, 8.1, 9.7, 13.3, 16.2, 17.7, 19.3, 20.0, 22.7 degrees (−)-α-methylbenzylamine salt 2θ = 7.2, 17.1, 17.4, 18.0, 18.3, 20.6, 22.5, 25.1, 26.6, 27.3 degrees

Example 6
The compound 9 is obtained according to the methods of Examples 2 to 4 using the various amine salts obtained in Example 5 as raw materials.

2 is a powder X-ray diffraction pattern and peak value of the diisopropylamine salt crystal obtained in Example 1. FIG. The vertical axis represents intensity (unit: cps), and the horizontal axis represents diffraction angle (2θ, unit: degree). 3 is a powder X-ray diffraction pattern and peak value of the dicyclohexylamine salt crystal obtained in Example 5. FIG. FIG. 5 shows a powder X-ray diffraction pattern and peak value of methylamine salt crystals in Example 5. FIG. Fig. 5 shows a powder X-ray diffraction pattern and peak value of a t-butylamine salt crystal in Example 5. FIG. 5 shows a powder X-ray diffraction pattern and peak value of (−)-α-methylbenzylamine salt crystal in Example 5. FIG.

Claims (15)

formula:

Or an amine salt thereof. The amine salt according to claim 1, wherein the amine is a primary amine or a secondary amine. The amine salt according to claim 1, wherein the amine is methylamine, ethylamine, isopropylamine, t-butylamine, (-)-α-methylbenzylamine, diisopropylamine, or dicyclohexylamine. The amine salt according to claim 1, which is a diisopropylamine salt. The amine salt according to any one of claims 1 to 4, which is a crystal. The diisopropylamine salt according to claim 4, which is a crystal having a main peak at 2θ = 8.7, 9.7, 15.7, 22.4 degrees in a powder X-ray diffraction pattern. The following reaction scheme:

Wherein R ¹ is a hydroxy protecting group; R ² is a carboxy protecting group; X is a halogen, and the following steps:
(Step 1) Step of producing Compound (III) by protecting carboxy of Compound (II),
(Step 2) A step of producing compound (V) by reacting compound (III) with compound (IV), and (Step 3) After subjecting compound (V) to a deprotection reaction, if desired, an amine and Reacting,
A process for producing compound (I) or an amine salt thereof according to claim 1, characterized in that The production method according to claim 7, wherein R ¹ is alkylsilyl and / or R ² is alkoxyalkyl. The production method according to claim 7, wherein R ¹ is t-butyldimethylsilyl and / or R ² is 1-isobutoxyethyl. A compound comprising the step of active esterification, active acid anhydride formation, thiol esterification, aryl esterification or heteroaryl esterification of the carboxy moiety of compound (I) or an amine salt thereof according to claim 1:

(Wherein COZ is an active ester or active acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group) Method. The compound (VI) in which COZ is COSPh (Ph is phenyl) is produced by subjecting the carboxy moiety of the compound (I) or the amine salt thereof according to claim 1 to thiol esterification in the presence of a condensing agent. Item 11. The production method according to Item 10. The production method according to claim 11, wherein the condensing agent is Ph ₂ P (O) Cl, (PhO) ₂ P (O) Cl (Ph is phenyl) or 2-chloro-4,6-dimethoxytriazine.
After preparing compound (VI) by the method of claim 10, it is subjected to a hydroxy protection reaction to give the formula:

(Wherein COZ is an active ester or an acid anhydride of a carboxyl group, a thiol carboxyl group protected with a protecting group for a thiol carboxyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group; R ³ is a hydroxy protected group A compound (VII) represented by the following formula), which is treated with a base and further treated with an active esterifying agent for a hydroxyl group:

(Wherein R ³ is a hydroxy protecting group; L is an esterified hydroxy group). The production method according to claim 13, wherein R ³ is alkylsilyl, Z is -SPh, and / or L is -OP (O) (OPh) ₂ (Ph is phenyl). Compound (VIII) represented by the formula: R ⁴ -SH (R ⁴ is a residue of a thioether-type side chain that can be bonded to the 2-position of a carbapenem derivative) after producing compound (VIII) by the method according to claim 14 Or reacting with a salt thereof and deprotecting the resulting compound

(Wherein R ⁴ is as defined above), a method for producing a compound (X), a pharmaceutically acceptable salt thereof, or a solvate thereof.

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