FI111942B - New 4-benzo:heterocyclyl:carbonyl ethyl-azetidinone derivs. - Google Patents

Abstract

N-(2-(2-Oxo-azetidin-4-yl)-propionyl)-isoquinoline, benzoxazine or benzothiazine-(thi)one derivs. of formula (I) and their salts are new. Q = N-contg. benzo-heterocyclic gp. of formula (i): benzene ring B is opt., substd.; R1 = opt. protected lower hydroxyalkyl; X = O or S; Y = O, S, CH2 or opt. substd. imino; Z = opt. substd. methylene. Ring B is opt. substd. by 1-4 of halogen, lower alkyl, lower alkoxy and aryl; Y = O, S, CH2 or imino (opt. substd. by lower alkyl, acyl or aralkoxycarbonyl); Z = methylene (opt. substd. by 1 or 2 of opt. substd. 3-7C alkylene, opt. substd. 1-20C alkyl, opt. substd. 4-7C cycloalkyl, aryl, aralkyl and heterocyclyl); the 3-position of the azetidinone gp. has S-configuration; R1 = opt. protected 1-hydroxyethyl; R3 = 2-thioxopyrrolidin-4-yl. Esp. Z = pentamethylene-substd. methylene or dibutyl-substd. methylene.

Description

111942

A novel azetidinone compound, a process for its stereoselective preparation and its use as a synthetic intermediate for the preparation of a 1-beta-methylcarbapenem derivative. a compound useful as a synthetic intermediate for an Ιβ-methylcarbapenem derivative having antibacterial activity, and a process for its preparation and its use.

The Ιβ-methylcarbapenem derivatives have been of great interest due to its excellent antibacterial activities against a wide range of microorganisms, including gram-positive and gram-negative bacteria, in particular cephem-resistant bacteria, and their excellent stability in the human body. Said Ιβ-methylcarbapenem derivatives have so far been synthesized by various methods. In these processes, the following three types of compounds are known as important synthetic intermediates: a) an azetidinone compound having a 1'-β-methyl group at the 4-position of the azetidinone backbone, i.e. a compound of formula A: CH 3; R>) - j § 00011. 'f A]

J MH

O

Where R a is a hydroxy-substituted lower alkyl group which may be protected, * · »b) a 1 β-methyl-2-oxocarbapenem compound of formula B:: V ch 3

::: · 30 rv UK

KA / ° C COORb 2 111942 wherein R b is a hydrogen atom or an ester residue, and R a is as defined above; and c) a reactive derivative of a compound of formula B, i.e., a compound of formula C: of the formula: -OAa is an esterified hydroxy group and Ra and Rb are as defined above.

A process for the preparation of these synthetic intermediates is known which comprises the steps of: 1) removing the Γ-hydrogen atom from the acetic acid group located at the 4-position of the compound of the formula: OSi-j-2 ° -J / SSSCOOCH3

. . J-NH

:: using a strong base, 2) adding a methyl group to the product, 3) hydrolyzing the product to give a compound of formula A wherein Ra is 1- t- butyldimethylsilyloxyethyl group, • 30 * 4) subjecting product to carbon atom addition reaction, »1 1: [": 5) subjecting product to diazotization, ii) »ta1 · 3 111942 6) subjecting product to intramolecular cyclization, to give a compound of formula B wherein R a is a 1-hydroxyethyl group and R b is a p-nitrobenzyl group, and then the product is subjected to esterification to give the corresponding compound of formula C Heterocycles butter. 21, p. 29 (1984).

However, the above process is thus unsatisfactory that the yield of the compound having the Γ-methyl group in the β-configuration is low because the above process for the preparation of the compound of formula A is not a stereoselective synthetic process and a mixture of the compound of formula A is obtained. wherein the Γ-methyl group has the α-configuration and the β-configuration. Therefore, a variety of methods for the stereoselective preparation of compounds A, B, and C have been extensively studied in recent years, and the typical process involves the use of an aldol-type reaction or a Re-15 formatsky type reaction.

For example, methods employing an aldol-type reaction are described in JP-A (unexamined) 252786/1987, which describes a process for preparing a compound of formula A wherein Ra is a t-butyldimethylsilyloxyethyl group in which the compound of formula D20: ..., JTT sOCOCHi D ^

/ - NH

Is reacted with a propionamide compound of the formula: · · ·: V: CH 3 CH 2 O-n-ζ \ iv cXXs: ...: 30 ®: in the presence of dibutylboron triflate to give a compound of the formula: * «I CH, 4 111942

ΛΙΑ _W

J-nh 5 and then hydrolyze the product.

Further, JP (unexamined) 284176/1988 describes a process for the preparation of compounds of formulas B and C, which comprises reacting a compound of formula D with a compound of the formula: XH 2 CH 3 CH 3 CH 2 CO-N- (15 in the presence of stannous triflate) to give the compound. having the formula: I ch 3? f + 1 Λ /,, CH 2 H 3 7) -f XCO-N- (α 1 ~ 1h x 2 3): The product is reacted with a compound of the formula:

In the presence of Mg (O 2 CCH 2 CO 2 CH NO 2) 2 # · · imidazole, the product is subjected to diazotization and then converted to the compound of formula B or C.

In addition, JP patents (unexamined) 77384/1987, 169781/1987, 30 246550/1987 and 292269/1990 describe methods in which the above-described prop. . ·. the following compound is used in place of the pionamide compound.

• · · »» · * · I · I * · »· 5 111942 ch, cH3co. ^ CH (CH!) 2 A '· ™ 5 CH £ H £ Ojf- ^ iCH3h CHiCHzCmJ— ^

CH CHtCO n- / 3 **? 1 "CH 3 CH 2 CO-N- (CH 2 °" O)

xo CHiC X $ 1 Λ) s s

However, although such aldol-type reactions may be stereoselectively attached to the β-methyl group, the methods are still unsatisfactory for production on an industrial scale because the expensive reagent tin triflate or boron triflate has to be used as a reagent.

On the other hand, a process using the Reformatsky-type reaction, for example, in JP (unexamined) 178262/1990, describes a process for preparing a compound of formula B or C, which comprises reacting a compound of formula D with a α-bromopropionamide compound • · V! Br: · ·: CH 3 CHCO-N-f CH 2 ° Tr 3,

! wherein Tr is a triphenylmethyl group in the presence of zinc to give E

v: Compound: I CH3 Γ '!: f ··:'> 30 [E]

O

. 111942

O

wherein Tr is as defined above, hydrolyzing the product to give a compound of formula A, and then converting the product into a compound of formula B or C. In addition, JP (unexplored) publications 10765/1988 and 188662/1988 disclose processes employing the following 5 compounds in place of the above α-bromopropionamide compound.

Br Br CH3CHCO- N v

Yeah. ALREADY

10 Br Br (CHjbCHj I '\ ^ (CH2) 3CH3 ch3chco ^ Q or ch3chco ^ 4 ^

However, using the Reformatsky-type reaction, the process has some drawbacks such that the β-methyl group cannot be added stereoselectively or the preparation of the α-bromopropionic acid compound is difficult. In addition, in order for the product to which the β-methyl group is attached to be converted to the compound of formula B or B, it is first necessary to remove the group of formula: rfO, υ 0 (CH 2) 3 CH 3 -N-0 nV / (ch 2 ) jv. ΟΗ, ΟΤτ O1: Λ) from said product and then activate the resulting compound by chemical modi fi cation, for example by adding a moiety suitable for the intramolecular cyclization.

• # * 1 · t I I * ·

It is an object of the invention to provide a bone azetidinone compound useful as a synthetic intermediate for an ßβ-methylcarbapenem derivative having 1119427 antibacterial activity. Another object of the invention is. to provide a new synthetic intermediate that can be converted to the compound of formula A by hydrolysis, but also by the addition of a protected or unprotected carboxymethyl group at the N-position of the alβ-methylcarbapenem compound, and then allylated for intramolecular cyclization. It is another object of the invention to provide a novel process for the stereoselective preparation of the above synthetic intermediate using the Reformatsky reaction. It is a further object to provide a novel process for the preparation of Ιβ-methylcarbapenem derivatives or an intermediate thereof using the above synthetic intermediate. These and other objects and advantages of the invention will be apparent to those skilled in the art from the following description.

As a result of various studies, the present inventors have found that when an α-halopropionamide derivative of formula II:

t I

L 0 CO - J 4b wherein ring B is a benzene ring which may have a substituent (s), X is an oxygen atom or a sulfur atom, Y is an oxygen atom, a sulfur atom, a methylene group or an imino group; which may have a substituent (s), Z is a methylene group which may have a substituent (s) and L ° is a halogen atom used as one starting material for the Reformatsky-type reaction, the β-methyl group may be attached stereoselectively; j * 25, and the product thus obtained has excellent characteristics as a synthetic intermediate of Ιβ-methylcarbapen, • neem derivatives.

• »a II» •

Thus, the present invention relates to an azetidinone compound of formula I:

... · 30 f X

Wherein R 1 is a hydroxy-substituted lower alkyl group which may be protected, and other symbols are as defined above, or a salt thereof, and a process for its preparation and its use. The compound of formula I of the invention is structurally quite different from the compound mentioned above in that the amido group of the compound of formula I of the invention (hereinafter referred to as the "support group") is a benzene ring-fused 6 membered heterocyclic group member heterocyclic groups such as thiazolodone or oxazolidine. In accordance with the invention, any group having a partial structure of the formula: wherein the symbols are as defined above may be used as a support group according to the invention and therefore when ring B and / or Z has a substituent (s), said substituents may be any substituent which does not adversely affect the reaction.

Examples of ring B substituents include a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl group and the like, and the benzene ring may have from 1 to 4 substituents, which may be the same or different.

Examples of the group R1 include e.g. The 1-hydroxyethyl group which may be protected and the hydroxy group protecting group is e.g. any group conventionally used is protected as a hydroxy group. Specific examples of the protecting group - · · 25 of the hydroxy group include e.g. lower alkoxycarbonyl group, halogen lower alkoxycarbonyl; A 'lower group, a lower alkyl group substituted by a phenyl group which may have a substituent (s) (for example, a benzyl group which may be substituted by a nitro group or a lower alkoxy group), a trialempalkylsilyl group, a lower alkoxy group; a phenyl group substituted by a phenyl group which may have a substituent / subs- • *; Tituents (for example, a benzyloxycarbonyl group which may be substituted by a nitro group or a lower alkoxy group).

«· • ·

Examples of the substituent on the imino group (Y) are e.g. lower alkyl group, acyl *: **: group, aralkyloxycarbonyl group and the like.

9111942

Examples of the substituent on the methylene group (Z) are e.g. A C 3-7 alkylene group which may have a substituent (s), a C 1-6 alkyl group which may have a substituent (s), a C 1-7 cycloalkyl group which may have a substituent (s), an aryl group, an aralkyl group, a heterocyclic group and the like; the substituent may be substituted by 1 or 2 substituents which may be the same or different.

Specific examples of the above substituents on ring B, Y and / or Z include, but are not limited to, the acyl group. a lower alkanoyl group, a lower alkoxycarbonyl-10 group, a substituted or unsubstituted phenylcarbonyl group or a substituted or unsubstituted phenyl-lower alkoxycarbonyl group; examples of the aryl group include e.g. a substituted or unsubstituted phenyl group; examples of aralkyl groups include e.g. a lower alkyl group substituted with a substituted or unsubstituted phenyl group; and examples of a heterocyclic group include, for example, a 15-substituted or unsubstituted 4- to 7-membered heterocyclic group containing an oxygen atom, a nitrogen atom, or a sulfur atom as a heteroatom (e.g., furyl group, pyrrolyl group, thienyl group).

Further examples of the substituent on the aforementioned alkylene group, alkyl group, cycloalkyl group, phenyl group and heterocyclic group include e.g. a lower alkyl group, a lower alkoxy group, a halogen atom and an amino group which may be protected. Any protecting group conventionally used in the field of peptide chemistry as an amino protecting group can be used as an amino protecting group.

Of these compounds of formula I, those having the S-configuration at the 3-position of the azetidinone ring are preferred, ring B is a benzene ring which may be substituted by a halogen atom, a lower alkyl group or a lower alkoxy group, Y is an oxygen atom, : ,,; * a sulfur atom, a methylene group or an imino group substituted by a lower alkyl group and Z is a methylene group which may be substituted by 1-2 groups which are a C 1-7 alkylene group, a C 1-20 alkyl group or an aralkyl group.

Of these, the more preferred compounds of formula I are those wherein ring B is a substituent: *: · *: an unprocessed benzene ring, X is an oxygen atom, Y is an oxygen atom, and Z is a methylene group ω 111942 substituted with C 3 A -7 alkylene group, a methylene group substituted by a di-C 1-20 alkyl group, or a methylene group substituted by a di (phenyl-lower alkyl) group.

Another group of more preferred combinations are compounds of formula I wherein the substituent on Z is a bulky group such as a C 1-4 alkylene group, a C 1-10 alkyl group, a phenyl lower alkyl group and the like.

Among these, the most preferred compounds are those of formula I wherein Z is a pentamethylene-substituted methylene group (i.e., a cyclohexylidene group) or a dibutyl-substituted methylene group.

When Z has one substituent or two different substituents, the compound of formula I may exist in the form of two optical isomers, and these optical isomers and mixtures thereof are included in the present invention.

Examples of the salt of the azetidinone compound of formula I include e.g. an inorganic acid addition salt such as hydrochloride, hydrobromide sulphate and the like; and an organic acid addition salt such as acetate, oxalate, tartrate, fumarate, ma-20-oleate, benzenesulphonate and the like.

According to the invention, an azetidinone compound of formula I may be prepared ;;; by reacting an α-halopropionamide compound of the formula II or a salt thereof with a compound of the formula III: 25: · K i / v ': [ΠΙ] o> -nh wherein L 1 is a leaving group and R 1 is defined above.

·: · 30:.:.: The reaction of the α-halopropionamide compound of the formula II with the compound of the formula III can advantageously be carried out in a suitable solvent with the metal compound used in the Grignard-type reaction, in particular the metal compound. suitably forming a chelate between u111942 of the compounds of formulas II and III. Examples of such metal compounds are e.g. zinc, magnesium, magnesium / magnesium bromide, tin, zinc / copper pair, zinc chloride / lithium naphthylidene, lithium and aluminum. Among these, zinc and magnesium are preferred examples. The leaving group (L1) can be any leaving group which can be readily replaced by a nucleophilic reagent. In particular, any leaving group which can be readily separated from the compound of formula III together with the halogen atom (L °) of the alpha-halopropionamide of formula II can be used, and then a carbon-carbon bond may be formed. Examples of such groups are e.g. an acyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkylsulfonyl group, an arylsulfonyl group, an arylthio group, and a halogen atom. Of these, the acyloxy group is preferred. Any inert solvent may be used as the solvent. For example, tetrahydrofuran, toluene, xylene, dimethoxyethane, dimethylformamide, dimethylsulfoxide and the like are preferably used.

15

The compound of the formula II is used in an amount of 1 to 3 moles, preferably 1.3 to 1.7 moles / mole of the compound of the formula III. And the metal compound (e.g., zinc, magnesium) is used in an amount of 1-6 moles, preferably 2-4 moles / mole of the compound of formula III.

20

When magnesium is used in the above reaction, the reaction is preferably carried out on a halogenated compound such as methyl iodide or 1,2-dibromoethane or the like; * in the presence of a mixture of a halogenated compound and iodine. Preferably, the reaction is carried out at a temperature of -20 to 100 ° C, in particular at 50 to 80 ° C in the case; ·; 25 using zinc, and at a temperature of -20 to 30 ° C, if magnesium is used.

* »· * * · When using 0.01 to 2 mol of Lewis acid as a catalyst (e.g., zinc» · ·: ,, * cybromide, triethylborane, trimethylsilyl chloride, magnesium bromide), the reaction «· 30 is accelerated and the reaction time can be shortened .

♦ · · * »·

III

: ...: The α-halopropionamide compound of formula II, which is one of the three starting materials according to the invention, is a novel compound and can be prepared by

• I

Benzene compound according to van IV: 12

X

[IV] 111942 wherein the symbols, as defined above, or a salt thereof, are reacted with a 2-halopropionamide acid compound of formula V:

COOH

Wherein L ° is as defined above, or a salt or reactive derivative thereof.

The reaction of the benzene compound of formula IV with the 2-halo-propionic acid compound of formula V can advantageously be carried out in a suitable solvent in the presence of a dehydrating reagent. Examples of dewatering reagents are e.g. carbonyldiimidazole, dicyclohexylcarbonyldiimidide, N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like. Preferably the solvent used is ether, methylene chloride, tetrahydrofuran, acetonitrile and the like. The reaction is preferably carried out at a temperature of -30 to 70 ° C, especially at a temperature of 0 to 30 ° C.

20

The reaction of the benzene compound of formula IV with the reactive derivative of the 2-halo ': propionic acid compound of formula V can be carried out in a suitable solvent in the presence of an acid acceptor. Examples of the reactive derivative of the '2-halopropionic acid compound of formula V include: equivalent ,; Acid halide, acid anhydride and the like. Examples of the acid acceptor are '»'; mm. bases such as alkali metal hydride, alkali metal, lower alkyl lithium, phenyl lithium, pyridine and di-lower alkyl aniline. As the solvent, ether, benzo,. . fungi, dichloromethane, chloroform and the like. The reaction is preferably carried out in t1 »'..! at -80 to 50 ° C.

# · T '30' ·: The azetidinone compound of the formula I of the invention may conveniently be converted to the desired Ιβ-methylcarbapenem-type antibacterial agent as described in the following lines:. Ts. the desired Ιβ-methylcarbapenem-type antibacterial agent may be prepared, for example, by reacting an azeol of formula I or a salt thereof with an acetic acid compound of formula VI: wherein R 2 is a hydrogen atom or an ester and L 2 is a leaving group, or a salt thereof, to give an N-substituted azetidinone compound of formula VII: 10 6 H 3 i Ϊ x N-ω-HIB [V H]

j-N

O I r CH2 I.

COOR2 wherein the symbols are as defined above by subjecting the compound of formula VII or a salt thereof to intramolecular cyclization, subjecting the product to esterification to give a 13-methyl-2-oxycarbapenem derivative of formula VIII: iCH3 2 ° V-rx J> - ° a [viii] Wherein the group of the formula: -OA is an esterified hydroxy group, and the other symbols are as defined above, and then modifying said Ιβ-methyl of formula VIII. : 2-oxycarbapenem derivative or a salt thereof as the desired ßβ-methylcarbapenem antibacterial agent by a known method, for example menene:. ·. by the method described in JP Patent Publication No. 279588/1992. For example. Wherein the R11 is a hydroxy-substituted lower alkyl group which may be protected, R21 is a hydrogen atom or ester residue, and R3 is an organic group, or a salt thereof. , may be prepared by performing the following three steps in an arbitrary order: (i) reacting a compound of formula VIII or a salt thereof with a thiol compound of formula IX: H-SR3 [IX] wherein R3 is as defined above, or a salt thereof; (ii) when R 1 is a lower alkyl group substituted with a protected hydroxy, a possible step for removing the protecting group, and (iii) when R 2 is an ester residue, a possible step for removing the ester residue.

When R 2 in the acetic acid compound of formula VI, the N-substituted azetidinone compound of formula VII, or the 1β-methyl-2-oxycarbapenem derivative of formula VIII, and R 21 in the 1 β-methylcarbapenem derivative of formula X are ester residues, examples include those that can be metabolized or hydrolyzed in the human body or those that can be used as a protecting group for a carboxyl group. Examples of ester-20 residues that can be metabolized or hydrolyzed in the human body include e.g. a group of the formula: -Q-OCOR4, -Q-OCO2R4 or -Q-O-R4 (wherein Q is a lower alkylene group

• I

and R 4 is a lower alkyl group, a cycloalkyl group, a lower alkenoyl group, a lower alkoxy-lower alkyl group or a lower alkanoyloxy-lower alkyl group). More specific examples of such an ester residue are e.g. lower alkanoyloxy-lower alkyl groups • Group 25, lower alkanoyloxy-lower alkyl group, lower alkoxy-lower alkanoyloxy • ·, ·: ·. lower alkyl group, lower alkanoyloxy-lower alkoxy-lower alkyl group, lower alkoxy-lower alkyl group, lower alkoxy-lower alkoxy lower alkyl group, lower: ·. ·. alkoxy-carbonyloxy-lower alkyl group, lower alkoxy-lower alkoxy-carbonyl-

• I

• t. · · ·. oxy-lower alkyl group and the like.

30 ;;; On the other hand, examples of an ester residue which can be used as a protecting group for a carboxyl group include e.g. any which may be readily removed by conventional means, for example, a lower alkyl group, a lower alkenyl group, a halo-lower alkyl group, a nitrobenzyl group, a lower alkoxy-benzyl group, a benzhydryl group, and the like.

Examples of the esterified hydroxy group of the formula: -OA are e.g. those which can be readily substituted with: -SR 3, for example a di-arylphosphoryloxy (for example diphenylphosphoryloxy) or a lower alkylphosphoryloxy group represented by the formula: -O P (O) (0 R °) 2 (where R 0 is an aryl group or a lower alkyl group), substitutions on-oimaton or substituted lower alkylsulfonyloxy group (e.g. methanesulphonyl-nyylioksiryhmä, ethanesulfonyloxy, trifiuorimetaanisulfonyylioksiryhmä), a sub-10 stituoimaton or substituted arylsulfonyloxy group (for example benzenesulphonic nyylioksiryhmä, toluenesulfonyloxy), a lower alkanoyloxy group (e.g., acetoxy), arylcarbonyloxy (e.g., benzoyloxy group) and the like. Preferred examples of these are e.g. an esterified hydroxy group such as a di-arylphosphoryloxy group, a di-lower alkylphosphoryloxy group, an unsubstituted or substituted lower alkylsulfonyloxy group, an unsubstituted or substituted arylsulfonyloxy group and the like.

The organic group R 3 in the thiol compound of formula IX and the 1 β-methylcarbapenem derivative of formula X is e.g. any group having anti-bacterial activity when used as a substituent of a carbapenem-like compound. : as a support, especially any group used as a substituent in the known>. . ·. carbapenem-type antibacterial agents, for example those described in JP (unexamined), 18779/1986, 202886/1985, 5081/1986,.:. 49783/1990; and 279588/1992; and U.S. Patent 4,149,407. Examples of such a group are e.g. lower alkyl group, cycloalkyl group, 6-8 membered aryl group, 4-8 membered aliphatic heterocyclic group, 4-8 membered aromatic heterocyclic group and the like. Besides, these groups may include: '. one or more substituents, and examples of such substituents include e.g.

lower alkyl group, hydroxy group, lower alkoxy group, lower alkylamino group,? an oxo group,

«» I

· '*' A halogen atom, a cycloalkyl group, a 6-8 membered aryl group, a 4-8 membered allyl 111942, a phased heterocyclic group, a 4-8 membered aromatic heterocyclic group and the like.

The reaction of the azetidinone compound of formula I with the acetic acid-5 compound of formula VI may be carried out in a suitable solvent in the presence of a base. Examples of leaving group (L2) are e.g. a halogen atom, an acyloxy group, and a sulfonyloxy group (e.g., a p-toluenesulfonyloxy group or a methanesulfonyloxy group). Examples of the base include e.g. an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene, an alkali metal compound such as an alkali metal hydride, an alkali metal 10-hydroxide or an alkali metal carbonate; Tetrahydrofuran, benzene, dichloromethane and the like can be used as the solvent. The reaction is preferably carried out at a temperature of -50 to -20 ° C.

The intramolecular cyclization of the N-substituted azetidinone compound of formula VII may be carried out in the presence of a base. Examples of the base include e.g. those used in the Dieckmann-type reaction, for example, an alkali metal salt of an amine (e.g., sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, and an alkali metal salt of an alcohol (e.g., potassium tert-butoxide), alkali metal 20 hydride (e.g., sodium hydride) The base may be used in an amount of 1.0 to 3.0 moles, preferably 2.0 to 2.5 moles, per liter t / m of the compound of formula VII Examples of the solvent include tetrahydrofuran, ethylene glycol-> * lidimethyl ether, dioxane, toluene, diethyl ether, benzene, etc. The reaction is preferably carried out at a temperature of -78 to 50 ° C, in particular at a temperature of -60 to 10 ° C.

• · t · 25 • ·! ·; ·, Assume that this intramolecular cyclization produces a compound of the structural formula • * »XI:: /. ch3 T · 30) Χ ^ ~ οθ [xn coor2: where the symbols are as defined above. The product of the intramolecular cyclization thus formed can be isolated from the reaction mixture or subjected to subsequent esterification without isolation. However, the intramolecular cyclization and esterification may preferably be carried out next in the same solvent without isolation of the cyclization product.

The esterification of the product of the intramolecular cyclization can be accomplished by reacting it with an esterifying reagent of a hydroxy group. Examples of the hydroxy group esterifying reagent include e.g. a reactive derivative (e.g. a corresponding acid halide, a corresponding acid anhydride), diaryl phosphates (e.g., diphenyl phosphate, dialempialkyylifosfaatista (e.g., diethyl phosphate), substi-tuoimattomasta or substituted alempialkaanisulfonihaposta (e.g., methane-10-sulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid), is substituted, non or substituted arylsulphonic (for example bentseenisulfoniha-acid , toluenesulfonic acid), lower alkanoic acid (e.g. etikkahapos-O) or aryl carboxylic acid (e.g. benzoic acid). of these, preferred hydroxy esterification reagent include. a reactive derivative (15 equivalent, for example, an acid halide, a corresponding acid anhydride), diaryl, dialempialkyylifosfaatista, unsubstituted or substituted alempialkaanisulfonihaposta or unsubstituted or substituted arylsulphonic Hydroxy group esterifying reagent, vol to the east, 1.0 to 4.0 moles, preferably 2.0 to 3.0 moles, are used per mole of the compound of formula VII. The reaction is preferably carried out at -75 to 40 ° C, in particular at -60 to 10 ° C.

When the esterification is carried out without isolating the product of the intramolecular cyclization from the reaction mixture, the intramolecular cyclization and / or esterification may be carried out in the presence or absence of acid, but it is preferred to carry out the reaction in the presence of an acid. '.' 25 widows. Both Lewis acid and protonic acid can be used as the acid, but Lewis acid is preferred. When Lewis acid is used as the »·» acid for the intramolecular cyclization, it must be added to the reaction vessel after addition of the base.

. v # Examples of Lewis acid are e.g. a metal halide such as copper (II) chloride, copper • i · i (i (i) iodide, zinc chloride, zinc iodide, zinc fluoride, iron (III) chloride, tin (II) chloride,> 30 tin (IV) chloride, and corresponding silyl compound such as tri-lower alkyl halosilane

t I I

';;; '(For example trimethylchlorosilane, t-butyldimethylchlorosilane), tetrahalogen »*'; · 'Silane (for example, tetrachlorosilane) and the like. The Lewis acid may be used in an amount of from 0.1 to 2.0 moles, preferably from 1.0 to 1.5 moles, per mole of the compound of formula VII: Examples of protonic acid include e.g. sulfuric acid, p-toluene-18-11-942 sulfonic acid, acetic acid, citric acid, hydrochloric acid, phosphoric acid, boric acid and the like. The protonic acid may be used in an amount of 0.1 to 1.0 mol per mol of compound of formula VII.

When the esterification is carried out in the presence of an acid, the esterification reagent may advantageously be used in an amount of 1.2 to 1.5 moles per mole of the compound of formula VII.

Reaction of the ip-methyl-2-oxycarbapenem derivative of formula VIII with a thiol compound of formula 10 IX, a possible step to remove a hydroxy protecting group from a compound of formula VIII wherein R 1 is a lower alkyl group substituted by a protected hydroxy; of a compound wherein R 2 is an ester residue may be carried out by a conventional method. For example, the hydroxy protecting group of Rx or the ester residue of R2 can be removed by hydrolysis, reduction, and the like.

The azetidinone compound of formula I or a salt thereof can be converted by hydrolysis to the azetidinone propionic acid compound of formula XII (which is an excellent synthetic intermediate of a carbepenem-20 type compound):

\ - / ^ COOH tXIIJ

\! v H

) -Nh ·. · · O wherein R 1 is as defined above, and in addition, the compound of formula XIII or a salt thereof • V may be converted to a compound of formula VIII or salt thereof by a conventional method, e.g. JP Patent Publication 123182/1982.

The hydrolysis of the compound of formula I or a salt thereof may be carried out by a conventional method, but is preferably carried out in a suitable solvent in the presence of hydrogen peroxide and an alkali metal hydroxide. Examples of the solvent include e.g. water and an organic solvent such as dioxane, tetrahydrofuran, dimethylformate,. ': A mixture of mid, methanol and the like, preferably a mixture of water and tetrahydrofuran.

i9 111942

Examples of alkali metal hydroxide are e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, preferably lithium hydroxide. Hydrogen peroxide may be used in an amount of 1 to 10 moles, preferably 6 to 8 moles, per mole of the compound of formula I, and alkali metal hydroxide may be used in an amount of 1 to 5 moles, preferably 2 to 2 mol, per mole of the compound of formula I The reaction is preferably carried out at -10 to 30 ° C, in particular at -5 to 5 ° C.

Conversion of a compound of formula XII or a salt thereof to a compound of formula VIII or a salt thereof may be accomplished by the method described in JP-P-10 (unexamined) 188662/1988.

In the above reactions, the compounds of Formulas I, II, IV, V, VI, VII, VIII, IX, X, XI and XII may also be used in the form of their appropriate salts, which salts are suitable for the particular compounds above. Examples of such a salt are 15 mm. a metal salt such as sodium salt, potassium salt and the like; an amine salt such as a trialkylamine salt, a pyridine salt, an ethanolamine salt, a triethanolamine salt, a dicyclohexylamine salt and the like; an inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate and the like; and an organic acid addition salt such as acetate, oxalate, tartrate, fumarate, maleate, benzenesulfonate and the like.

»I

According to the invention, the azetidinone compound of the formula I or a salt thereof may be converted to the 13-methyl-2-oxycarbapenem derivative of the formula VIII or the salt of v and the Ιβ-methylcarbapenem derivative of the formula X or its salt, retaining the stereo structure.

In addition, a benzene compound of formula IV wherein Y is an oxygen atom, a sulfur atom or an imino group which may have a substituent (s) may be prepared:. * by the method described in the American Chemical Society vol. 72, »* · '· · · * 30 s 721 (1950). Specifically, said compound of formula IV may be::: prepared by condensation of a compound of formula XIII: xi '·':; I b I [xinj 20 111942 wherein the symbols are as defined above, with a compound of formula XIV: Z = 0 [xiv] wherein Z is as defined above.

5

In addition, a compound of formula XIII wherein X is oxygen and Y is a sulfur atom may be prepared by halogenation of a compound of formula XV: wherein ring B is as defined above to give a compound of formula XVI wherein X 2 is a halogen atom and ring B is as defined above, by subjecting the compound of formula XVI to amidation to give a compound of formula XVII: 20 Λ, -S-s-.: Π b I J | b J [XVH], CONH2 H2NOC / V'Sv ^: wherein ring B is as defined above, and then reducing the compound of formula XVII.

In addition, a compound of formula XIII wherein X is oxygen and Y is an amino group which may have a substituent (s) may be prepared such that a compound of formula i V XVIII: ... x 30

H-N

::: I b [xvni]; · '·. cAyAAa: v. wherein Y 1 is an imino group which may have a substituent (s) and other symbols .... as defined above, is reacted with ammonia.

111942 21

In addition, a compound of formula XIII wherein X is a sulfur atom and Y is a sulfur atom or an imino group which may have a substituent (s) may be prepared such that a compound of formula XIII wherein X is oxygen and Y is a sulfur atom or imino substituent (s) is subjected to thiocarbonylation.

5

In addition, a benzene compound of formula IV wherein Y is a methylene group can be prepared such that a compound of formula XIX:

Ij b] [XIX] 10 wherein L 3 is a halogen atom or a hydroxy group and ring B is as defined above, is reacted with a compound of the formula XX: HZ-NO 2 [XX] wherein Z is as defined above to give a compound of the formula XXI:

CrO

Wherein the symbols are as defined above, the compound of formula XXI is reduced to provide a compound of formula XXII: t I · • »» ^ I b [xxn] 25 ch 2 • »

v: wherein the symbols are as defined above, the product is reacted with formula XXIII

with: I · »» ·:. * x

. · · ·; I

'' 11 * 30 CH3O-C-Cl [XXIII] »: *: where X is as defined above, and the product is then subjected to intramolecular cyclization. Nille.

22 1 1 1942

The condensation reaction of a compound of formula XIII with a compound of formula XIV may be carried out in a suitable solvent in the presence of an acid. Examples of acid include e.g. an organic acid (e.g. p-toluenesulfonic acid) and an inorganic acid (e.g. sulfuric acid, hydrochloric acid). Examples of a suitable solvent are e.g. an organic solvent having a boiling point higher than the boiling point of water (e.g., toluene). The reaction is preferably carried out at a temperature of 50-180 ° C, especially at a temperature of 80-130 ° C.

Halogenation of the compound of formula XV may be accomplished by treatment of the compound 10 with a halogenating reagent in a suitable solvent. Examples of the halogenation reagent include e.g. thionyl chloride, phosphorus oxychloride and the like, and examples of a solvent include: inert solvents such as toluene. The reaction is preferably carried out at a temperature of from 20 to 120 ° C, in particular from 70 to 80 ° C.

Amidation of a compound of formula XVI may be accomplished by treating the compound with ammonia in a suitable solvent. Ammonia can advantageously be used in the form of an aqueous solution of ammonia, and examples of a preferred solvent are e.g. a solvent which may be miscible with water, for example ethers such as dioxane and alcohols such as ethanol. The reaction is preferably carried out at a temperature of 30 to 120 ° C, in particular at 80 to 90 ° C.

; The reduction of the compound of formula XVII may be carried out in a suitable solvent. * in the presence of a zinc and acid catalyst. An example of a preferred acid catalyst is e.g. an inorganic acid such as hydrochloric acid, and examples of a preferred solvent for the. ethers such as dioxane. The reaction is preferably carried out at a temperature of: 40-100 ° C, in particular 60-70 ° C.

i I t I «

»I

The reaction of the compound of formula XVIII with ammonia may be carried out in a · »: · In a day solvent. Ammonia can be used in the form of an aqueous solution of ammonia, and examples of a preferred solvent are e.g. water, ethers which may be miscible with water (e.g. dioxane) and alcohols (e.g. ethanol).

The reaction is preferably carried out at a temperature of 0 to 100 ° C, in particular at a temperature of 25 ° to 80 ° C.

> »• {1 I I I» 23 1 1 1942

Thiocarbonylation of a compound of formula XIII wherein X is an oxygen atom and Y is a sulfur atom or an imino group which may have a substituent (s) may be accomplished by treating the compound with a thiocarbonylation reagent in a suitable solvent. Examples of a preferred thiocarbonylation reagent are e.g. 2,4-bis (4-methoxyphen-5-yl) -1,3-dithia-2,4-diphosphane-21 H-disulfide, 2,4-dimethyl-1,3-dithia-2,4-diphosphane-2, 4-disulfide, phosphorus pentasulfide and the like. Examples of the solvent include e.g. any inert solvent such as dimethoxyethane, pyridine, xylene, toluene, benzene and the like. The reaction is preferably carried out at room temperature or under heating, in particular at 60-100 ° C.

10

The reaction of a compound of formula XIX with a compound of formula XX may be carried out in a suitable solvent in the presence of an acid acceptor. Examples of the acid acceptor include e.g. alkali metal hydride, alkali metal, alkali metal fluoride, lower alkyl lithium, phenyl lithium and the like. Examples of the solvent include e.g.

Dimethylformamide, tetrahydrofuran and the like. The reaction is preferably carried out under cooling or heating, for example at a temperature of 30 to 120 ° C, especially at a temperature of 30 to 80 ° C.

The reduction of a compound of formula XXI may be carried out in a suitable solvent 20 either by treatment with a reducing agent of the compound or by catalytic hydrogenation.

* ·: ·. In the case where it is treated with a reducing agent, examples of the reducing agent include e.g. metal hydride such as lithium aluminum hydride, sodium bis (methoxyethoxy) aluminum hydride, sodium borohydride and the like. Examples. : solvent are e.g. ethers such as tetrahydrofuran, diethyl ether, dioxane and the like. The reaction is preferably carried out at a temperature of 0 to 100 ° C, especially at a temperature At age 30-60 ° C.

On the other hand, in the case of catalytic hydrogenation, preferred examples of catalytic hydrogenation are used. from the market are eg. Pd / C, palladium black and the like. Examples of the solvent include alcohols such as methanol, ethanol and the like. The reaction is preferably carried out at a temperature of 0 to 70 ° C, in particular at 20 to 30 ° C.

• * «* · • · 111942 24

The reaction of a compound of formula XXII with a compound of formula XXIII may be carried out in a suitable solvent in the presence or absence of an acid acceptor. Examples of the acid acceptor include e.g. a base such as an alkali metal, an alkali metal hydride, an alkali metal hydroxide, an alkali metal alkoxide, an alkaline earth metal hydroxide, an alkaline earth metal alkoxide, a lower alkyl lithium, a phenyl lithium, pyridine, a dialem alkyl alkyl aniline and the like. Examples of the solvent include e.g. dimethylformamide, tetrahydrofuran, ether and the like. The reaction is preferably carried out at a temperature of 0-100 ° C, preferably at a temperature of 20-50 ° C. Subsequent intramolecular cyclization of the product may be carried out in the presence of a dehydrating reagent. Examples of 10 dewatering reagents are e.g. polyphosphoric acid, phosphorus oxychloride and the like. Examples of the solvent include e.g. inert solvents such as toluene, benzene and the like. The reaction is preferably carried out at a temperature of 50-150 ° C, especially at a temperature of 80-130 ° C.

Throughout the specification and the claims, the terms "lower alkyl group", "lower alkylene group" and "lower alkoxy group" are e.g. a linear or branched alkyl group having 1 to 6, preferably 1 to 4 carbon atoms, a linear or branched alkylene group having 1 to 6, preferably 1 to 4 carbon atoms, and a linear or branched alkoxy group having 1 to 6, preferably 1 to 4 carbon atoms carbon atom, corresponding to -20 ti. And the terms "lower alkanoyl group" and "lower alkenyl group" are e.g. a straight-chain or branched alkanoyl group having from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms; mia and a linear or branched alkenyl group having from 2 to 8, preferably from 2 to 8 ;; 6 carbon atoms, respectively. Further, the terms "lower alkenoyl group" and "cycloalkyl-" group "are, e.g. a linear or branched alkenoyl group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms and a cycloalkyl group having 3 to 8 carbon atoms, preferably 4 to 7 carbon atoms;

»I

'; carbon atom, respectively.

* · * • · ♦ ... Example 1 A solution of 89.1 ml of 2-bromopropionyl bromide in 95 ml of methylene chloride and ** · '' 'solution of 61.13 g of pyridine in 95 ml methylene chloride is added dropwise to a suspension of 140 g of spiro [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane] - 4-one in 190 ml of methylene chloride in a nitrogen atmosphere at -5 ° C for 45 minutes. The mixture of Sit- * '* is stirred at room temperature for six hours. The reaction mixture is poured into 111942 ml of water and extracted with methylene chloride. The extract is washed, dried and evaporated to remove the solvent, and the resulting residue is crystallized from methanol and the crystals are collected by filtration to give 197.3 g of 3- (2-bromopropionyl) spiro [2,3-dihydro-4H-1,3-benzoxazine-2]. l'-cyclohexan] -4-one.

Mp: 74-76 ° C

Examples 2-10

The corresponding starting compounds and 2-bromopropionyl bromide are treated as described in Example 1 10 to give the compounds listed in Tables 1 and 2.

Table 1 CH3 15 Γ ° b / ^ go—

Esirr Z2 no ._____________________ 20 _1 „9 v Physical properties of Z Tr i Ring B,. ------ jn £ j_ 2 CHj CH ^ O syrup 3 -¾¾ "-c4h9 o X) silrappl 25 * * · mmm» ------ - ___ V: 4 n'C15H31 n'C15H31 O Ό Syrup

N 5 -CH * O -CH 2 O 0) mp 114-115 ° C

= ::> 30 ------ \ .V 6 CH3 CH3 -CH2-0OCH3 Syrup * »·

• · I

I "" "*" "**" * ^^ I I I. I I I -. ...........— »· · IM IM: IMMR Data for Example 6 Compound 111942 26 NMR (CDCl 3) δ: 1.68 (3H, d), 1, 82 (3H, s), 2.05 (3H, d, J = 7.5Hz), 3.10 (2H, s), 3.72 (3H, s), 5.22 (1H, q, J = 7.5Hz), 6.90 (1H, d, J = 9Hz), 7.55 (1H, d, J = 3Hz, 9Hz), 7.88 (1H, d, J = 3Hz).

Γ O

Br Xoo— ah 10 First C \ no.

_ ^ Ring B fys. properties, jn <7 ς Li colorless syrup *

15 Ο Λ v ^ vCI

8 0 \ J sp,: .89-91 * C

90 ° C: 99-100 ° C

CH3

20 10 ° m.p. 111-112 ° C

OCH3 • ·; ·, *: NMR data of Example 7 NMR (CDCl 3) δ: 1.1 - 2.6 (10H, m), 1.94 (3H, d, J = 6.6Hz), 4.87 (1H, q, J = 6.6Hz), iv. 7.2-7.4 (2H, m), 7.48 (1H, t, J = 7.5Hz), 8.11 (1H, d, J = 7.7Hz) »* · i i |

Example 11 »» # »·. · · ·. 1.0 g of (3R, 4R) -4-Acetoxy-3 - [(1R) -lt-butyldimethylsilyloxyethyl] -2-azetidinone, 1.8 g, 3- (2- (Bromopropionyl) spiro [2 , 3-Dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane-4-one and 0.68 g of zinc powder are added to 15 ml of tetrahydrofuran and the mixture is refluxed for 30 minutes. After cooling, the reaction mixture is poured into: V 0.2M phosphate buffer (pH 7.0) and the mixture is extracted with methylene chloride, The extract is washed, dried and evaporated to remove the solvent.

Column chromatography (solvent; hexane: ethyl acetate = 3: 1) gives 1/3 g of 3 - {(2R) -2 - [(3S, 4R) -3 [(1R) -lt-butyldimethylsilyloxyethyl] -2-oxoazetide -4yylilpropionyyli} spiro [2,3-dihydro-4H-l, 3-bentsoksatsiini2il'-cyclohexan] one. mp: 154-155 ° C

Examples 12-20

The corresponding starting compounds and (3R, 4R) -4-acetoxy-3 - [(1R) -1-t-butyldimethylsilyloxy) ethyl] -2-azetidinone are treated in the same manner as in Example 11 to give the compounds listed in Tables 3 and 4.

Table 3 TOSO S »*

H B

A-NH \

Be "Y

Well. O Z2 ^ 2 v physical proprietary 2Q Z1 Tr Y Ring B females, etc.

•. '| 12 CH 3 CH 3 o X) mp: 133-134 ° C

* · Ι · ι ι ιι ·· ι —— ^^,: T:, 3 n-C4H9 „.C4H9 o X) sllrappi 'I · M nC15H31 n'C35H31 OX) syrup <* ·, v 15 -CH rQ -CHrO o X) syrup »» • · * 30 16 CH3 CH3 -CH2- X) ° CH3 syrup * »* * ::: ______ I» * ·

I t I

! TBS is the t-butyldimethylsilyl group (the same below) *: NMR data for Example 16 281-11942 NMR (CDCl3) δ: 0.07 (6H, s), 0.89 (9H, s), 1.22 (3H) , d, J = 6Hz), 1.28 (3H, d, J = 7.5Hz), 1.72 (3H, s), 1.80 (3H, s), 3.10 (2H, s), 3.20 (1H, m), 3.50-3.60 (1H, m), 3.72 (3H, s), 4.02-4.08 (1H, m), 4.10-4, 25 (1H, m), 5.95 (1H, s), 6.93 (1H, d, J = 9Hz), 7.53 (1H, dd, J = 3Hz, 9Hz), 7.92 (1H, d, J = 3Hz)

Table 4 TBSO * H3 1h Swim? 10 °° 7f | 0)

First J-NH

Well. O

__Y__Read B_ fys. characteristics, etc ^ 5 ^ S syrup * 18 ° 0 'move

19 O 0 sp: 173-175'C

ch3 20____

20 O 'Ό mp: 155-158 * C

. och3 # # * NM NM NM NM NM: NMR data for Example 17: δ: 0.08 (3H, s), 0.09 (3H, s), δ 86 (9H, s), 1.22 (3H, d, J = 6.3), 1.26 '(3H, d, J = 7.2Hz), 1.5-2.5 (10H, m) ), 3.13.2 (1H, m), 3.2-3.4 (1H, m), 4.11 (1H, dd, J = 2.3Hz, 4.0Hz), 4.22 (1H , dt, J = 6.2Hz, 10.7Hz), 5.92 (1H, lev.s), 7.26 (1H, d, J · 7.3Hz), 7.47 (1H, dt) , J = 1.5Hz, 7.5Hz), 8.13 (1H, dd, J = 1.4Hz, 8.4Hz) 30h • · ·

Example 21 * · * # • (1) 16.2 ml of a 1M solution of sodium bis (trimethylsilyl) amide (solvent: tetrahydrofuran) are added to a mixture of 7 g of 3 {(2R) -2 - [(3R, 4R) -3- [ (1R) -lt-Butyldimethylsilyl-29,11,1942 oxyethyl] -2-oxoazetidin-4-yl] propionyl} spiro [2,3-dihydro-4 H -1,3-benzoxazin-2,1'-cyclohexane] - Of 4-one and 2.89 g of allyl bromoacetate in 35 ml of tetrahydrofuran at -60 ° C and warming to -30 ° C over one hour. The re-reaction mixture is poured into a mixture of water and ethyl acetate, and the ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 20: 1-5: 1) to give 8.03 g of 3 - {(2R) -2 - [(3S, 4R) -1-allyloxycarbonylmethyl-3]. [(1R) -lt-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} spiro [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane] -4-one as a syrup.

10 (2) A solution of 1.2 g of 3 - {(2R) -2 - [(3S, 4R) -1-allylcarbonylmethyl-3 - [(1R) -lt-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] priopionyl} -spiro [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane] -4-one in 6 ml of tetrahydrofuran is added dropwise to 4.4 ml of 1M sodium bis (trimethylsilyl) amide solution (solvent: tetrahydro). -15 furan) at -20 ° C to -30 ° C for one minute. At -50 ° C, 261 mg of trimethylsilyl chloride is added and the mixture is stirred for two minutes. Then, at -50 ° C, 645 mg of diphenylphosphoryl chloride is added and the mixture is stirred for two hours at 0 ° C. The reaction mixture is poured into 50 ml of 0.2M phosphate buffer (pH 7.0) and extracted with ethyl acetate. The extract is washed, dried and evaporated to remove solvent. Isopropyl ether is added to the residue, and the resulting precipitate in which: 355 mg of spiro [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane] -4-one is removed by filtration. The filtrate is condensed to give 1.04 g of (1R, 5R, 6S) -6-1. ·. [(1R) -1-t-Butyldimethylsilyloxyethyl] -1-methyl-2-diphenylphosphoryloxycarboxylic acid. pen-2-em-5-carboxylic acid allyl ester as a syrup.

! V. 25 * ·

Example 22 * * ·: ·. ·. To a solution of 500 mg of 3 - {(2R) -2 - [(3S, 4R) -3 - [(1R) -1-t-butyldimethylsilyl] · ·. * ". oxyethyl] -2-oxoazetidin-4-yl] propionyl} spiro [2,3-dihydro-4 H -1,3-benzoxybenzyl] azine-2,1'-cyclohexane] -4-one In 20 ml of a mixture of tetrahydrofuran and water, add additional · · · ;;; 0.9 ml of 30% aqueous hydrogen peroxide and 84 mg of lithium hydroxide in this order are added and the mixture is stirred at the same temperature for one hour. The pH of the mixture is adjusted to 10 by the dropwise addition of 5 ml of 1.5N aqueous sodium sulphite at a mass temperature, and the tetrahydrofuran is removed under reduced pressure. Precipitated crystals

is removed by filtration and the aqueous layer of the filtrate is washed with 20 ml of chloroform. 10 ml of 10% hydrochloric acid are added thereto and the pH of the mixture is adjusted to about 1. The aqueous layer is dried and then evaporated under reduced pressure to give the crude product. The product is recrystallized from a mixture of ethyl acetate and hexane to give 216 mg of (2R) -2 - [(3S, 4R) -3 - [(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionic acid. mp. 146-147 ° C

Example 23 10

A mixture of 10 ml of tetrahydrofuran and a small amount of iodine is added to a 437 mg portion of magnesium at room temperature and 0.75 g of 1,2-dibromoethane is added dropwise with stirring. When the exothermic reaction begins and the mixture begins to reflux, a solution of 1.51 g of 1,2-dibromoethane in 3 ml of tetrahydro-rofuran is added dropwise. The mixture is then refluxed for 30 minutes. The mixture is cooled to 5 ° C and a mixture of 1.15 g of (3R, 4R) -4-acetoxy-3 - [(1R) -lt-butyldimethylsilyloxyethyl] -2-azetidinone and 2.11 g is added dropwise to this cooled liquid. 3- (2-Bromopropionyl) spiro [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane] -4one in 5 ml tetrahydrofuran. The mixture is then stirred at 10 ° C for one 20 hours. To it is added 60 ml of aqueous saturated ammonium hydrochloride and. the mixture is extracted with ethyl acetate. The extract is washed, dried and evaporated with solvent

• I I

to remove. The residue is purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 6: 1 to 3: 1) to give 1.61 g of 3 - {(2R) -2 - [(3S, 4R) -3- »* · ';. [(1R) -lt-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} spiro: v. 25 [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane] 4 -one.

* ·

M.p .: 154-155 ° C

Examples 24 - 33 »· 30 The corresponding starting compounds are treated as described in Example 1 to give the compounds listed in Table 5 Further compounds listed in Table 5 and • · * (3R, 4R) -4-acetoxy-3 - [(R) -butyldimethylsilyloxy) ethyl ] -2-Azetidonone is treated as described in Example 11 to give the compounds listed in Table 6.

Table 5 „111942 31 CH3, λ

Br CO-N γ ^

I'm from. Z2 z1 z2 x y

10 24 CH3 CH3 s S

25 - (CH 2) 4 -S S

26 - (CH 2) r -O / NCH 3 27 n-C 4 H 9 n-C 4 H 9 O / NCH 3 15 ----- 28 - (CH 3 j O - CH 2 -)

Table 6 20 TBSO | H3:! H il f / '' 'l-j / g CO—

I'm J-NH

No. <j z2 25 ____

z1 Z2 x Y

29 CH3 CH3 S S

: it; * 30 - (CH 2) 4 - S S

30 31 - (CH 2) 5 -O / NCH 3 32 n-C 4 H 9 n-C 4 H 9 O / NCI-fe ', 33 - (CH 2) 5 -O CH 2 32 1 11 1942

Comparative Example 1

A mixture of 20 g of dibutyl ketone, 19.3 g of salicylamide and 2.7 g of p-toluenesulfonic acid monohydrate is added to 300 ml of toluene and the mixture is refluxed overnight using a Dean Stark dehydrator. After cooling, the reaction mixture is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 95: 5) to give 34 g of 2,2-dibutyl-4-oxo-2,3-dihydro-4H-1,3-benzoxazine as a yellow oil.

10 Comparative Examples 2 to 6

The corresponding starting compounds [XIII] and the corresponding starting compounds [XIV] are treated as described in Comparative Example 1 to give the compounds listed in Table 7.

15 Table 7

O

1 ^ I I B I

? n, Tert · 2 2 0 akim. Z * 10.

i * H n • Z Z Ring B fys. characteristics, etc; 2 n'C15H31 n'C15H31) 0 yellow oil I _____

I; 25 3 -CHrQ -CHa-O (X) m.p. 159-161 ° C

> »—1I I I I I II ...... 1 '' I 'I ·« I I I I

* · ·

4- (CH-2) s X) ° m.p .: 168-170 ° C

3 --- 5--

30 - (CH 2) s - 'V' m.p .: 175-177 ° C

::: CH3 * t »*» i _______ _ ^^

: V. 6 ~ (CH 2) 5 -X) m.p .: 193-195'C

: * 'OCKj 33 111942

Comparative Example 7 (1) 12.5 mL of thionyl chloride is added dropwise to a solution of 25.0 g of 2,2'-dithio-dibenzoic acid in a mixture of 120 mL of toluene and 0.5 mL of dimethylformamide at room temperature. The mixture is heated to 70-80 ° C and then stirred at the same temperature overnight. After 20 hours, the crystals are collected by filtration to give 14.9 g of 2,2'dithiodibenzoyl chloride as a colorless crystal, m.p.

10 (2) 20 ml of ammonia solution are added to a suspension of 7.03 g of 2,2'-dithiobenzoyl chloride in 20 ml of dioxane at room temperature. The mixture is heated to 80-90 ° C and stirred for 5 hours at the same temperature. The mixture is cooled to room temperature to give 4.8 g of 2,2'-dithiodibenzoylamide as a colorless crystal.

Yield: 77% m.p .: 249-250 ° C

(3) 41 ml of 2N hydrochloric acid are added dropwise to a suspension of 4.14 g of 2,2'-di-thiodobenzoylamide and 2.5 g of zinc powder in 70 ml of dioxane. The mixture is heated to 60-70 ° C and stirred for 4 hours at the same temperature. Reaction mixture: Pour into 50 ml of water and extract with ethyl acetate. Ethyl acetate layer: washed, dried and evaporated under reduced pressure to remove solvent. A mixture of 5.64 ml of cyclohexanone and 1.03 g of p-toluenesulfonic acid monohydrate is added to a solution of the residue obtained above in toluene and the mixture is refluxed for 25 minutes using a Dean Stark dehydrator. Cool to room temperature

• I

the reaction mixture is then condensed under reduced pressure and methanol is added thereto. The precipitates are collected by filtration to give 3.05 g of spiroL2,3-dihydro-4 H -1,3-benzothiazine-2,1'-cyclohexane] -4-one as a colorless crystal.

M.p .: 193-195 ° C.

. ! ·. 30 • t »··! Comparative Example 8 »» I. —.Il - .........

• (1): · [(1) 10.0 g of N-methylacetic acid are gradually added to 140 ml of water at room temperature.

9.6 g of ammonia solution are added dropwise to the patient and added thereto. The mixture is heated to 34 L 1942 at 80 ° C for 45 minutes and ethanol is added until the mixture becomes colorless. The reaction mixture is then cooled to room temperature and the precipitated crystals are collected by filtration to give 7.11 g of 2-carbamoyl-N-methylaniline as a colorless crystal.

Yield: 84% m.p .: 155-156 ° C

(2) A mixture of 6.9 ml of cyclohexanone and 633 mg of p-toluenesulfonic acid monohydrate is added to a solution of 5.00 g of the product obtained above in toluene and the mixture is refluxed by dehydration using a Dean Stark dehydrator for one hour. After cooling to room temperature, the precipitated crystals are collected by filtration and washed with methanol to give 6.32 g of spiro [1-methyl-1,2,3,4-tetrahydroquinazoline-2,1'-cyclohexane] -4-one as a colorless crystal . Yield: 83%

M.p .: 183-185 ° C

Comparative Example 9

A mixture of 11.5 mL of 5-oxononane and 633 mg of p-toluenesulfonic acid mono-20 hydrate is added to a solution of 5.00 g in the previous Comparative Example 8- (1) | the product obtained in toluene, and the mixture is refluxed for 30 minutes using a Dean, \ Stark dehydrator. After cooling to room temperature, the mixture is condensed under reduced pressure and the resulting residue is purified by silica gel column chromatography. graphically (solvent; chloroform: methanol = 100: 1) to give 9.16 g of 1-methyl. 2,2-Dibutyl-4-oxo-1,2,3,4-tetrahydroquinazoline as a yellow crystal.

·. Yield: 100%

mp: 77-78 ° C

»· <·: '' *; Comparative Example 10 30 * · * _ -! The nitrocyclohexane and benzyl bromide are subjected to a condensation reaction in the presence of sodium hydride to give 1-benzyl-1-nitrocyclohexane. The product is reduced with lithium aluminum hydride to give 1-benzyl-1-aminocyclohexane.

The product is reacted with methyl chloroformate to give 1-benz-1, 1942-syl-1-methoxycarbonylaminocyclohexane, and the product is subjected to intramolecular cyclization in the presence of phosphorus oxychloride to give spiro [1,2,3,4-tetrahydroisoquinoline-2 -cyclohexane] -L-one.

Comparative Example 11 (1) A solution of 9.6 g of ethoxycarbonyl chloride in 25 ml of ether is added dropwise to a solution of 30 g of 1- (2 amino-2-methylpropyl) -4-methoxybenzene in 300 ml of ether under ice-cooling. A solution of 10 9.6 g of ethoxycarbonyl chloride in 25 ml and 8 g of sodium hydroxide in 50 ml of water is then added dropwise.

After the addition, the mixture is stirred for one hour and water is added. The ether ether layer is removed and the aqueous layer is extracted twice with ether. The mixture of the ether layer and the extract are dried and evaporated to remove the solvent. The residue is purified by column chromatography to give 29.1 g of 1- [2- (N-ethoxycarbonyl) -15 amino-2-methylpropyl] -4-methoxybenzene as an oil.

NMR (CDCl 3) δ: 1.63 (6H, s), 3.12 (2H, s), 3.72 (3H, s), 6.707.10 (4H, m), 6.7-7.1 ( 4H, m) (2) 10 g of the product obtained above are added to 100 ml of polyphosphoric acid and the mixture is stirred at room temperature for 30 minutes. The mixture is then gradually heated to 100 ° C and stirred at the same temperature. Cool to room temperature. ·. 300 ml of water are added thereto and the mixture is extracted with chloroform.

. ·. The extract is dried and evaporated to remove the solvent. The residue is purified by column chromatography to give 5.43 g of 1-oxo-3,3-dimethyl-7-methoxy-1,2,3,4-. 25 tetrahydroisoquinoline as an oil.

! ·. NMR (CDCl 3) δ: 1.62 (6H, s), 3.10 (2H, s), 3.72 (3H, s), 6.90 (1H, d, J = 9Hz), 7.45 ( 1H, dd, J = 3Hz, 9Hz), 7.85 (1H, d, J = 3Hz) '. '*. According to the invention, the azetidinone compound of the formula I or a salt thereof can be prepared stereoselectively. Said azetidinone compound of formula I is useful as a synthetic intermediate for the Ιβ-methylcarbenepenem derivative of formula X having antibacterial activity since the compound of formula I has a partial backbone (i.e., a support group) of formula: 1942 5 wherein the symbols are as defined above, suitable for the preparation of the Ιβ-methylcarbapenem ring. Specifically, a compound of formula II or a salt thereof can be converted to a compound of formula I or a salt thereof with high stereo-selectivity by reacting it with a compound of formula III without thereby requiring optical resolution, and the expensive compound of formula III can be effectively used.

In addition, the compound of formula I or a salt thereof can be readily converted by hydrolysis to a compound of formula XII or a salt thereof, which is an important intermediate of the Ιβ-methylcarbapenem compound since the compound of formula I has an Γ-β-methyl group at position 4 of the azetidinone backbone.

In addition, after conversion of a compound of formula I or a salt thereof to a compound of formula VII or a salt thereof, a compound of formula VII thus obtained can be converted into a compound of formula XI or a salt thereof or a compound of formula VIII or a salt thereof by intramolecular cyclization without chemistry; activation by position modification at the 4-position of the azetidinone backbone.

In addition, the support group of the invention may be altered by intramolecular cyclization such as a compound of formula IV or a salt thereof, and therefore a compound of formula I or a salt thereof is useful as a derivative of a Ιβ-methylcarbapenene of formula X. as a synthetic intermediate of its salt, either for use or economically.

1 I | On the other hand, an α-halopropionamide compound of formula II or a salt thereof can be readily prepared. For example, a compound of formula II wherein both X and Y are, · '. oxygen atoms can be prepared from commercially available salicylamide phase.

»» 37 1 1 1942

Therefore, the Ιβ-methylcarbapenem derivative of formula X or a salt thereof can be readily prepared according to the invention on an industrial scale as it is not necessary to perform optical resolution, use expensive Lewis acid such as tinatriflate or boron triflate and activate the side chain moiety on the 4

t · * •

1> j I

f »· I t • · t» t> »* I I 1 I ·! »

Claims (23)

1 is substituted with a lower alkyl group, lower alkoxy group, halogen atom or alternatively protected amino group, or its site. 10. A compound according to claim 9, characterized in that the ring B is a benzene ring which can be substituted by a halogen atom, lower alkyl group or lower: alkoxy group, Y is an oxygen atom or sulfur atom, a methylene group or imino group which may be substituted by a lower alkyl group and Z is a methylene group: which may be substituted by one or two groups of a C3.7 alkylene group, C1-20 alkyl group and phenyl lower alkyl group (said phenyl group may be substituted by a lower alkyl group, lower alkoxy group, halogen atom or alternatively a protected amino group). A compound according to claim 8, characterized in that the ring B is a substituted benzene ring, X is an oxygen atom, Y is an oxygen atom, and Z is a methylene group which is substituted by a C3.7 alkylene group, methylene group which is substituted by a di-C1-20 alkyl group, or methylene group which is substituted by a di- (phenyl-lower alkyl) group. 10 A compound according to claim 11, characterized in that Z is a pentamethylene-substituted methylene group or dibutyl-substituted methylene group. Compound according to claim 8, characterized in that the compound is 3- (2-15 bromopropionyl) -spiro [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane] -4-one. A process for the preparation of an α-halogenopropanamide compound of formula [II] ch3 * Λ-Λα, Wherein the ring B, X, Y and Z are defined as in claim 1 and L ° is a halogen atom,, t '· or its site, characterized in that a benzene compound of the formula [ IV] iv MM \ j 30 »:; *: where the symbols refer to the same as above, or its site, is reacted with a 2- [I]: “': halo propionic acid compound of the formula [V]» to Li CH 3 111942, where CO ° 5 where L ° represents the same, as above, its salt or reactive derivatives, and if necessary, the product is converted to its salt. A process for preparing an ip-methyl-2-oxycarbapenem derivative ch3 1 ° VrA ο <Π [vmi COOR2 where R 1 is a hydroxy-substituted lower alkyl group, which may be protected, R 2 is a hydrogen atom or ester residue, and the group of the formula - OA is an esterified hydroxy group, or its site, characterized in that a) an azetidinone compound of formula [I] CH3 I x: M 'S- / g-oo-N ^ Y ^,: Λ I 7 I BJ tn ::: J — nh::: o> ..I:' 25 where the ring B, X, Y and Z are defined as in claims 1 and R 1 refer to the same IV as above, or its site, is reacted with an acetic acid compound of formula [VI] * L 2 - CH 2 - COOR 2 [VI] IV a L 2 is a leaving group and R 2 is the same as above, or its site, where: - in an N-substituted azetidinone compound of formula [VII] and HIB [VII] JN 5. In CH2 I, COOR2 where symbols mean the same as above are obtained, b) the preceding compound [VII] or its salt undergoes an intramolecular cyclization, c) the intramolecular cyclized product or its salt is subjected to an esterification, and d) if necessary, is converted the product further to its salt. Method according to claim 15, characterized in that either the intramolecular cyclization of the N-substituted azetidinone compound of formula [VII] or its salt or the esterification of the intramolecular cyclized product or bSda its salt is carried out in the presence of of a Lewis acid. I I 17. A process for preparing a Ιβ-methylcarbapenem derivative of the formula [X] CH 3 r WA, 1 X 1 COOR 21: · ·: where R 11 is a hydroxy-substituted lower alkyl group which may be protected, R 21 is a hydrogen atom or ester residue and R 3 is an organic group, or its sait, characterized. Wherein: a) an azetidinone compound of formula [I] + ch3 (b °° - rV> I in 1 BJ m Wherein R 1 is a hydroxy-substituted lower alkyl group, the ring B, X, Y and Z are as defined in claim 1, or its salt, reacted with an acetic acid compound of formula [IV] Wherein L2 is a leaving group and R2 is a hydrogen atom or ester residue, or with its salt, wherein an N-substituted azetidinone compound of the formula [VII] wH3 TX \ - {I CO - HIB [ In which the symbols refer to the same as above are obtained, b) the compound [VII] or its salt is subjected to an intramolecular cyclization; c) the intramolecularly cyclized product or its salt is subjected to esterification, wherein an ip-methyl-2-oxycarbapenem derivative of the formula [VIII] ch3, VrV C: Wherein the group of formula -OA is an esterified hydroxy group, and R 1 and R 2 represent the II ·: same as above, are obtained, and d) a compound of formula [VIII] or its salt is converted to the corresponding 1β-methylcarbapenem derivative of formula [X] or its salt by known methods. 18. A process according to claim 17, characterized in that R 1 is a 1-hydroxyethyl group which can be protected and R 3 is a 2-thioxopyrrolidin-4-yl group. A process for preparing an azetidinone compound of the formula [XII] CH3 Wherein R 1 is a hydroxy-substituted lower alkyl group which may be protected, or its site, characterized in that an azetidinone compound of the formula [I] wherein the ring B, X, Y and Z are as defined in claim 1, and R1 is the same, hydrolyzed as above, or its site, and converted as needed to the products; to its site. * »· A process for the preparation of an azetidinone propionic acid compound of formula iv. [XII] CH3 * * * V _ / KoOH [χ111 • * t In J-NH.;% 30 0 y. '.' wherein R1 is a hydroxy-substituted lower alkyl group, which may be protected, or its', characterized in that: a) an α-halogenopropionamide compound of formula [II] 57 Γαι- / γΛ I Β [Π] , wherein the ring Β, X, Υ and Ζ are defined as in claim 1 and L ° is a halogen atom, or its salt, is reacted with a compound of formula [III] R1 L1 w [ΠΙ] O} - NH 0 where L1 is a leaving group, and R 1 is the same as above, wherein an azetidine compound of the formula [I] is CH3 ν ^ "~ OΘ J-NH 0 where the symbols refer to the same as above are obtained, 20: b) (I) or its salt is subjected to hydrolyzing, and (c) if needed, the product is converted to its salt. 21. Process for the preparation of an ip-methyl-2-oxycarbapenem derivative with the formula [VIII] * 'CH3: · ... Rn Λ o [previous: · · yes 0] COOR2 * · · · · R1 is a hydroxy substituted lower al cooling group, which may be protected, R 2 is a hydrogen atom or ester residue, and the group of formula -OA is an esterified hydroxy group, or its site, characterized in that a) an azetidinone compound of formula [I] CH3 N— / K co— A L 1BJ [I] J-NH 0 1 wherein the ring B, X, Y and Z are as defined in claim 1, and R 1 is the same as above or hydrolyzed, wherein an azetidinone propionic acid compound of formula [XII] cH3 Where J 1 represents the same as above, and b) a compound [XII] or its salt is converted to the corresponding 1-methyl-2-oxy-carbapenem derivative [VIII ] or its sait pl known way. 22. A process for preparing an ip-methylcarbapenem derivative of the formula [X] CH3: N see? [X]: V: COOR21 where R11 is a hydroxy substituted lower alkyl group which may be protected, R21 is a * ·; *: ·; hydrogen atom or ester residue, and R 3 is an organic group, or its site, characterized in that: a) an azetidinone compound of formula [I]. HII bJ (I) J-nh o 5g 111942 wherein R1 is a hydroxy-substituted lower alkyl group which may be protected and the ring B, X, Y and Z are defined as in claim 1, or its site, is hydrolyzed, wherein an azetidinone propionic acid compound of the formula [XII] CH3 IR \ _ / φαοοΗ [χΠ) H oj-nh where R1 represents the same as above is obtained, and b) a compound [XII] or its salt is converted to the corresponding Ιβ-methylcarbapene derivative [X] or its site on known way. 23. A process according to claim 22, characterized in that R 1 is a 1-hydroxyethyl group which can be protected and R 3 is a 2-thioxopyrrolidin-4-yl group. • »» ► · r · • t »* I i« »· (i · 1 f 1 1. Azetidinone compound of the formula [I] ch 3 R 1 - / l 2 co-I [1 B C Cl] J-NH 0 characterized in that the ring B is a benzene ring which may be substituted by 1-4 groups from the group a halogen atom , lower alkyl group, lower alkoxy group and phenyl group which may be substituted by a lower alkyl group, lower alkoxy group, halogen atom or with an alternatively protected amino group, R 1 is a hydroxy substituted lower alkyl group which may be protected, X is an oxygen atom or sulfur atom, Y is an oxygen atom or sulfur atom, methylene group or imino group which may be substituted by a lower alkyl group, acyl group or aralkyloxycarbonyl group, and Z is a methylene group which may be substituted by one or two groups selected from the group C3.7 alkylene group , C 1-20 alkyl group, Q 7 cycloalkyl group, phenyl group (said alkylene group, alkyl group, cycloalkyl group and phenyl group may be substituted by a lower alkyl group, lower alkoxy group, halogen atom or alternatively phenyl-lower alkyl group (said phenyl group may be substituted by a lower alkyl group, lower alkoxy group, halogen atom or alternatively protected amino group), or a 4-7 membered heterocyclic group comprising an oxygen atom , nitrogen atom, sulfur atom or hetero atom, which may be optionally substituted with a lower alkyl group, lower alkoxy group, halogen atom or an alternatively protected amino group, or its salt. • · t t I I t · * »· v A compound according to claim 1, characterized in that the ring B is a benzene ring which may be substituted by a halogen atom, lower alkyl group or lower: · alkoxy group, Y is an oxygen atom or sulfur atom, a methylene group or imino group, Which may be substituted by a lower alkyl group and Z is a methylene group which:: =: may be substituted by one or two groups selected from a C3-7 alkylene group,: '': C1-20 alkyl group and phenyl lower alkyl group ( said phenyl group which may be substituted with a lower alkyl group, lower alkoxy group, halogen atom or alternatively .... protected amino group). 50 1 1 1942 A compound according to claim 2, characterized in that the ring B is a substituted benzene ring, X is an oxygen atom, Y is an oxygen atom, and Z is a methylene group which is substituted by a C3.7 alkylene group, methylene group which is substituted by a di-C1-20 alkyl group, or a methylene group which is substituted by a di- (phenyl-lower alkyl) group. A compound according to claim 3, characterized in that Z is a pentamethylene-substituted methylene group or dibutyl-substituted methylene group. A compound according to any one of claims 1-4, characterized in that the 3-position of the azetidinone compound has an S-configuration. Compound according to claim 1, characterized in that the compound is 3 - {(2R) -2 - [(3S, 4R) -3 - [(1R) -l-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] - propionyl} spiro- [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan] -4-one. A process for the preparation of an azetidinone compound of the formula [I] ch 3 e.g. 20 Ih] [n) -NH, ·, · o, wherein the ring B, R1, X, Y and Z is defined in claim 1, or its site , characterized in that an α-halogenopropionamide compound of the formula [II] is %ν XJ j II] B j [II]> · ·% ··· * where L ° is a halogen atom, and the the other symbols refer to the same as above:: or its site is reacted with a compound of formula [III] W: ·· In [ΠΙ] *: ·: A-NH 0 51 111942 where L1 is a leaving group, and R1 refers to the same, as above, and at the product is converted to its site. 8. α-Halogenopropionamide compound of formula [II] Characterized in that the ring B, X, Y and Z are defined as in claim 1 and L ° is a halogen atom, or its site. A compound according to claim 8, characterized in that the ring B is a benzene ring which may be substituted by 1-4 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group and a phenyl group which may be substituted by a lower alkyl group, lower alkoxy group, halogen atom or alternatively protected amino group, Y is an oxygen atom or sulfur atom, methylene group or imino group which can be substituted by a lower alkyl group, acyl group or aralkyloxycarbonyl group, and Z is a methylene group which may be substituted by one or two group 20 selected from a C3-7 alkylene group, C1-20 alkyl group, Q.? in addition, cycloalkyl group, phenyl group (said alkylene group, alkyl group, cycloalkyl group and phenyl group may be * ': substituted by a lower alkyl group, lower alkoxy group, halogen atom or alternatively a protected amino group), phenyl lower alkyl group (said phenyl group may be' ': substituted by a lower alkyl group, lower alkoxy group, halogen atom or alternatively a protected amino group), or a 4-7 membered heterocyclic group comprising an oxygen atom, nitrogen atom, sulfur atom or hetero atom, which may be alternative sub- • I · 4. I> »ä ·; t i t I 1 »· · i ·