KR820001604B1 - Process for preparing cephalosporin analogs - Google Patents

Abstract

Cephalosporin analogs(I; R1 = H, hydroxy, lower alkoxy, aryl oxy, aralkuloxy,acyloxy, sulfonyloxy, lower alkylthio,arylthio, aralkylthio, lower alkyl sulfinyl, arylsuifinyl, aralkylsulfinyl; R2 = R1, lower alkyl, halogen substituted lower alkyl, azido, nitryl; R3 = H , alkyl, aryl, aralkyl; X1 = azido), having antibacterial activity, were prepd, by substituting X1 group and C00R3 of compd.(II) to the amino and COOH resp. Thus, intermediate (±)cis-2-t-butyloxycarbonyl-7-azi-do-l-azabicyclo≮4,2,0≉-oct-2-en-8-one 55mg was dissolved in the trifluoro acetic acid 2 ml, aged 10 min, condensed under the reduced pressure, benzene was added and then condensed again to give compd.(I; X =N3 ; R1,R2,R3 = H) 51mg.

Description

Method for producing cephalosporin flexible

The present invention relates to a novel cephalosporin flexible body of formula (I) and a process for the preparation thereof.

Wherein X is an amino group, an azido group or a phthalylimino group,

R₄R(식중 R₄및 R₄는 서로 동일하거나 또는 상이해도 좋은 것으로 저급알킬기, 아릴기 또는 아랄킬기임)으로 표시되는 술포늄기, 저급알킬술포닐기, 아릴술포닐기, 아랄알술포닐기, 일반식 N

R₆,R₇R₈(식중 R₆R₇및 R₈은 서로 동일하거나 또는 상이해도 좋은 것으로 저급알킬기, 아릴기 또는 아랄킬기임)으로 표시되는 사급 암모늄기, 아릴셀레닐기 또는 아릴셀레니닐기이고,R 'is a hydrogen atom, halogen atom, hydroxy group, lower alkoxy group, aryloxy group, aralkyl, oxy group, acyloxy group, sulfonyloxy group, lower alkyloxy group, arylthio group, arylalkylthio group, lower group, Arylsulfinyl, aralkylsulfinyl, general formula-S

A sulfonium group, a lower alkylsulfonyl group, an arylsulfonyl group, an aralsulfonyl group represented by RR (wherein R 'and R' may be the same or different from each other and may be a lower alkyl group, an aryl group or an aralkyl group)

A quaternary ammonium group, an arylselenyl group or an arylseleninyl group represented by R ₆ , R ₇ R ₈ (wherein R ₆ R ₇ and R ₈ may be the same or different from each other and may be a lower alkyl group, an aryl group or an aralkyl group); ,

R ₂ has the same meaning as that of R ₁ or lower alkyl group, halogen substituted lower alkyl group, azido group, nitrile group or general formula NR ₉₁₀ (wherein R ₉ and R ₁₀ may be the same as or different from each other. An atom, a lower alkyl, an aryl or an aralkyl group)

R ₃ is a hydrogen atom, a substituted or unsubstituted alkyl, aryl, aralkyl or silyl group.

That is, this invention relates to the novel cephalosporin flexible body of the following general formula (I-1) and the following general formula (I-2), and its manufacturing method.

Wherein X ₁ is an azido group or phthalylimino group, and R _1, R ₂ and R ₃ are as described above.

The cephalosporin flexible of formula (I), ie the carbacefem compound, whose name is taken from those described in U.S. Patent Application Publication Nos. 96,7584 (1974) and 20,551 (1977), are described in detail below. do.

For reference, carbacefem substituted with a methyl group in the third position. For example, it is known that (±) -1-carbacephalotin represented by the following general formula has antibacterial activity.

R <_1> and R <_2> of general formula (I) are demonstrated concretely below. Halogen atoms are fluorine, chlorine, cancelled or oxo.

As a lower alcohol group, the alkoxy group which has 1-5 carbon atoms, for example, a methoxy group, an ethoxy group, a linear or branched propoxy group, butoxy group, etc. are mentioned. As an aryloxy group, the phenoxy group or the phenoxy group which has substituents, such as a methyl group, a methoxy group, a nitro group, in an ortho, meta, or para position, etc. are mentioned.

Examples of the aralkyloxy group include aralkyloxy groups having 7-10 carbon atoms, for example, benzyloxy group and phenethyloxy group. Substituted or unsubstituted acyloxy groups having 1-5 carbon atoms, for example, a benzo group such as acetoxy group, propionyloxy group, trifluoroacetoxy group, or methyl group, methoxy group at ortho, meta or para position, Benzo group which has substituents, such as a nitro group, etc. are mentioned.

Examples of the oxy group include alkylsulfonyloxy groups having 1-5 carbon atoms such as methyl group, ethyl group, propyl group, butyl group and the like or aryl sulfonyloxy groups having 6-8 carbon atoms such as benzenesulfonyloxy group and toluenesulfonyloxy group Can be mentioned. Examples of the lower alkylthio group include alkylthio groups having 1-5 carbon atoms such as methyl group, ethyl group, linear or branched propyl group or butyl group. As an arylthio group, the arylthio group which has 6-10 carbon atoms, for example, a phenylthio group, a methoxyphenylthio group, a tolylthio group, etc. are mentioned. Examples of the aralkylthio group include aralkylthio groups having 7-10 carbon atoms, for example, benzylthio group, methoxybenzylthio group, and phenethylthio group.

The sulfoxide corresponding to the lower alkylthio group, arylthio group, and aralkylthio group mentioned above is mentioned as a lower alkyl sulfinyl group, an aryl sulfinyl group, and an aralkyl sulfinyl group.

Examples of the lower alkylsulfonyl group, arylsulfonyl group, and aralkylsulfonyl group include sulfones corresponding to the lower alkylthio group, arylthio group, and aralkylthio group.

As an aryl seleninyl group, the selenium oxide corresponding to said aryl selenyl group is mentioned.

As a lower alkyl group, the alkyl group which has 1-5 carbon atoms, for example, a methyl group, an ethyl group, a linear or branched propyl group, or a butyl group etc. can be mentioned.

Examples of the halogen-substituted lower alkyl group include lower alkyl groups substituted with fluorine, chlorine, cancellation, or oxo.

As an aryl group, the aryl group which has 6-10 carbon atoms with or without a phenyl group or a substituent, such as a methyl group, a methoxy group, a nitro group, in an ortho, meta, or para position, etc. are mentioned.

Examples of the aralkyl group include aralkyl groups having 7-15 carbon atoms, such as benzyl, phenethyl and methoxybenzyl.

As an ester group represented as -COOR _3, a deulsu the esters commonly used in the field of synthetic chemistry of penicillins or cephalosporins. This ester is suitably selected from the group which can be easily converted to a carboxyl group without degrading the substituents and functional groups of carbacepem under suitable conditions.

As esters, esters having the following R ₃ groups, that is, allyl groups having 1-5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, etc. , Halogenated alkyl groups having 1-5 carbon atoms such as chloromethyl group, 2,2,2-trichloroethyl group, 2,2,2-trifluoroethyl group, benzyl group, diphenylmethyl group, triphenylmethyl group, etc. Arylmethyl groups having 20 carbon atoms, 7-20 carbon atoms, and arylmethyl groups having a methoxy group, a nitro group and the like in the phenyl ring, and substituted silyl groups such as trimethylsilyl group and triphenylsilyl group.

The manufacturing method of the compound of general formula (I) is described below. Then, general formulas (I) and (II). The compounds of formula (I) and (II). It is called.

The manufacturing method of the compound of general formula (I) is described below. Hereinafter, compounds of the general formulas (I) and (II) ... are referred to as compounds (I) and (II) ..., respectively.

Compound (I) may be prepared by methods I-VIII described below, i.e. compound (I-1) is prepared by methods I, II, III, IV, V, VI and or VII, and compound (I-2) ) Is prepared by methods VII and or VIII.

(1) Method I

In general formula (I), X is an azido group or a phthalylimino group, R <_1> is a hydrogen atom, R <_2> is a hydrogen atom or a lower alkyl group, R <_3> is a substituted or unsubstituted alkyl, aryl, or aralkyl group ( la) can be prepared by the method shown in the reaction flowchart (I) below.

Reaction Process Chart I

In the compound of reaction process diagram I, X ₁ is an azido group or a phthalylimino group, R ₂₁ is a hydrogen atom or a lower alkyl group, R ₃₁ is a substituted or unsubstituted alkyl, aryl or aralkyl group, X ₁ CH ₂ COOH The reactive derivative of is an acid halide, an acid anhydride, a mixed acid anhydride of X ₁ CH ₂ COOH or a functional derivative thereof, and R is a lower alkyl group.

Compound (II), a starting compound, is known and is synthesized by the Klyzen potential of substituted allylvinyl ether of CH ₂ = CHO-CH ₂ = CH-R ₂₁ (wherein R ₂₁ is as described above). See Volume 22, Page 1 (1975) and Journal of the Chemical Society, page 4092 (1961).]

Compound (III), which is a known compound, can be produced by the method described in German Patent Publication No. 2365456. Moreover, compound (III) of general formula (III) whose R <_31> is t-butyl can be manufactured by the method of reducing the oxime obtained by nitrosing dialkylphosphonoacetate by the conventional method.

The reaction shown in the reaction flow chart (I) can be carried out under known reaction conditions that can be used to perform each reaction. Reaction of each process is demonstrated concretely below.

Process 1

Compounds of the following general formula (IV) are prepared by dehydrating compounds (II) and (III).

Where

R, R ₂₁ and R ₃₁ are as described above.

This concentrated reaction is usually performed in a nonaqueous solvent that does not affect the reaction.

Compound (II) is preferably used in an amount of 1-2 equivalents based on compound (III). As a solvent, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and tichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as n-hexane, cyclohexane, petroleum ether and ligroin, diethyl ether and tetrahydrofuran And ethers such as methylmethyl cellosolve, esters such as methyl acetate and ethyl acetate, amides such as dimethylacetoamide, dimethylformamide, acetonitrile, dimethyl sulfoxide, hexamethylphosphoryltriamide, and mixtures thereof. Suitable. Since this reaction by-produces water as a by-product, it is suitable to use the solvent in anhydrous conditions. It is also preferable to increase the yield of the target compound by reacting while removing water. The dehydration reaction is preferably carried out by 1) passing the reaction solution through a column filled with the above dehydrating agent in the presence of a suitable dehydrating agent such as molecular sieve, anhydrous magnesium sulfate, sodium sulfate or 3) by azeotropic distillation of the formed water.

The reaction is suitably carried out while cooling or heating under reflux, ie, for 30 minutes-5 hours at a temperature of -20 to 50 ° C.

After completion of the reaction, the reaction mixture can be used on its own or after the solids have been filtered off for the next reaction. The filtrate can also be concentrated under reduced pressure and the solvent of the concentrate is removed under reduced pressure before the residue can be used for the next reaction.

Process 2

Compound (VI) of the following general formula (VI) reacts the compound (IV) obtained in step 1 with a reactive derivative represented by X ₁ CH ₂ CO ₂ H of general formula (V) in the presence of a base in a non-aqueous solvent. It can be obtained by obtaining a lactam ring.

Where

X ₁ , R, R ₂₁ and R ₃₁ are as described above.

As the reaction derivative, acid halides, acid anhydrides, mixed acid anhydrides, active esters and the like can be used.

This reaction is carried out by slowly adding a solution containing compound (V) or compound (V) to a solution containing compound (IV) and a base. This reaction is performed by adding a base or a solution containing the base to a solution containing the compound (IV) and the compound (V).

As the base, organic bases such as triethylamine, N-methylmorpholine and pyridine can be used. Base and compound (V) are used in the same amount or in excess, suitably 1-2 equivalents, relative to compound (IV).

As the solvent, a solvent which does not affect the reaction, and suitably a solvent used in the base 1 is used.

This reaction is cooled or heated under reflux and is generally carried out at -20 to 50 DEG C for 1 to 7 hours for conjugation.

Base and compound (V) are added within 30 minutes-5 hours. The reaction is continued for 15 minutes-2 hours after addition.

After completion of the reaction, isolation of the desired compound is carried out in a conventional manner, for example, the reaction solution is washed successively in the order of acid, alkali and water, or in the reverse order, followed by dehydration, and the solvent is removed under reduced pressure to obtain a residue. Column chromatography as needed.

Process 3

Compound (VIII) of the following general formula (VIII) may be prepared by oxidizing compound (VI) obtained in Step 2.

Where

X ₁ , R, R ₂₁ and R ₃₁ are as described above.

As the oxidation method, the following four methods can be mentioned.

1) Remieux-Johnson's Method Compound (VIII) is prepared by oxidatively cleaving the double bond of compound (VIII) with osmium tetraoxide and sodium periodate in a solvent.

In the reaction, osmium tetraoxide is 0.005-0.5 molar equivalents relative to compound (VI). Preferably, it is used in 0.01-0.1 molar equivalents, and sodium periodate is used in 1-5 molar equivalents, suitably 2-3 molar equivalents with respect to compound (VI).

As the solvent, a solvent which does not affect the reaction, suitably a mixed solvent of water and dioxane, tetrahydrofuran, acetone, ether, methanol or acetic acid, and the like are used.

The reaction is generally carried out at 0-50 ° C. for 30 minutes-2 hours.

2) Lemieux-Von Rudloff's Method

Compound (VIII) is prepared by oxidatively cleaving the double bond of compound (VI) with sodium periodate and potassium permanganate.

In this reaction, sodium periodate is 1-10 molar equivalents to compound VI, suitably 2-4 molar equivalents, and potassium permanganate 0.01-0.5 molar equivalents to compound VI, suitably It is used at 0.05-0.3 molar equivalent.

It is preferable to use the same solvent as that used in the method 1) as the solvent. The reaction is generally carried out at 0-50 ° C., suitably 5-25 ° C. for 30 minutes-48 hours, suitably 2-12 hours.

3) ozone method

Compound (VIII) can be prepared from compound (VI) by using ozone, i.e., compound (VI) reacts with ozone to convert into its ozonate and decomposes this ozonate to produce compound (VII).

In this reaction, ozone gas was passed through until there was no double bond in compound (VI).

As a solvent, a solvent which does not affect the reaction, suitably ethyl acetate, benzene, chloroform, methylene chloride, methanol, ethanol, acetic acid, etc. may be used alone or in combination.

The reaction is generally carried out at -80 to 0 DEG C, -80 to 40 DEG C, dropwise for several minutes to several hours.

The ozone formed was decomposed into zinc-acetic acid, dimethyl sulfide, potassium iodide and stannous chloride to obtain compound (VIII).

Reactants are generally used in excess.

4) Dior method

Compound (VII) may be prepared via conventional methods such as sodium periodate and aqueous sulfuric acid solution via the diol compound, ie compound (VI ′) of general formula (VI ′).

In the above formula

X ₁ , R, R ₂₁ and R ₃₁ are as described above.

The diol compound, i.e. compound (VI '), can be produced by a conventional method for synthesizing a diol compound from an olefin compound.

As a typical example, a method of treating an olefin compound with osmium tetraoxide and chloride is used. In the reaction, osmium tetraoxide is used at 0.05-0.5 molar equivalents, preferably 0.01-0.1 molar equivalents, relative to compound (VI), and chlorate is 1-5 molar equivalents, preferably 2, relative to compound (VI). Use at -3 molar equivalents. As the chlorate, it is preferable to use sodium chlorate, calcium chlorate, chloric acid or barium chlorate.

As a solvent, a solvent which does not affect the reaction, for example, a mixed solvent of water and dioxane, tetrahydrofuran, ether, ethanol and the like are used. The reaction is carried out at 0-80 ° C., preferably at 10-50 ° C. for 1-48 hours, preferably 10-20 hours.

Diol compounds, ie compounds (VI '), can also be prepared via epoxy compounds. As the epoxidation agent, an epoxidation agent which does not affect other functional groups, preferably organic peracids such as metachloroperbenzoate and per acetate is used. The obtained epoxy compound is converted into a diol compound by a known method.

Process 4

Compound (Ia) of the general formula (Ia) is prepared by cyclization of compound (VII) obtained in Step 3 by condensation reaction in the presence of a base in a nonaqueous solvent.

Where

X ₁ , R ₂₁ and R ₃₁ are as described above.

This reaction is generally referred to as the Horner Wittig reaction described in Organic Reaction Vol. 25, page 73 (1977), published by John Wiley & Sons.

As the base, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate and the like can be used. The base is generally used in 1-1.2 molar equivalents relative to compound (VII).

Solvents that do not affect the reaction as solvents, preferably dimethoxyethane, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoryltriamide, tetrahydrofuran, dioxane, ethyl ether, acetonitrile, benzene, toluene, Ethanol, t-butanol, etc. can be used individually or in mixture.

The reaction is carried out under cooling or heating, for example at 0-50 ° C., preferably at 0-25 ° C. for several minutes.

Isolation of the target compound is carried out by known methods. For example, use the following method. After completion of the reaction, acetic acid is added to the reaction mixture in the same amount or in excess with the base used. After distilling a portion of the solvent, the reaction solution was poured into ice water.

The resulting solution was extracted with a solvent such as ethyl ether, ethyl acetate, benzene, and the extract was concentrated under reduced pressure and then recrystallized or treated with silica gel chromatography.

(2) Method II (Selective Preparation Method of Compound (VII))

Compound (Ia) can also be manufactured by the method described in reaction flowchart (II).

Reaction Flow Chart II

기를 나타낸다.In the compound described in the process diagram (II), X ₁ , R ₂₁ and R ₃₁ are as described above, and R 'is a methyl, ethyl, or -CH (OR') ₂ group.

Group.

CH=CH₂의 치환 알릴비닐에테르를 클라이젠 전위 반응시켜 합성한다(유기반응 제22권, 제1페이지(1975년)). 화합물(IX)로 부터 화합물(X)으로의 변환 반응은 과망간산칼륨으로 처리한 후 과요오드산 나트륨으로 산화적으로 개열하는 방법으로 수행될 수 있다. 반응 공정도(II)에 나타낸 각 반응은 각 만족하는, 공지의 반응조건에 따라 수행될 수 있다.Compound (VIII) is a known compound, generally R ₂₁ -CH = CH-O-CH ₂

Substituted allylvinyl ether of CH = CH ₂ is synthesized by kreisen rearrangement (organic reaction volume 22, page 1 (1975)). The conversion reaction from compound (IX) to compound (X) can be carried out by treating with potassium permanganate and then oxidatively cleaving with sodium periodate. Each reaction shown in the reaction flowchart (II) can be carried out according to known reaction conditions, each satisfying.

Reaction of each process is demonstrated concretely below.

Process 5

Compound (IX) of the following general formula (IX) is a compound (VIII) represented by the general formula (VIII) in the presence of an acid and a dehydrating agent and R'OH (wherein R 'has the same meaning as described above) Can be prepared by reaction.

CH ₂ = CH'CH ₂ CH (R ₂₁ ) CH (OR ') ₂ (IX)

CH ₂ = CHCH ₂ CH (R ₂₁ ) CHO (VIII)

Where

R 'and R ₂₁ are as described above.

As the acid, hydrochloric acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, borontrifluoride ethyl etherate, carboxylic acid, phosphoric acid and the like can be used. This acid is used in catalytic amounts. Calcium chloride, molecular sieves, magnesium sulfate, etc. can be used as a dehydrating agent. Alcohol recipe used in the reaction, methanol, ethanol, ethylene glycol and the like are used.

As the solvent, a solvent which does not affect the reaction, preferably benzene, toluene, xylene or the like is used. The reaction is carried out for 1-24 hours while heating under silol or reflux. Separation of the target compound is carried out by a known method.

Process 6

Compound (X) of the following general formula (X) can be prepared from compound (IX) obtained in step 5 by a method similar to that described in step 3 of method 1.

OHC-CH ₂ -CH (R ₂₁ ) -CH (OR ') ₂

Where

R ₂₁ and R 'are as described above.

Process 7

Compound (XI) of formula (XI) below may be prepared from compound (X) and chemical (III) obtained in step 6 in a similar manner as described in process 1 of process I.

Where

R ₂₁ , R ′, R and R ₃₁ are as described above.

Process 8

Compound (XII) of the general formula (XII) can be prepared from compound (XIII) and compound (V) obtained in step 7 by a method similar to that described in step 2 of method I.

Where

X ₁ , R ₂₁ , R ', R and R ₃₁ are as described above.

Process 9

Compound (VII) of the following general formula (VII) may be prepared by deacetalization of compound (XIII) obtained in step 8.

Where

X ₁ , R ₂₁ , R and R ₃₁ are as described above.

Deacetalization, comprising: 1) hydrolyzing compound (XII) with acid in a solvent such as water or a mixture of water and an organic solvent, 2) carbonyl compound and acetyl in the presence of a catalytic amount of acid in a solvent The method of making an exchange reaction is mentioned.

As the acid used in the above method, hydrochloric acid, sulfuric acid, p-toluene sulfonic acid, phosphoric acid, acetic acid, boron trifluoride etherate and the like can be used. As the solvent used for the acetyl exchange reaction, hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters and the like can be used. Moreover, a carbonyl compound can be used as a solvent.

In this reaction, it is preferable to use acetone as the solvent and the carbonyl compound. The reaction is carried out for several minutes at room temperature or at a high temperature, for example at the reflux temperature of the solvent used.

Process 10

The reaction of step 10 is carried out in a similar manner as described for step 4 of method I.

(3) method

In general formula (I), X is an azido group or a phthalylimino group, R <_1> is a lower alkylthio group, an arylthio group, an arylthio group, or an aryl seleno group, R <_2> is a hydrogen atom, R <_3> is substituted or Compound (Ib) which is an unsubstituted alkyl group, an aryl group or an aralkyl group can be produced by the method described in Reaction Process Diagram III.

In the compounds described in Reaction Process Diagram III, X ₁ , R ₃₁ and R ′ are as described above, and R ₁₁ represents a lower alkylthio group, arylthio group, aralkylthio group or arylseleno group.

Compound (XIII), which is a known compound, can be synthesized by known methods (e.g., Izvestiia Akademii Nauk USSR, page 2189, 1962).

Reaction described in reaction process diagram III can be performed on well-known reaction conditions which can be used to perform each reaction. Reaction of each process is demonstrated concretely below.

Process 11

Compound (XIV) of formula (XIV) is prepared in a manner similar to that described in process 1 of process I and process 7 of process II, wherein formula (XII) OHC.CH = CH.CH (OR ′) ₂ (where R is 'Can be prepared from compound (XIII)).

X ₁ , R, R ₁₁ and R ₃₁ are as described above.

This addition reaction is carried out in the presence of a base in a solvent.

As a solvent, it is suitable to use a solvent which does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene, alcohols such as methanol and ethanol, ethers such as dimethyl cellosolve and tetrahydrofuran.

As the base, sodium hydride, butyllithium, piperidine, pyrrolidine and the like can be used. When using sodium hydride or butyllithium as a base, the reaction is carried out at a temperature of -70 to -40 ° C, and the compound of the general formula R ₁₁ H is used in 2-5 equivalents to compound (XVI), and the base is a compound Used in 1-1.2 equivalents to (XVI).

When using an amine such as piperidine or pyrrolidine as the base, the reaction is carried out at room temperature or at a high temperature, and the compound of the general formula R ₁₁ H is used in the same amount or slightly in excess with respect to the compound (XVI), It is enough to use about the catalytic amount. This reaction is carried out for 1-3 hours to obtain compound (XVI).

Process 15

Compound (Ib) of the following general formula (Ib) may be prepared by condensation reaction of compound (XVI) obtained in step 14 to cyclize.

In the above formula,

X ₁ , R ₁₁ and R ₃₁ are as described above.

This ring formation is carried out in a manner similar to that described in Step 4 of Method I and Step 10 of Method II.

(4) Method IV

In the general formula (I), X and R ₃ are as described above, R ₁ is a hydrogen atom, and R ₂ is a halogen atom such as chloro, bromo and iodo, and the compound (Ic) is a general formula (Ia) as a raw material. using the compound (la ') R ₂₁ is H in the reaction process also can be produced in the method described in IV.

In the compounds described in Reaction Process Diagram IV, R ₃ is as described above and R ₂₂ represents a halogen atom such as chloro, bromo or iodine.

Compound (la ') which is a raw material compound is compound (la) wherein R ₂₁ is H in general formula (la).

Halogenation generally uses halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride as solvents, and aryl such as N-halosuccinimide, N-haloacetamide and pyrrolidone hydrotribromide at room temperature or the reflux temperature of the solvent used. Halogenation of methylene is carried out using the halogenating agent used. The yield is good when a reaction initiator such as perbenzoic acid or azobisisobutyronitrile is added during the reaction.

Where

R ', R and R ₃₁ are as described above.

Process 12

Compound (XV) of the following general formula (XV) can be prepared from compound (XIV) compound (XV) obtained in step 11 by a method analogous to that described in step 2 of method I and step 8 of method II.

Where

X ₁ , R ', R and R ₃₁ are as described above.

Process 13

Compound (XVI) of the following general formula (XVI) can be prepared by deacetalization of compound (XV) obtained in step 12.

Where

X ₁ , R and R ₃₁ are as described above.

This deacetylation can be carried out by a method similar to that described in Step 9 of Method II. Acetalization in this step can be carried out more easily than the acetalization of step 9 of Method II. More preferably, deacetalization is carried out in acetone at room temperature in the presence of P-toluene sulfonic acid.

Process 14

Compound (XVII) of the general formula (XVII) is represented by compound (XVI) obtained in step 13 and general formula R ₁₁ H (wherein R ₁₁ represents a lower alkylthio, arylthio, aralkylthio or arylseleno group) It can manufacture by addition reaction between the compound shown.

Where

(5) Method V

In the compound (Id) of formula (Id), i.e., in formula (I), X and R ₃ are as described above, R ₁ is a hydrogen atom, R ₂ is a fluoro, hydroxyl group, dalkyl group, acyl The compound which is an oxy group, an alkoxy group, an aryloxy group, an aralkyloxy group, an alkylthio group, an arylthio group, an aralkylthio group, a pri-, sec- or t-amino group, an azido group, or a nitrile group is a raw compound. The reaction process can also be manufactured by the method as described in V using (Ic).

In the compound described in the reaction process diagram V, X ₁ , R ₂₂ and R ₃ are as described above, and R ₂₃ is a fluoro, hydroxyl group, alkyl group, acyloxy group, alkoxy group. Aryloxy group, aralkyloxy group, alkylthio group, arylthio group, aralkylthio group, pri-, sec- or t-amino group, azido group or nitrile group.

In this reaction, compound (Id) can be prepared by substituting a nucleophilic group R ₂₃ for a halogen atom of compound (Ic).

(6) Method IV

In formula (I), R ₃ is as described above, X is an azido or phthalylimino group, R ₂ is a hydrogen atom, R ₁ is an alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group or aryl A compound of formula (Ie) representing a selenyl group, or X ₁ in formula (Ie) is as described above, R ₁₂ is a lower alkyl, aryl or aralkyl group, and Y represents a sulfur atom or a selenium atom. Compound (Ie) is a starting compound as described above in formula (I), wherein X ₁ is as described above, R ₂ is a hydrogen atom, and R ₁ is YR ₁₂ (where Y and R ₁₂ are as described above). Or a compound represented by the formula (Ib), wherein X ₁ is as described above, R ₃₁ is R ₃ , and R ₁₁ is YR ₁₂ (where Y and R ₁₂ are as described above). ) Can be produced by the method described in IV as follows.

In the compounds described in Reaction Flow Chart IV, X ₁ , R ₃ and R ₁₂ are as described above.

As the oxidizing agent, organic peroxides such as periodioic acid or salts thereof, organic peroxides such as hard peroxide, metachlorobenzoic acid or chloro-gold acid are used.

(7) Method VII

The compound (If) in which R ₃ represents a hydrogen atom in general formula (I) is obtained by the method described in the reaction process diagram VII using the compound (I ') in which R ₃ represents R ₃₁ in general formula (I) as a raw material. It can manufacture.

In the compounds described in the reaction process diagram VII, X ₁ , R ₁ , R ₂ and R ₃₁ are as described above.

This reaction can be carried out using a known method commonly used in the field of synthesizing penicillin or cephalosporin. In this reaction, the compound (If) can be prepared by selecting appropriate reaction conditions and reactants to avoid degradation of substituents of the carbacepem molecule or the reaction group.

A reaction for converting a -COOR ₃₁ group to a -COOH group, comprising: 1) catalytic reduction method 2) acid decomposition method 3) cleavage reaction method using Lewis acid 4) hydrolysis method 5) reduction method other than catalytic reduction using a reducing agent and 6) estera The method of using an agent, etc. are mentioned. Each method is demonstrated concretely below.

1) Catalytic Reduction Method

COOR ₃₁ is converted to a COOH group in the presence of a catalyst in a hydrogen atmosphere in an inert solvent. As the solvent, it is preferable to use a solvent which does not affect the reaction, for example, alcohol, tane water, tetrahydrofuran, dioxane, ethyl acetate, acetic acid, or the like, alone or in combination.

As the catalyst, palladium / carbon, platinum oxide, palladium / calcium carbonate and Raani nickel can be used. This reaction is generally carried out at 1-50 atm and 0-100 ° C., preferably at atmospheric pressure and room temperature.

This method is preferably used when R ₃₁ is a benzyl group, P-nitrobenzyl group, nitrobenzyl group, diphenylmethyl group, P-methoxybenzyl group or the like.

When X is an azido group, the azido group can be reduced to an amino group when R ₃₁ is converted to a hydrogen atom by catalytic reduction. The resulting compound having an amino group is also a target compound of the present invention.

2) acid decomposition

The COOR ₃₁ group is converted to a COOH group using an acid in an inert solvent. As the acid, hydrogen chloride, P-toluenesulfonic acid, trifluoroacetic acid and the like are used. As the solvent, a solvent which does not affect the reaction, for example, ethyl acetate, benzene, ethanol, acetic acid, dioxane, methylene chloride, chloroform or the like is used alone or in combination.

The reaction is carried out at −15 to 50 ° C., and preferably at 0-25 ° C. for 10 minutes-5 hours, preferably 30 minutes-3 hours. This method is preferably used when R ₃₁ is a t-butyl group, a trityl group or the like.

3) Series reaction method using Lewis acid

The COOR ₃₁ group is converted to the COOH group by cleavage in the presence of Lewis acid in an inert solvent. As the solvent, it is preferable to use a solvent which does not affect the reaction, for example, a mixture of nitroalkane such as nitromethane and methylene haloalkane chloride. As the Lewis acid, aluminum chloride, boron trifluoride, titanium tetrachloride, tin tetrachloride and the like can be used. The acid is used in 1.0-1.5 molar equivalents relative to compound (I '). The reaction is preferably carried out in the presence of a reagent that generates a carbonium cation such as an azole. The reaction is carried out at 0-50 ° C., preferably at room temperature for 1-10 hours.

This method is preferably performed when R ₃₁ is a P-nitrobenzyl group or the like.

4) Hydrolysis

COOR ₃₁ groups are converted to COOH groups by hydrolysis in the presence of an acid or alkali in an inert solvent. As the acid, P-toluene sulfonic acid, hydrochloric acid, acetic acid and the like can be used. As the solvent, it is preferable to use a solvent which does not affect the reaction, for example, a 2% methanol aqueous solution, N, N-dimethylformamide, acetic acid-water-tetrahydrofuran, or the like. This reaction is carried out at 0-50 ° C., preferably 15-25 ° C. for 10 minutes-2 hours.

This method using an acid is preferably carried out when R ₃₁ is a t-butyldimethylsilyl group.

As the alkali, calcium carbonate is preferably used in 1-6 molar equivalents with respect to compound (I '). As the solvent, it is preferable to use a solvent which does not affect the reaction, for example, tetrahydrofuran / water, dioxane / water, acetone / water and the like. The reaction is generally carried out at 0-30 ° C. for 30 minutes to 24 hours.

This method using alkali is preferably carried out when R ₃₁ is a methyl group, an ethyl group or the like.

5) Reduction method using a reducing agent (methods other than the catalytic reduction method)

COOR ₃₁ groups are converted to COOH groups by reduction in an inert solvent. As the reduction method, a method using zinc / acid can be used. As the solvent, acetone, water, dioxane, tetrahydrofuran, ethanol, acetonitrile, N, N-dimethylformamide and acetic acid are used alone or in combination. As the acid, hydrochloric acid or acetic acid is used. This reaction is carried out at 0-100 占 폚, preferably 0-40 占 폚 for 1-10 hours. Zinc used in the reaction is usually used in 1-10 molar equivalents.

This method is preferably performed when R ₃₁ is a 2,2,2-trichloroethyl group or the like.

(8) Method VIII

Compound (Ih) in which X represents NH ₂ in formula (I) may be prepared by the following reaction process diagram VIII using compound (Ig) in which X represents N ₃ in formula (I) as a raw material. have.

This reaction can be carried out using known methods commonly used in the art of penicillin or cephalosporin synthesis. In the reaction, compound (I) may be prepared by selecting appropriate reaction conditions and reactants to avoid degradation of substituents or functional groups of the carbacepemmo molecule.

As a reduction method, 1) a catalyst reduction method, 2) a reduction method using hydrogen sulfide and tertiary amine, 3) a reduction method using sodium borohydride, 4) a reduction method using zinc-acid, and 5) a first chromium chloride It is preferable to use the reduction method. These reduction methods are specifically explained below.

1) Catalyst Reduction Act

Compound (Ig) was catalytically reduced in a hydrogen stream in the presence of a catalyst in an inert solvent to obtain compound (I-2). As the solvent, for example, ethanol, water, tetrahydrofuran, dioxane, ethyl acetate, acetic acid or mixtures thereof can be used as the solvent that does not affect the reaction. As the catalyst, palladium / carbon, platinum oxide, palladium / potassium carbonate and raninickel may be used.

The reaction is generally carried out at 0-100 ° C., preferably at room temperature at 1-50 atm, preferably at atmospheric pressure.

In this reaction, when R ₃ is a raw material of a compound of formula (Ig), which is a substituted arylmethyl group such as benzyl group, paramethoxybenzyl group, paranitro benzyl group, benzhydryl group, trityl group, etc., R ₃ is Compounds of the general formula (Ih) which are hydrogen atoms can also be obtained.

2) Hydrogen Sulfide-Reduction Method Using Tertiary Army

Compound (Ig) was reduced with hydrogen sulfide and tertiary amine in the presence of an inert solvent base to give compound (I-2). As the solvent, methylene chloride, chloroform and the like are used alone or in combination. As the base, triethylamine, pyridine and the like can be used. This reaction is carried out at 0-50 ° C, preferably at room temperature.

3) Reduction method using sodium borohydride

Compound (Ig) was reduced with sodium borohydride in an inert solvent to obtain compound (I-2). As the solvent, methanol, ethanol, dioxane, tetrahydrofuran and the like are used alone or in combination. Sodium borohydride is used in one equivalent or excess. The reaction is carried out at 0-100 占 폚, preferably at 10-50 占 폚.

4) Reduction method using zinc / acid

Compound (Ig) was reduced with zinc / acid in an inert solvent to give compound (I-2). As the solvent, acetone, water, dioxane, tetrahydrofuran, ethanol, acetic acid and the like are used alone or in combination. As the acid, hydrochloric acid or acetic acid can be used. Zinc and acid are used in one equivalent or excess. The reaction is carried out at 0-100 占 폚, usually at room temperature to 60 占 폚.

5) Reduction Method Using Chromium (II) Chloride

Compound (Ig) was reduced to chromium (II) chloride in the presence of acid in an inert solvent. The acid solvent and reaction conditions are the same as those used in 4).

Compounds of interest of the invention, represented by formula (I) and prepared by process (I) (VIII), are useful as intermediates for preparing carbacephalosporins having a skeleton similar to cephalosporins. The azido group and phthalylimino group of compound (I) were converted into an amino group, and compound (Ih) of general formula (I) in which X represents NH ₂ was prepared.

Compound (Ih) is further converted to a compound of the following general formula.

Where

Z is an acyl group, and R ₁ , R ₂ and R ₃ are as described above.

Common acyl groups used in the synthesis of penicillin and cephalosporins were introduced into amino groups to obtain cephalosporin analogs with strong antimicrobial activity (see Reference Example below).

As salts (cephalosporin analogs) of compound (I), salts of inorganic or organic acids such as hydrogen chloride, sulfate, phosphate, formate, malate of compound (Ih) in which X represents NH ₂ in formula (I) And salts of inorganic or organic bases such as sodium salts, potassium salts, calcium salts and organic amine salts of carboxylic acids of the compound (If) in which R ₃ represents a hydrogen atom in general formula (I).

Example 1

(±) -cis-2-t-butyloxycarbonyl-7-azido-1-azabisaaclo [4,2,0] oct-2-en-one {X ₁ in General Formula (I) N ₃ , R ₁ and R ₂ are hydrogen atoms, R ₃ is t-butyl, and in the general formula (Ia), X ₁ is N ₃ , R ₂₁ is hydrogen atom, R ₃₁ is t-butyl Preparation of cis compound}

This compound can be prepared by the following methods 1) and 2). Cis and trans refer to stereoisomers at the 3 or 4 position of the 2-azetidinone ring or at the 6 or 7 position of the 1-azabicyclo [4,2,0] octane ring.

1) 2- [4- (3-butenyl) -3-azido-2-oxo-azetidin-1-yl] -2-diethylphospho acetate-t-butylester {in formula (VI) Preparation of the compound wherein X <_1> is N <_3> , R <_21> is a hydrogen atom and R <_31> is t-butyl.

In this example, t-butyl-α-aminodiethylphosphonoacetate {in Formula (III), R ₃₁ is t-butyl, R is ethyl, and has the following physical properties. Oily substance;

, 1735-1745, 1020-1060; NMR(CDCL₃)δ(ppm), 4.20(d-q,4H), 3.83(d,1H,J=20Hz), 1.76(br,2H), 1.50(s,9H), 1.35(t.6H) Mass(m/e) : 268(M⁺)} 447mg(1.78밀리몰)을 무수에테르 25ml중에 용해시키고, 4-펜텐-1-알 164mg(1.96밀리몰)을 이용액에 부가했다. 이 용액을 실온에서 1시간 동안 교반시키고, 이 용액에 분자체(4A)(와꼬쥰야꾸 회사제, 이후 분자체라고 함) 200mg 및 무수황산마그네슘 150mg을 용액에 첨가시켰다.IR (neat)

, 1735-1745, 1020-1060; NMR (CDCL ₃ ) δ (ppm), 4.20 (dq, 4H), 3.83 (d, 1H, J = 20 Hz), 1.76 (br, 2H), 1.50 (s, 9H), 1.35 (t.6H) Mass ( m / e): 268 (M ⁺ )} 447 mg (1.78 mmol) was dissolved in 25 ml of anhydrous ether, and 164 mg (1.96 mmol) of 4-penten-l-al was added to the solution. The solution was stirred at room temperature for 1 hour, and 200 mg of molecular sieve 4A (manufactured by Wako Pure Chemical Industries, Inc., molecular sieve) and 150 mg of anhydrous magnesium sulfate were added to the solution.

The mixture was stirred for 1 hour.

C-200, 와꼬쥰 야꾸회사제, 동일한 실리카겔을 다음 실시예와 참고예에서 사용함) 45g을 채운 컬럼에 흡착시키고, 용출제로서 n-헥산 및 초산에틸(1:2용적비, 이후에 원용함)의 혼합물로 용출시켜 2가지 형태의 이성체를 얻었다. 이성체의 물성을 이하에 기재하며, 이것은 3- 및 4- 위치에서 이성체로서 동정되었는데, 즉 시스-이성체 345mg 및 트란스-이성체 58mg을 얻었다. 총수율 54.2%The reaction mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to give a pale yellow oil. Anhydrous benzene was added to this product, and the mixture was concentrated under reduced pressure to give a pale yellow oil. The presence of Schiff bases in the product was confirmed by hex resonance spectra. The product was dissolved in 12.5 ml of cyclohexane, and 12.5 ml of anhydrous benzene, 0.369 ml (2.66 mmol) of triethylamine and 200 mg of molecular sieve 4A were added to this solution. Azido acetylchloride [319 mg (2.66 mmol)] dissolved in 12.5 ml of cyclohexane was added dropwise to the mixture with stirring at room temperature for 1.5 hours. The reaction mixture was further stirred for 30 minutes and diluted in 10 ml of benzene. The reaction solution was washed with 5% dilute hydrochloric acid, saturated sodium bicarbonate solution, deionized water and saturated aqueous sodium chloride solution and concentrated under reduced pressure to then dehydrated over anhydrous sodium sulfate, was obtained a brown oily product, which is X ₁ in the general formula (VI) It was identified as a crude product of the target compound wherein N ₃ , R ₂₁ is a hydrogen atom, and R ₃₁ is t-butyl. This oily substance is silica gel (wako-gel)

C-200, manufactured by Wako Pure Chemical Industries, the same silica gel used in the following examples and reference examples) was adsorbed onto a column filled with 45 g, and n-hexane and ethyl acetate (1: 2 volume ratio, later used) as eluent. Elution with a mixture of gave two forms of isomers. The physical properties of the isomers are described below, which were identified as isomers in the 3- and 4- positions, ie 345 mg cis-isomer and 58 mg trans-isomer. Total yield 54.2%

Cis-isomer

: 2120, 1775, 1770(sh), 1750,1740(sh), 1645.

2120, 1775, 1770 (sh), 1750, 1740 (sh), 1645.

NMR (CDCL ₃ ) δ (ppm): 6.13-6.33 (1H, m), 4.93-5.17 (2H, m), 4.50-4.93 (2H, m), 3.80-4.40 (5H, m), 1.93-2.17 ( 4H, m), 1.50 (9H, s), 1.33 (6H, t).

Trans-isomer

: 2120,1780,1755,1755,1750(sh),1650.IR (CDCl ₃ )

: 2120,1780,1755,1755,1750 (sh), 1650.

NMR (CDCl ₃ ) δ (ppm): 5.43-6.20 (1H, m), 4.80-5.30 (2H, m), 3.75-4.75 (7H, m), 2.0-2.50 (5H, m), 1.50 (9H, d), 1.17 (6H, m).

2) (±) -cis-2-t-butyloxycarbonyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-one {wherein X is general formula (I) The cis-isomer of the compound whose N <_3> , R <_1> and R <_2> is a hydrogen atom and R <_3> is t-butyl}.

Cis-2- [4- (3-butenyl) -3-azido-2-oxoazetidin-1-yl] -2-diethylphosphono obtained in this Example 1-1) 298 mg (0.716 mmol) of acetate-t-butyl ester were dissolved in 8.5 ml of dioxane, and 2.5 ml of deionized water and 30 mg of osmium tetraoxide were added thereto. This solution was stirred for 30 minutes. Sodium periodate powder [496 mg (2.32 mmol)] was added to the black reaction mixture for 20 minutes, stirred for 1.5 hours, and then the reaction solution was extracted three times with 50 ml of ether. The combined ether layers were washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give a dark brown oil. The oil was added to a column filled with 5 g of silica gel, eluted with a solvent of benzene and ethyl acetate (1: 2), and collected and concentrated to give a fraction positive for the 2,4-dinitrophenylhydrazine reaction. Was obtained, which was identified as cis isomer of an aldehyde compound in formula (VII) wherein X ₁ is N ₃ , R ₂₁ is hydrogen atom, and R ₃₁ is t-butyl.

This oily substance was dissolved in 15 ml of anhydrous acetonitrile and 27.1 mg (0.563 mmol) of 50% sodium hydride under nitrogen stream was added while stirring at room temperature. After stirring for 20 minutes, the reaction mixture was poured into 20 ml of 2% aqueous acetic acid solution, the solution was extracted four times with 50 ml of ether, the ether layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give an oil phase. 180 mg of water were obtained. This was identified as a crude product of the cis-isomer of the compound of formula (I) wherein X is N ₃ , R ₁ and R ₂ are hydrogen atoms, and R ₃ is t-butyl. This oily substance was placed in a column filled with 5 g of silica gel, and eluted with a solvent of n-hexane, ethyl acetate (3.5: 1) and volume ratio to obtain white crystals (91 mg) of the target compound. Yield 51%. The physical properties of this compound are as follows.

Melting Point: 64.5-65.6 ℃

: 2130,1790,1730,1640

: 2130,1790,1730,1640

NMR (CDCl ₃ ) δ (ppm): 6.30 (1H, t, J = 4 Hz), 4.93 (1H, d, J = 5 Hz), 3.80 (1H, q), 1.6-2.6 (4H, m), 1.52 ( 9H, s)

Example 2

(±) -trans-2-t-butyloxycarbonyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one {X ₁ in Formula (I) In which N ₃ , R ₁ and R ₂ are hydrogen atoms, R ₃ is t-butyl, X ₁ is N ₃ , R ₂₁ is hydrogen atom, and R ₃₁ is t-butyl in formula (Ia) Preparation of trans-compounds represented by the formula

Trans-2- [4- (3-butenyl) -3-azido-2-oxoazetidin-1-yl] -2-dietalphosphono acetate-t-butyl obtained in Example 1-1) 767 mg (1.84 mmol) of the ester was dissolved in 22 ml of dioxane and 6.5 ml of deionized water, and 100 mg of osmium tetraoxide was added thereto, followed by stirring for 30 minutes. 1.5 g (7.04 mmol) of sodium periodate powder was added to the obtained black reaction mixture within 30 minutes, stirred for 1 hour, and then extracted three times with 150 ml of ether. The ether layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure. Obtained an oil. This oily substance was placed in a column filled with 20 g of silica gel, and eluted with a solvent of benzene and ethyl acetate (1: 2) to obtain an oily substance (561 mg0) from fractions positive for 2,4-dinitrophenylhydrazine reaction. The product was identified in formula (VII) as a trans compound of an aldehyde compound in which the X ₁ group N ₃ was tbutyl, The product was dissolved in 6 ml of anhydrous acetonitrile and 61.4 mg (2.56 mmol) of 50% sodium hydride was added.

The mixture was heated to 50 ° C. and extracted four times with 50 ml of ether. The ether layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oil. The baby product was placed in a column filled with 20 g of silica gel, and eluted with a solvent of n-hexane and ethyl acetate (3.5: 1) to yield white crystals (218 mg) of the target compound. This compound was identified in the general formula (I) at the trans compound of the target compound whose X is N <_3> , R <_1> and R <_2> is a hydrogen atom, and R <_3> is t-butyl. The physical properties of this compound are as follows.

Melting Point: 80.5-81.5 ℃

:2110,1780,1720,1635

: 2110,1780,1720,1635

NMR (CDCl ₃ ) δ (ppm): 6.27 (1H, t), 4.28 (1H, d, J = 2Hz), 3.53 (1H, q), 2.0-2.6 (4H, m), 1,63 (9H, S)

Example 3

(±) -cis-2-carboxy-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one {In Formula (I), X is N ₃ , R ₁ Preparation of cis-compound} wherein R ₂ and R ₃ are hydrogen atoms and X ₁ is N ₃ , R ₂₁ and R ₃₁ are hydrogen atoms in general formula (Ia)

55 mg (0.224) of (±) -cis-2-t-butyloxycarbonyl-7-azido-1-azabisagichloro [4,2,0] oct-2-en-8-one obtained in Example 1 Mmol) was dissolved in 2 ml of trifluoroacetic acid, the solution was left at room temperature for 10 minutes and then concentrated under reduced pressure, again benzene was added and the resulting solution was concentrated under reduced pressure to give 51 mg of a yellow subsolid. The physical properties of the semisolid were as follows, and the semisolid was identified as the desired carboxylic acid. Yield 100%.

: 2120,1770(sh),1760,1715,1635

: 2120,1770 (sh), 1760,1715,1635

NMR (CD ₃ OD) δ (ppm): 6.48 (1H, t, J = 4Hz), 5.10 (1H, d, J = 5Hz), 3.83 (1H, q), 1.1-2.5 (4H, m)

Example 4

(±) -cis-2-t-butyloxycarbonyl-4-bromo-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one In I) X ₁ is N ₃ , R ₁ is a hydrogen atom, R ₂ is bromine, R ₃ is t-butyl, X ₁ is N ₃ , R ₂₂ is bromine, R ₃ in formula (Ic) of Method V Is a t-butyl cis-compound represented by the following general formula}

50 mg (0.203) of (±) -cis-2-t-butyloxycarbonyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one obtained in Example 1 Mmol) was dissolved in 2 ml of anhydrous chloroform, and 36.0 mg (0.202 mmol) of N-bromosuccinimide and azobisisobutyronitrile in a catalytic amount were added thereto. The mixture was heated for 30 minutes with stirring under reflux and then diluted in 5 ml of chloroform. The diluted solution was washed with 3 ml of water and 3 ml of saturated sodium chloride solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 53 mg of an oil.

The product was poured into a column filled with 4.0 g of silica gel, and eluted with a solvent of n-hexane and ethyl acetate (3.5: 1) to obtain an oily substance (23 mg). This product was identified as the target cis-compound having the following physical properties in Formula (Ic), wherein X ₁ is N ₃ , R ₂₂ is bromine, R ₃ is t-butyl. Yield 33%

: 2120,1790,1730,1620.

: 2120,1790,1730,1620.

NMR (CDCL ₃ ) δ (ppm): 6.33 (1H, d, J = 6Hz), 5.07 (1H, d, J = 5Hz), 4.93 (1H, m), 4.50-3.90 (1H, m), 2.50- 1.72 (2H, m), 1.52 (9H, s)

Example 5

(±) -trans-2-t-butyloxycarbonyl-4-bromo-7-azido-1-azabisaaclo [4,20] oct-2-en-8-one {General Formula (I X ₁ is N ₃ , R ₁ is hydrogen atom, R ₂ is bromine, R ₃ is t-butyl, and in formula (Ic) of Method IV, X ₁ is N ₃ , R ₂₂ is bromine, R ₃ is Preparation of trans-compound represented by the following general formula which is t-butyl}

100 mg (0.407 mmol) of (±) -trans-2-t-butyloxycarbonyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one obtained in Example 2 ) Was dissolved in 5 ml of anhydrous carbon tetrachloride, and 72.4 mg of N-bromosuccinimide was added, followed by heating for 30 minutes while stirring under reflux. Thereafter, 10 ml of methylene chloride was added to the reaction mixture, and the resulting mixture was washed with 5 ml of deionized water and 5 ml of saturated aqueous sodium chloride solution. The resulting solution was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give 102 mg of an oil. This oily substance was placed in a column filled with 5 g of silica gel, and eluted with a solvent of n-hexane and ethyl acetate (3.5: 1) to obtain an oily substance (24 mg). This product was identified as general purpose compound (Ic) in which X ₁ is N ₃ , R ₂₂ is bromine, R ₃ is t-butyl, and has the following physical properties. Yield 18.1%

:2130,1790,1730,1620.

: 2130,1790,1730,1620.

NMR (COCl ₃ ) δ (ppm): 6.23 (1H, d, J = 6Hz), 5.93 (1H, m), 4.37 (1H, d), 4.00 (1H, m), 2.93-1.93 (2H, m) , 1.50 (9H, s)

Example 6

-아세톡시-7

-아지도-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온{일반식(I)에서 X가 N₃,R₁이 수소원자, R₂가 OCOCH_3,R₃가 t-부틸기이며, 일반식(Id)에서 X₁이 N₃,R₂₃이 OCOCOH, R₃가 t-부틸기인 다음과 같은 일반식으로 표시되는 시스-화합물}의 제조(±) -cis-2-t-butyloxycarbonyl-4

Acetoxy-7

Azido-1-azabicyclo [4,2,0] oct-2-en-8-one {In Formula (I), X is N ₃ , R ₁ is a hydrogen atom, R ₂ is OCOCH _3, R ₃ is a t- butyl group, the X ₁ in the general formula (Id) N _3, R ₂₃ is a sheath OCOCOH, R ₃ represented by the following formula, such as t- butyl group, and then - producing a compound}

(±) -cis-2-t-butyloxycarbonyl-4-bromo-7-azido-1-azabicyclo [4,2,0] oct-2-ene-8- as obtained in Example 4 75 mg (0.219 mmol) of C. {cis-compound in which X ₁ is N ₃ , R ₂₂ is bromine and R ₃ is t-butyl in general formula (Ic)} were dissolved in 2 ml of acetic acid.

While protecting the reaction system from light, 39.4 mg (0.241 mmol) of acetic acid was added to the solution, and the mixture was stirred for 2 hours and 20 minutes. The reaction mixture was filtered and concentrated under reduced pressure to afford crude acetoxy product of the desired compound. The product was placed in a column filled with 3.5 g of silica gel, and eluted with a solvent of n-hexane and ethyl acetate (3.5: 1) to give 51 mg of an oil. This product was identified as the target cis-compound in formula (Id) wherein X ₁ is N ₃ , R ₂₃ is OCOCOH ₃ , R ₃ is t-butyl, and has the following physical properties. Yield 72.1%.

NMR (CDCl ₃ ) δ (ppm): 6.21 (1H, d, J = 6Hz), 5.42 (1H, d, J = 5Hz), 3.95 (1H, m), 2.02 (13H.S), 2.6-1.7 ( 2H, m), 1.53 (9H, s)

Example 7

(±) -cis-2-t-butyloxycarbonyl-4-methyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one {General Formula (I ), X ₁ is N ₃ , R ₁ is hydrogen atom, R ₂ is methyl, R ₃ is t-butyl, and in formula (Ia), X ₁ is N ₃ , R ₂₁ is methyl, R ₃₁ is t-butyl Preparation of cis-compound} represented by the following general formula

에 화합물은 다음과 같은 1) 및 2) 방법에 의해 제조할 수 있다.

The compound can be prepared by the following 1) and 2) methods.

1) 2- [4- (2-methyl-3-butenyl) -3-azido-2-oxoazinin-1-yl] -2-dimethylphosphoacetate t-butyl ester {General formula (IV) In which X ₁ is N ₃ , R ₂₁ is methyl and R _{31 is} t-butyl.

-아미노디에틸포스포노아세테이트[일반식(III)에서 R₃₁이 t-부틸인 화합물]2.13g(8밀리몰)을 무수 에테르 80ml중에 용해시키고, 이 용액에 3-메틸-4-펜텐알 902mg(9.2밀리목)을 교반하면서 가하고 실온에서 1시간 동안 교반한 후, 여기에 분자체 4A 900mg 및 황산마그네슘 700mg을 가했다. 1.5시간동안 교반시킨 후에, 반응 혼합물을 감압하에서 여과시켰다. 생성되는 여액을 농축하여 담황색 유상물을 얻었다. 여기에 무수 벤젠(30ml)을 가하여, 다시 농축시켜 유상물 2.82g을 얻었다. 생성물 중에 쉬프 염기의 존재는 NMR스펙트럼에 의해 확인되었다. 유상물을 무수 사이클로헥산 56ml 및 무수 벤젠 56ml에 녹이고, 분자체 4A 90mg 및 트리에틸아민 1.67ml(12밀리몰)을 가한 후 실온 교반하에, 건조 사이클로헥산 56ml 중에 녹인 아지도아세틸클로라이트 1.43g(12밀리몰)을 1.5시간 동안 적하했다. 이 혼합물을 30분 더 교반시키고, 여기에 벤젠 30ml를 가하고, 분리 깔대기를 옮기고, 10% 시트르산, 염화나트륨 포화수용액, 중탄산나트륨 포화수용액 및 염화나트륨 포화수용액 각 30ml를 이 순서로 세척하고, 무수 황산나트륨으로 탈수시키고, 감압하에서 농축시켜 유상물 2.8g을 수득했다.t-butyl-

2.13 g (8 mmol) of aminodiethylphosphonoacetate [a compound in which R ₃₁ is t-butyl in formula (III)] is dissolved in 80 ml of anhydrous ether, and 902 mg of 3-methyl-4-pentenal is dissolved in this solution. 9.2 millimolar) was added with stirring and stirred at room temperature for 1 hour, followed by addition of 900 mg of molecular sieve 4A and 700 mg of magnesium sulfate. After stirring for 1.5 hours, the reaction mixture was filtered under reduced pressure. The resulting filtrate was concentrated to give a pale yellow oil. Anhydrous benzene (30 ml) was added and concentrated again to give 2.82 g of an oily substance. The presence of Schiff base in the product was confirmed by NMR spectrum. The oil was dissolved in 56 ml of anhydrous cyclohexane and 56 ml of anhydrous benzene, 90 mg of molecular sieve 4A and 1.67 ml (12 mmol) of triethylamine were added, and then 1.43 g of azidoacetylchlorite dissolved in 56 ml of dry cyclohexane under room temperature stirring. Mmol) was added dropwise for 1.5 hours. The mixture is further stirred for 30 minutes, to which 30 ml of benzene is added, the separating funnel is transferred, 30 ml of 10% citric acid, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution are washed in this order, and dehydrated with anhydrous sodium sulfate. And concentrated under reduced pressure to yield 2.8 g of an oil.

The presence of two main isomeric mixtures in the product was confirmed by thin layer chromatography [silica gel, n-hexane-ethyl acetate (1: 1)]. The product was poured into a column filled with 300 g of silica gel, and eluted using a mixed solvent of n-hexane and ethyl acetate (1: 1). In the formula (VI), X is N ₃ , R ₂₁ is methyl, and R ₃₁ is t. 380 mg (yield 11.0%) of the less polar isomer of the target compound being -butyl, 570 mg (yield 16.7%) of the more polar isomer of the target compound and 201 mg (yield 5.5%) of the mixture of the two isomers were obtained.

The physical properties of each isomer are described below. From this data more polar isomers were identified as cis-isomers of the desired compound.

Less polar isomers

: 2110,1770,1745.

: 2110,1770,1745.

NMR (CCCl ₃ ) δ (ppm): 5.40-6.10 (1H, m), 5.27-4.90 (2.5H, m), 4.68 (0.5H, d), 4.23 (6H, m), 2.60-1.77 (3H, m), 1.53 (9H, s), 1.37 (6H, t, J = 7.0 Hz), 1.10 (3H, d, J = 6.0 Hz)

Large polar isomers (cis-compounds)

: 2110,1765,1745.

: 2110,1765,1745.

NMR (CDCl ₃ ) δ (ppm): 5.45-6.13 (1H, m), 4.83-5.20 (2.5H, m), 4.67 (0.5H, d), 3.97-4.45 (6H, m), 1.77-2.55 ( 3H, m), 1.50 (9H, s), 1.33 (6H, t), 1.08 (3H, d)

2) (±) -cis-2-t-butyloxycarbonyl-4-methyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one In (I), X ₁ is N ₃ , R ₁ is a hydrogen atom, R ₂ is methyl, R ₃ is t-butyl, and in general formula (Ia), X ₁ is N ₃ , R ₂₁ is methyl, R ₃₁ is t Of cis-compound represented by the following general formula:

(±) -cis-2- [4- (2-methyl-3-butenyl) -3-azido-2-oxoazetidin-1-yl] -2- obtained in Example 7-1) 240 mg (0.56 mmol) of t-butyl ester of diethylphosphonoacetate was dissolved in 6.6 ml of dioxane and 2 ml of deionized water. Osmium tetraoxide (20 mg) was added and the mixture was stirred for 10 minutes. Sodium periodate powder [390 mg (1.82 mmol)] was added to the black reaction solution in small portions for 30 minutes.

After stirring for 40 minutes, the reaction solution was extracted three times with 30 ml of ether and the extracts were combined. The ether layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate and concentrated to give 230 mg of oil. This oil-based radish was placed in a column filled with 6 g of silica gel, eluted with a solvent of benzene and ethyl acetate (1: 2), and the fractions positive for 2,4-dinitrophenylhydrazine were collected and concentrated to give 185 mg of an oil. This was identified in formula (VII) as a cis-compound of a cis-compound of an aldehyde compound wherein X ₁ is N ₃ , R ₂₁ is methyl, and R ₃₁ is t-butyl.

The product was immediately dissolved in 8 ml of anhydrous acetonitrile, and 21.6 mg (0.45 mmol) of 50% sodium hydride was added to the solution in an orderly air stream with stirring at room temperature. After stirring for 30 minutes, the reaction solution was poured into 15 ml of 2% acetic acid-aqueous solution, and the mixed solution was extracted twice with 20 ml of ether. The ether layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give an oil.

This product was identified in formula (I) as a crude product of the desired cis-compound, wherein X is N ₃ , R ₁ is a hydrogen atom, R ₂ is methyl, and R ₃ is t-butyl. This oily substance was placed in a column filled with 20 g of silicagen, and eluted with a solvent of n-hexane and ethyl acetate (3.5: 1, volume ratio). The desired compound (70 mg) was obtained as a colorless oil, which crystallized after standing. The physical properties of this product are as follows. Yield 48.1%

:2110,1784,1715,1623.

: 2110,1784,1715,1623.

NMR (CDCl ₃ ) δ (ppm): 6.30 (4 / 5H, d, J = 5.1Hz)), 6.10 (1 / 5H, d, J = 2.7Hz), 4.98 (4 / 5H, d, J = 5.0 Hz), 4.89 (1 / 5H, d, J = 5 Hz), 3.60-3.90 (1H, m), 2.65 (1H, m), 1.70-1.80 (2H, m), 1.51 (9H, m), 1, 20 (3 / 5H, d, J = 8.0 Hz), 1.13 (12 / 5H, d, J = 8 Hz)

-메틸이성체와 4

-메틸이성체의 혼합물로서 동정되었다.The obtained crystals were obtained at about 4: 1 ratio by the NMR data.

Methyl isomers and 4

It was identified as a mixture of -methyl isomers.

Example 8

(±) -cis-2-t-butyloxycarbonyl-5-phenylthio-7-azido-1-azabisaaclo [4,2,0] oct-2-en-8-one In (I), X is N ₃ , R ₁ is SC ₆ H ₅ , R ₂ is hydrogen atom, R ₃ is t-butyl, and in formula (Ib), X ₁ is N ₃ , R ₁₁ is SC ₆ H ₅ , Cis compound represented by the following general formula wherein R ₃₁ is t-butyl}

This compound can be manufactured by the following method 1) -4).

1) Preparation of Compound (XIV) [Shiff Base of Formula (XIV) wherein R 'is methyl and R ₃₁ is t-butyl

-아미노디에틸포스포노 아세테이트 {일반식(III)에서 R₃₁이 t-부틸인 화합물} 1.08g(4밀리몰)을 무수 염화메틸렌 100ml에 용해시키고, 여기에 일반식(XIII)에서 R'이 메틸기인 4, 4-디메톡시-트랜스-2-부텐알 580mg(4.4밀리몰)을 무수염화메틸렌 20ml에 용해시킨 용액을 가했다.t-butyl-

-Aminodiethylphosphono acetate {compound in which R ₃₁ is t-butyl in formula (III)} 1.08 g (4 mmol) is dissolved in 100 ml of anhydrous methylene chloride, where R 'is a methyl group in formula (XIII) A solution in which 580 mg (4.4 mmol) of phosphorous 4 and 4-dimethoxy-trans-2-butenal was dissolved in 20 ml of anhydrous methylene chloride was added.

The mixture was stirred at rt for 1 h. Anhydrous magnesium sulfate (600 mg) was added to this mixture, followed by further stirring for 1 hour. The reaction solution was filtered under reduced pressure, and methylene chloride was distilled off under reduced pressure to obtain 1.63 g of an oily substance. Yield 100%

This product was identified as a Schiff base of the target compound having the physical properties described below in which R 'is a methyl group and R ₃₁ is a t-butyl group in the general formula (XIV).

NMR (CDCl ₃ ) δ (ppm): 8.00 (1H, dd), 6.67 (1H, dd), 4.93 (1H, d), 3.97-4.33 (4H, m), 3.33 (6H, s), 1.50 (9H , s), 1.33 (6H, t).

Mle: 380 (M + 1)

2) The compound (XV) {the formula (XV) in X ₁ is N _3, R 'is methyl, R ₃₁ is t- butyl acetal compound} from and compound (XVI) Formula (XVI) X ₁ is N ₃ , Aldehyde compound wherein R ₃₁ is t-butyl

1.6 g (4.2 mmol) of Schiff base {Compound (XIV) '} obtained in Example 8-1) were dissolved in 30 ml of anhydrous benzene, and 30 ml of anhydrous cyclohexane and 0.84 ml (7 mmol) of anhydrous triethylamine were added thereto. . To this mixture, 580 mg (4.8 mmol) of azido acetyl chloride dissolved in 40 ml of cyclohexane were added dropwise and stirred slowly at room temperature for about 1.5 hours.

The mixture was stirred for another 1 hour at room temperature. Benzene was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The resulting solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 1.88 g of crude product. The product was placed in a column filled with 90 g of silica gel and eluted with a mixture of n-hexane and ethyl acetate (1: 2) to give Compound (XV) '[55 mg (28.2%)] and Compound [220 mg (11.3%). Got it. The properties of the acetal and aldehyde compounds obtained are as follows. Acetal compounds

NMR (CDCl ₃ ) δ (ppm): 5.83-6.07 (2H, m), 4.50-5.00 (3H, m), 4.23 (4H, q), 3.33 (6H, s), 1.50 (9H, s), 1.37 (6H, t)

:2120, 1780, 1745

2120, 1780, 1745

Aldehyde compounds

:2120, 1785, 1750, 1700

2120, 1785, 1750, 1700

NMR (CDCl ₃ ) δ (ppm): 9.62 (1H, d), 7.00 (1H, dd, J = 8Hz, 15Hz), 6.26 (1H, dd, J = 7Hz, 15Hz), 4.84 (1H, d, J = 24 Hz), 4.80-5.02 (2H, m), 4.16 (4H, m), 1.46 (9H, 2), 1.26 (6H, dt)

Mass (m / e): 417 (M + 1)

An aldehyde compound uses an acetal compound as a raw material and can be manufactured by the following method. 520 mg (1.13 mmol) of the acetal compound obtained in Example 8-2 [Acetal compound having X ₁ in N ₃ , R ′ in methyl group and R ₃₁ in t-butyl in General Formula (XV)] are dissolved in 10 ml of acetone. To this, 50 mg of monohydrate of p-toluenesulfonate was added.

The mixture was stirred at room temperature for 1 hour 45 minutes. 20 ml of ethyl acetate was added to the reaction solution, and the resulting mixture was washed with 5% sodium bicarbonate and saturated aqueous sodium chloride solution, dehydrated with sodium sulfate, and concentrated under reduced pressure to give 430 mg (91.8%) of an aldehyde compound (Compound (XVI) '). Obtained.

3) Preparation of Compound (XVII) 'thiophenyl compound wherein X ₁ is N ₃ , R ₁₁ is SC ₆ H ₅ , and R ₃₁ is t-butyl in formula (XVII)}

120 mg (2.5 mmol) of 50% sodium hydride was added to a mixture of 970 mg (8.8 mmol) of thiophenyl and 6.5 ml of absolute ethanol. After sodium hydride was completely reacted, it was cooled to -78 ° C on the roof of dry ice-methanol, and a solution of 920 mg (2.2 mmol) of the aldehyde compound {Compound (XVI) '} obtained as described above was dissolved in 6.5 ml of ethanol It was added dropwise within about 15 minutes.

The mixture was stirred at -78--20C for 2 hours. Acetic acid and water were added to this mixture, and the temperature was raised to room temperature. The solution was extracted with ether and the ethyl layer was washed with saturated aqueous sodium chloride solution. The resulting solution was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.12 g of an oil. The product was charged into a column filled with 60 g of silica gel, eluted with a solvent of n-hexane and ethyl acetate (2: 1) to form a thiophenyl compound {X ₁ in formula (XVII), wherein N ₁ and R ₁₁ were SC ₆ H ₅ 470 mg (40.4%) of thiophenyl compounds whose R ₃₁ is t-butyl. The yield of the product is as follows.

:2120,1780,1735

: 2120,1780,1735

Mass (m / e): 526 (M ⁺ )

4) (±) -cis-2-t-butyloxycarbonyl-5-phenylthio-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one {general Preparation of cis-compound having the following general formula wherein X is N ₃ , R ₁₁ is SC ₆ H ₅ , R ₃₁ is t-butyl in formula (Ib)

470 mg (0.89 mmol) of the thiophenyl compound [Compound (XVII) '] obtained in Example 8-3) were dissolved in 14 ml of anhydrous dimethoxyethane, and 47 mg (0.98 mmol) of 50% sodium hydride was added thereto. The mixture was stirred at room temperature for 3.5 hours, and kerker was added thereto.

The mixture was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure to give 340 mg of an oil, which is a mixture of stereoisomers at the 5-position of the target compound. This oily substance was placed in a column filled with 15 g of silica gel, and eluted with a solvent of n-hexane and ethyl acetate (4: 1, volume ratio) to obtain two types of isomers. These isomers have the following physical properties and are less polar (is cis-compounds in which X is N ₃ , R ₁₁ is SC ₆ H ₅ , and R ₃₁ is t-butyl in the formula (Ib)). The arrangement of protons at the -position is the same as the arrangement of protons at the 6- and 7-positions and the polar isomers (the arrangement of protons at the 5-positions is opposite to the arrangement of protons at the 6- and 7- and positions). I was identified.

Less polar isomer A: 80 mg (yield 9.7%, from compound (XVI) '(XVI)')

: 2130, 1790, 1725, 1640

: 2130, 1790, 1725, 1640

NMR (CDCl ₃ ) δ (ppm): 7.24-7.56 (5H, m), 6.21 (1H, dd, J = 3.0,5.5Hz), 5.06 (1H, d, J = 5Hz), 3.65 (1H, dd, J = 5,11Hz), 3.19 (1H, ddd, J = 5.5,11,11Hz), 2.74 (1H, ddd, J = 5.5,19Hz), 2.29 (1H, ddd, J = 3,11,19Hz), 1.50 (s, 9H)

Mass (m / e): 372 (M ⁺ )

Large polar isomer B: 125 mg (yield 15.2%, compound (XVI) 'to (XVI)')

: 2120, 1790, 1720, 1630.

: 2120, 1790, 1720, 1630.

Mass (m / e): 372 (M ⁺ )

NMR (CDCl ₃ ) δ (ppm): 7.20-7.52 (5H, m), 6.21 (1H, dd, J = 3.5,4.5Hz), 4.98 (1H, d, J = 5Hz), 3.99 (1H, dd, J = 2.5,5.0 Hz), 3.82 (1H, m), 2.58-2.70 (2H, m), 1.54 (9H, s).

Less polar isomers can also be prepared by the following methods.

56 mg (1.16 mmol) of sodium hydride (50% in oil dispersion) were added with a mixture of 440 mg (4 mmol) of thiophenol and 3 ml of anhydrous ethanol. After completion of the sodium hydride reaction, the mixture was cooled to -75 ° C on a dry ice methanol bath. 440 mg (1.06 mmol) of the aldehyde compound [Compound (XVI) '] obtained in Example 8-2) were added dropwise to this mixture. The mixture was stirred at -75 [deg.] C. for 50 minutes, to which acetic acid and water were added and the temperature was raised to room temperature.

The resulting solution was extracted with ether, the ether layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, the solvent was evaporated and 53 mg (1.1 mmol) of crude product 50% sodium hydride were added. The resulting solution was stirred at room temperature for 1 hour 45 minutes and 595 mg were obtained. The product was dissolved in 15 ml of anhydrous dimethoxyethane, and ether ether was added, the ether layer was washed with saturated aqueous ammonium chloride solution and aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give 410 mg of an oil. The product was charged into a column filled with 16 g of silica gel and eluted using a solvent of n-hexane and ethyl acetate (4: 1, volume ratio).

100 mg (25.4%) of desired minor isomers were obtained.

The physical properties of the product are the same as those of the isomers having the low polarity. In this case, large isomers were not obtained.

Example 9

가 수소원자, R₃가 t-부틸이며, 일반식(Ie)에서 X₁이 N₃, R₁₂가 유황원자, R₃가 t-부틸인 다음과 같은 일반식으로 표시되는 시스-화합물}의 제조(±) -cis-2-t-butyloxycarbonyl-5-phenylsulfinyl-7-azido-1-azabisaaclo [4,2,0] oct-2-en-8-one In formula (I), X is N ₂ , R ₁ is

Is a hydrogen atom, R ₃ is t-butyl, and in formula (Ie), X ₁ is N ₃ , R ₁₂ is sulfur atom, and R ₃ is t-butyl} Produce

(±) -cis-2-t-butyloxycarbonyl-5-phenylthio-7-azido-1-azabicyclo [4,2,0] oct- which is a less polar isomer obtained in Example 8 110 mg (0.296 mmol) of 2-en-8-one were dissolved in 8 ml of methanol, and 0.8 ml of benzene and 140 mg (0.655 mmol) of an aqueous sodium periodate solution were added thereto. The mixture was stirred at rt for 60 h. Water was added to the reaction mixture, followed by extraction by adding 15 ml of methylene chloride. The methylene chloride solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure to yield 105 mg of an oil. Based on the following data, this product contains (±) -cis-2-t-butyloxycarbonyl-5-phenylsulfinyl-7-azido- which is a mixture of two stereoisomer 1: 1 ratios at sulfur atoms. It was identified as 1-azabicyclo [4,2,0] oct-2-en-8-one.

: 2130, 1790, 1725, 1640, 1050.

: 2130, 1790, 1725, 1640, 1050.

NMR (CDCl ₃ ) δ (ppm): 7.55 (5HH, m), 6.30 (1H.m), 5.27 (0.5H, d, J = 5Hz), 4.78 (0.5H, d, J = 5Hz), 4.07 ( 1H, dd, J = 5,10 Hz), 2.40-3.00 (2H.m)

Example 10

(±) -cis-2-carboxy-7-amide-1-azabicyclo [4,2,0] oct-2-en-8-one [wherein X is NH ₂ , R ₁ , R ₂ and R ₃ is a hydrogen atom, the preparation of the R _1, R ₂ and R ₃ is an amino compound] a hydrogen atom in the general formula (Ih)

(±) -cis-2-carboxy-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one obtained in Example 3 {X in Formula (If) ₁ is N _3, and R ₂ is dissolved in 6.5ml towels to a hydrogen atom, R ₁ is a hydrogen atom compound 91mg}, to give a 10% palladium / carbon 26mg here.

The mixture was stirred for 2 hours at room temperature and atmospheric pressure. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The concentrate was again dissolved in 10 ml of methanol and thereto was added 26 mg of 10% palladium / carbon. The mixture was catalytically reduced for 3 hours and 50 minutes at room temperature and atmospheric pressure and filtered using a filter aid, Hyflo super Cel. The filtrate was concentrated under reduced pressure to give 88 mg (100%) of a semi-solid product. This product was identified as the desired amino compound based on the following data.

: 3450, 2950, 1770, 1650

3450, 2950, 1770, 1650

Example 11

Preparation of (±) -cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one.

10 ml of 178 mg (0.67 mmol) of (±) -cis-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one obtained in Example 1 Was dissolved in and 25 mg of 10% palladium / carbon (catalyst) was added thereto. This mixture was stirred for 50 min in hydrogen gaseous at room temperature. The reaction solution was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to afford the desired compound as a yellow oil.

Quantity of product: 159.5mg

Yield: 100%

: 1775,1725,1640

: 1775,1725,1640

NMR (CDCl ₃ ) δ (ppm): 6.27 (m, H1H), 4.50 (m, 1H), 4.2-3.1 (m, 3H), 2.6-1.7 (m, 4H), 1.5 (s, 9H)

Example 12

(±) -cis-2-t-butyloxycarbonyl-4-methyl-7-azido-1-azabicyclo [4,2,0] oct-2-ene- represented by the following general formula: Preparation of 8-Ons.

This compound was prepared by the following methods 1) and 2).

1) Preparation of t-butyl ester of 2- [4- (2-methyl-3-butenyl) -3-azido-2-oxoazetidin-1-yl] -2-diethylphosphono acetate.

-아미노디에틸포스포노아세테이트 2.13g(8밀리몰)을 무수에테르 80ml에 용해시키고, 3-메틸-4-펜덴알 902mg(9.2 밀리몰)을 교반시키면서 가했다. 이 혼합물을 실온에서 1시간 동안 교반시키고, 여기에 분자체 4A 900mg 및 황산마그네슘 700mg을 가했다. 이 혼합물을 1.5시간 동안 교반시키고 감압하에서 여과시켰다. 이 여액을 농축시켜 담황색 유상물을 얻었다. 이 생성물에 부수 벤제 30ml를 가하고, 이 혼합물을 다시 농축시켜 유상물 2.82g을 수득했다. 쉬프 염기의 존재는 NMR 스펙트럼으로 확인했다.t-butyl-

2.13 g (8 mmol) of aminodiethylphosphonoacetate was dissolved in 80 ml of anhydrous ether, and 902 mg (9.2 mmol) of 3-methyl-4-pentenal was added with stirring. The mixture was stirred at room temperature for 1 hour, to which 900 mg of molecular sieve 4A and 700 mg of magnesium sulfate were added. The mixture was stirred for 1.5 hours and filtered under reduced pressure. The filtrate was concentrated to give a pale yellow oily substance. 30 ml of incidental benze was added to this product, and the mixture was concentrated again to give 2.82 g of an oil. The presence of the Schiff base was confirmed by NMR spectrum.

This oily substance was dissolved in 56 ml of anhydrous cyclohexane and 56 m of anhydrous benzene, and 900 mg of molecular sieve 4A and 1.67 ml (12 mmol) of triethylamine were added thereto.

To this mixture, 1,43 g (12 mmol) of azido acetyl chloride dissolved in 56 ml of anhydrous cyclohexane was added dropwise while stirring at room temperature for 1.5 hours, and the mixture was stirred for 30 minutes. The reaction mixture was transferred to a separatory funnel with 30 ml of benzene. The benzene layer was washed with 10 ml of 10% citric acid, aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.8 g of an oily substance.

The presence of two isomers in the product was detected by thin layer chromatography [silica gel, n-hexane and ethyl tetra (1: 1)]. The product was placed in a column filled with 300 g of silica gel, eluted with a mixture of n-hexane and ethyl acetate (1: 1) to give 380 mg of a less polar compound (yield 11.0%) and 570 mg of a large polar isomer (yield 16.7%). ) And 201 mg (yield 5.8%) of two isomeric compounds.

The physical properties of each isomer are described below. High polar isomers have been identified as cis-isomers of the target compound.

Less polar isomers (trans isomers).

: 2110,1770,1745.

: 2110,1770,1745.

NMR (CDCL ₃ ) δ (ppm): 5.40-6.10 (1H, m), 5.27-4.90 (2.5H, m), 4.68 (0.5H, d), 4.23 (6H, m), 2.60-1.77 (3H, m), 1.53 (9H, s), 1.37 (6H, t, J = 7.0 Hz)), 1.10 (3H, d, J = 6.0 Hz).

Large polar isomers (cis isomers)

: 2110,1765,1745.

: 2110,1765,1745.

NMR (CDCl ₃ ) δ (ppm): 5.45-6.13 (1H, m), 4.83-5.20 (2.5H, m), 4.67 (0.5H, d), 3.97-4.45 (6H, m), 1.77-2.55 ( 3H, m), 1.50 (9H, s), 1.33 (6H, t), 1.08 (3H, d).

2) (±) -cis-7-azido-2-t-butyloxycarbonyl-4-methyl-7-azido-1-azabicyclo [4,2,0] oct-2-ene-8 -On.

(±) -cis-2-4- (2-methyl-3-butenyl) -3-azido-2-oxoazetidin-1-yl-2-diethyl obtained in Example 12-1) 240 mg (0.56 mmol) of t-butyl ester of phosphonoacetic acid was dissolved in 6.6 ml of dioxane and 2 ml of deionized water, 20 mg of osmium tetraoxide was added thereto, stirred for 10 minutes, and 390 mg (1.82 mmol) of sodium periodate powder. ) Was added to the black reaction mixture in small portions within 30 minutes.

After stirring for 40 minutes, the reaction solution was extracted three times with 30 ml of ether, and the ether layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate and concentrated to give 230 mg of an oil. The oil was charged into a column filled with 6 g of silica gel, eluted with a solvent of benzene and ethyl acetate (1: 2), and the fractions positive for 2,4-dinitrophenyl hydrazine were collected and concentrated to give 185 mg of an oil. This has been identified as a compound of the target compound. This product was immediately dissolved in 8 ml of anhydrous acetonitrile, and 21.6 mg (0.45 mmol) of 50% sodium hydride was added in a nitrogen stream with stirring at room temperature.

After stirring for 30 minutes, the reaction mixture was poured into 15 ml of 2% acetic acid solution, and the mixture was extracted twice with 20 ml of ether. The obtained ether layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain an oily substance. The product was poured into a column filled with 20 g of silicagen, and eluted with a solvent of n-hexane and ethyl acetate (3.5: 1, by volume) to obtain the desired product (70 ml) as a colorless product. Yield: 48.1%

This product was left to crystallize. The physical properties of this product are as follows.

:2110,1784,1715,1623.

: 2110,1784,1715,1623.

NMR (CDCl ₃ ) δ (ppm): 6.30 (4 / 5H, d, J = 5.1Hz), 6.10 (1 / 5H, d, J = 5.0Hz), 3.60-3.901H, m), 2.65 (1H, m), 1.70-1.80 (2H, m), 1.51 (9H, s), 1.20 (3 / H, d, J = 8.0 Hz), 1.13 (12 / 5H, d, J = 8.0 Hz).

-메틸 이성체와 4

-메틸이성체 약 4:1의 비율로서 동정했다. 이 화합물을 n-헥산 및 초산에틸(3:1)의 용매를 사용하여 실리카겔 크로마토 그라피에 의해 분리시킬 수 있다.The crystal obtained on the basis of NMR data is 4

-Methyl isomer and 4

-Isomer was identified as the ratio of about 4: 1. This compound can be separated by silica gel chromatography using a solvent of n-hexane and ethyl acetate (3: 1).

-CH₃이성체 즉, (±)-시스-7

-아지도-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온에 대응하며, 극성이 적은 이성체는 4

-CH₃이성체에 해당한다. 이들은 각각 다음과 같은 물성을 갖는다.Isomer with large polarity is 4

-CH ₃ isomer, i.e. (±) -cis-7

-Azido-4

-Methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one, with less polar isomers

Corresponds to the -CH ₃ isomer. These have the following physical properties, respectively.

-CH₃이성체4

-CH ₃ isomer

Melting Point: 84.0-86.5 ℃

: 2135, 1783, 1715, 1622.

: 2135, 1783, 1715, 1622.

NMR (CDCl ₃ ) δ (ppm): 6.13 (1H, d, J = 2,7Hz), 4.90 (1H, d, J = 5.0Hz), 3.93-3.73 (1H, m), 2.35 (1H, m) , 2.16-1.75 (2H.m), 1.53 (9H, s), 1.20 (3H, d, J = 6.0 Hz).

-CH₃이성체4

-CH ₃ isomer

Melting Point: 82.0-84.0 ℃

: 2120, 1790, 1721, 1630.

: 2120, 1790, 1721, 1630.

NMR (CDCL ₃ ) δ (ppm): 6.33 (1H, d, J = 5.0Hz), 5.00 (1H, d, J = 5.5Hz), 3.89-3.68 (1H, m), 2.66 (1H, m), 2.66 (1H, m), 1.82-1.57 (2H.m), 1.53 (9H, s), 1.12 (3H, d, J = 7.0 Hz).

Example 13

-아미노-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조.(±) -cis-7

-Amino-4

Preparation of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one.

-아지도-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 255mg(0.67밀리몰)을 에탄올 10ml에 용해시키고, 여기에 10% 팔라듐/탄소 100mg을 가했다.(±) -cis-7 obtained as a less polar isomer in Example 12-2)

-Azido-4

255 mg (0.67 mmol) of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one are dissolved in 10 ml of ethanol, where 10% palladium is added. 100 mg of carbon was added.

The mixture was catalytic hydrogenated for 1.5 hours and filtered to remove the catalyst. This catalyst was washed with methanol.

The filtrate and washings were combined and concentrated under reduced pressure to give a pale yellow oil. This product was dissolved in 8 ml of ethyl acetate and the solution was extracted five times with 3 ml of 10% citric acid. The water layer was added to potassium carbonate to adjust the pH to 6-7 to obtain a white suspension. This suspension was extracted twice with 5 ml of ethyl acetate and washed with saturated aqueous sodium chloride solution. This wash was dehydrated with anhydrous sodium sulfate to give 177 mg (76.6%) of an oil.

:3400,1770,1720, 1630

: 3400,1770,1720, 1630

NMR (CDCl ₃ ) δ (ppm): 6.23 (1H, d, J = 5.0Hz), 4.53 (1H, d, J = 5.8Hz), 3.93-3.47 (1H, m), 2.56 (1H, m), 1.92 (2H, br), 1.80-1.60 (2H.m), 1.50 (9H, s), 1.31 (3H, d, J = 7.0 Hz).

Example 14

-아미노-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사아클로[4,2,0]옥트-2-엔-8-온의 제조.(±) -cis-7

-Amino-4

Preparation of -methyl-2-t-butyloxycarbonyl-1-azabisaaclo [4,2,0] oct-2-en-8-one.

-아지도-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 655mg(2.35밀리몰)을 에탄올 6ml에 용해시키고, 여기에 3N-염산 0.79ml(2.37밀리몰)을 가했다. 이 혼합물을 10% 팔라듐/탄소 200mg으로 70분 동안 수소화하였다. 생성혼합물에 메탄올을 가하여 목적화합물의 침적염을 용해시켰다. 이 촉매를 여거하고 여액을 농축시켜 조생성물을 수득했다. 이 생성물을 에테르를 가하여 혼합해서 여과하고, 여액을 건조시켜 여액적 화합물의 염화수소물 512mg(75.4%)을 수득했다. 융점: 216-221℃(분해)(±) -cis-7 obtained as a highly polar isomer in Example 12-2)

-Azido-4

655 mg (2.35 mmol) of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one are dissolved in 6 ml of ethanol, and 3N-hydrochloric acid is added thereto. 0.79 ml (2.37 mmol) was added. This mixture was hydrogenated at 200 mg of 10% palladium / carbon for 70 minutes. Methanol was added to the resulting mixture to dissolve the deposited salt of the target compound. The catalyst was filtered off and the filtrate was concentrated to give the crude product. The product was added with ether, mixed, filtered, and the filtrate was dried to give 512 mg (75.4%) of hydrogen chloride of the filtrate compound. Melting Point: 216-221 ° C (Decomposition)

: 3430, 2590, 1780, 1712, 1630.

3430, 2590, 1780, 1712, 1630.

Example 15

-아미노-4

-메틸-2-카르복시-1-아자바이사아클로[4,2,0]옥트-2-엔-8-온의 트리플루오로 아세테이트의 제조.(±) -cis-7

-Amino-4

Preparation of trifluoro acetate of -methyl-2-carboxy-1-azabisaaclo [4,2,0] oct-2-en-8-one.

-아미노-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 196mg(0.78밀리몰)을 무수 디클로로메탄 4.2ml에 용해시키고, 여기에 트리플루오로 초산 1.8ml를 실온에서 교반시키면서 가했다.(±) -cis-7 obtained in Example 13

-Amino-4

196 mg (0.78 mmol) of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one is dissolved in 4.2 ml of anhydrous dichloromethane, and 1.8 ml of trifluoroacetic acid was added with stirring at room temperature.

After 1.5 hours the mixture was concentrated under reduced pressure. This concentrate was azeotropically streamlined with anhydrous benzene to afford an oil. This product was dissolved in ether and filtered to give 167 mg (69.3%) of the title compound powder.

:3460,2980-2500,1780,1685,1630.

: 3460,2980-2500,1780,1685,1630.

PMR (D ₂ O, DSS as internal standard) δ (ppm): 6.77 (1H, d, J = 5.8Hz), 5.00 (1H, d, J = 5.6Hz), 4.10 (1H, m), 2.83 (1H , m), 1.86 (2H. m), 1.15 (3H, d, J = 8.0 Hz).

Example 16

-아세톡시-1-아자바이사아클로[4,2,0]옥트-2-엔-8-온-2-카르복실산의 제조.(±) -cis-7 -Amino-4

Preparation of Acetoxy-1-azabisaaclo [4,2,0] oct-2-ene-8-one-2-carboxylic acid.

-아지도-4

-아세톡시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온-2-카르복실산의 제조.1) (±) -cis-7

-Azido-4

Preparation of Acetoxy-1-azabicyclo [4,2,0] oct-2-ene-8-one-2-carboxylic acid.

-아지도-4

-아세톡시-2-t-부틸옥시카르보닐-1-아자바이사아클로[4,2,0]옥트-2-엔-8-온 179mg을 염화메틸렌 3ml과 트리몰루오로초산 3ml에 용해시켰다.(±) -cis-7 obtained in Example 16

-Azido-4

179 mg of -acetoxy-2-t-butyloxycarbonyl-1-azabisaaclo [4,2,0] oct-2-en-8-one was dissolved in 3 ml of methylene chloride and 3 ml of trimoloacetic acid. .

This solution was left at room temperature for 2 hours and concentrated to yield 145 mg of the target compound as a yellow powder.

The physical properties of this compound are described below.

: 2130, 1790, 1715, 1445

: 2130, 1790, 1715, 1445

-아미노-4

-아세톡시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온-2-카르복실산의 제조2) (±) -cis-7

-Amino-4

Preparation of Acetoxy-1-azabicyclo [4,2,0] oct-2-ene-8-one-2-carboxylic acid

-아미노-4

-아세톡시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온-2-카르복실산 145mg 을 에탄올 14ml에 용해시키고, 여기에 10% 팔라듐/탄소 40mg을 가했다. 이 혼합물을 상압에서 1시간 동안 교반시키면서 촉매수소화 했다. 반응 혼합물을 여과시키고, 여액을 농축시켜 목적 화합물 126mg을 수득했다.(±) -cis-7 obtained in Example 6

-Amino-4

145 mg of -acetoxy-1-azabicyclo [4,2,0] oct-2-ene-8-one-2-carboxylic acid was dissolved in 14 ml of ethanol, and 40 mg of 10% palladium / carbon was added thereto. The mixture was catalytic hydrogenated with stirring for 1 hour at atmospheric pressure. The reaction mixture was filtered and the filtrate was concentrated to give 126 mg of the target compound.

Example 17

-아지도-2-t-부틸옥시카르보닐-4

-하이드록시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 [일반식(I)에서 X가 N₃, R₁이 수소원자, R₂가 하이드록시, R₃가 t-부틸인 시스 화합물]의 제조(±) -cis-7

Azido-2-t-butyloxycarbonyl-4

-Hydroxy-1-azabicyclo [4,2,0] oct-2-en-8-one [In Formula (I), X is N ₃ , R ₁ is a hydrogen atom, R ₂ is hydroxy, R Cis compound which is _trivalent t-butyl]

,

-아자비스이소부티로니트릴을 가했다. 이 혼합물을 환류하에 30분 동안 가열시켰다. 냉각시킨 후에 반응 혼합물을 클로로포름 5ml로 희석시키고, 물 및 염화나트륨 포화수용액 각 3ml로 세척시켰다.222 mg of (±) -cis-2-t-butyloxycarbonyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one obtained in Example 1 was carbon tetrachloride. Dissolved in 8.8 ml, and the amount of N-bromosuccinimide and 134.9 mg

,

Azabisisobutyronitrile was added. This mixture was heated at reflux for 30 minutes. After cooling the reaction mixture was diluted with 5 ml of chloroform and washed with 3 ml each of water and saturated aqueous sodium chloride solution.

The wash was dehydrated with anhydrous sodium sulfate and filtered.

This filtrate was concentrated to give a bromo compound which is the same oil as obtained in Example 4. This product was immediately dissolved in 10 ml of acetone, to which 50 mg of carbonic acid and 50 µl of water were added, followed by stirring at room temperature for 10 minutes. The reaction mixture was filtered and concentrated to afford crude product. The product was poured into a column filled with 20 g of silica gel, eluted with a mixture of n-hexane and ethyl acetate (2: 1), and concentrated to give 86.4 mg of the target compound as pale yellow crystals. Yield: 40.7%

The physical properties of the crystal are described below.

Melting point: 100.0-101.0 ° C.

:2130,1790,1635,1630

: 2130,1790,1635,1630

NMR (CDCl ₃ ) δ (ppm): 6.30 (11H, d, J = 5Hz), 5.03 (1H, b, J = 5.2) 44.7 (1H, m), 39.3 (1H, m), 3.20 (1H, br ), 2.1-1.8 (2H, m), 1.55 (9H, s).

Example 18

Preparation of (±) -cis-7-amino-2-carboxy-1-azabicyclo [4,2,0] oct-2-en-8-one

300 mg of (±) -cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one obtained in Example 11 was prepared by methylene chloride. In 3.0 ml, 3.0 ml of trifluoroacetic acid was added thereto. This mixture was left at room temperature for 1 hour 20 minutes.

The reaction mixture was concentrated and benzene was added to the residue. The solution was concentrated again to give 250 mg of trifluoroacetate of the target compound as a pale yellow powder. The physical properties of this product are described below.

:1780,1680,1630

: 1780,1680,1630

Example 19

-아지도-2-카르복시-4

-메틸-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조.(±) -cis-7

Azido-2-carboxy-4

Preparation of -methyl-1-azabicyclo [4,2,0] oct-2-en-8-one.

-메틸-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 238mg(0.703밀리몰)을 트리플루오로초산 42ml에 용해시키고, 이 혼합물을 실온에서 10분동안 방치시켰다. 반응 혼합물을 25℃의 감압하에서 농축시킨 후 무수벤젠 5ml로 2회 추출했다. 수득된 유상물 255mg을 초산에틸 5ml에 녹이고, 이 용액을 10% 탄산칼륨 2ml로 2회 추출시키고, 물층에 0.5N 염산을 가하여 pH 약 3으로 조정했다. 이 용액을 초산에틸 2ml로 2회 추출하고, 무수황산나트륨으로 탈수했다. 용매를 감압하에서 유거하여 유상물로서 목적물 166mg을 수득했다.(±) -cis-7-azido-2-t-butyloxycarbonyl-4 obtained in Example 12

238 mg (0.703 mmol) of -methyl-1-azabicyclo [4,2,0] oct-2-en-8-one were dissolved in 42 ml of trifluoroacetic acid and the mixture was left at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure at 25 ° C. and then extracted twice with 5 ml of anhydrous benzene. 255 mg of the obtained oil was dissolved in 5 ml of ethyl acetate, the solution was extracted twice with 2 ml of 10% potassium carbonate, and 0.5N hydrochloric acid was added to the water layer to adjust the pH to about 3. This solution was extracted twice with 2 ml of ethyl acetate and dehydrated with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 166 mg of the target substance as an oil.

Yield: 83.8%. After standing, the product crystallized. The physical properties of the product are described below.

Melting Point: 121.5-123.0 ℃

:2110,1769,1750,1716,1630

: 2110,1769,1750,1716,1630

NMR (CD ₃ OD) δ (ppm): 6.47 (1H, d, J = 5.6Hz), 5.22 (1H, d, J = 5.0), 4.2 = 3.7 (1H, m), 2.3-2.9 (1H, br ), 1.1 (3H, d, J = 7.2)

Example 20

-아미노-2-카르복시-4

-메틸-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조.(±) -cis-7

-Amino-2-carboxy-4

Preparation of -methyl-1-azabicyclo [4,2,0] oct-2-en-8-one.

-아지도-2-t-부틸옥시카르보닐-4

-메틸-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 800mg을 물 2ml와 에탄올 2ml에 용해시킨 다음에 10% 팔라듐/탄소 75mg을 가했다. 이 혼합물을 상압하에서 수소기류 중에서 교반시켰다. 20시간 후에 반응 혼합물을 감압하에서 여과시켰다. 이 케이크에트리 플루오로 초산 2ml를 가했다.(±) -cis-7

Azido-2-t-butyloxycarbonyl-4

800 mg of -methyl-1-azabicyclo [4,2,0] oct-2-en-8-one was dissolved in 2 ml of water and 2 ml of ethanol and then 75 mg of 10% palladium / carbon was added. The mixture was stirred in a hydrogen stream at atmospheric pressure. After 20 hours the reaction mixture was filtered under reduced pressure. 2 ml of trifluoroacetic acid was added to this cake.

After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and then 10 ml of anhydrous ether was added thereto. 120 mg of the target compound was obtained from the precipitated crystals. Yield 43%, the physical properties of this compound are consistent with those obtained in Example 15.

Example 21

-아미노-4

-하이드록시-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조.(±) -cis-7

-Amino-4

Preparation of hydroxy-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one.

-아지도-4

-하이드록시-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔 54.0mg(0.19밀리몰)을 에탄올 20ml에 용해시키고, 여기에 10% 팔라듐/탄소 15mg을 가했다. 이 혼합물을 상압 및 실온에서 1.5시간 동안 수소기류중에서 교반시켰다. 반응 혼합물을 여과하여 촉매를 제거하고, 여액을 농축시켰다.(±) -cis-7 obtained in Example 17

-Azido-4

54.0 mg (0.19 mmol) of hydroxy-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-ene was dissolved in 20 ml of ethanol, where 10% palladium / carbon was added. 15 mg was added. The mixture was stirred in hydrogen stream for 1.5 hours at atmospheric pressure and room temperature. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated.

The concentrate was subjected to silica gel chromatography (a mixture of eluent silica gel 5g, chloroform and methanol (4: 1) to give 21.7 mg of the target compound as a yellow glassy product. Yield 44.3%.

:3250-3400,1775,1730,1635

: 3250-3400,1775,1730,1635

NMR (CDCl ₃ ) δ (ppm): 6.28 (1H, d, J = 6.0), 4.62 (1H, d, J = 5.0), 4.47 (1H, m), 4.50-3.30 (1H, m), 2.52 ( 3H, br), 2.50-1.50 (2H, m), 1.53 (9H, s).

In the reference examples described later it can be seen that the compound derived from formula (I) is a useful compound having excellent antimicrobial activity.

Reference Example 1

(±) -cis-2-carboxy-7- [2- (thiophen-2-yl) acetylamino] -1-azabicyclo [4,2,0] oct-2 represented by the following general formula: Preparation of -en-8-one

Obtained in Example 10, 88 mg (0.489 mmol) of the amino compound in formula (I), wherein X is NH ₂ , R ₁ , R ₂ and R ₃ are hydrogen atoms, are dissolved in 2 ml of deionized water and 1 ml of acetone, and 84 mg of aqueous sodium bicarbonate solution was added. To this mixture, 78 mg of 2-diethylacetyl chloride dissolved in 0.5 ml of acetone were added dropwise under ice-cooling. The mixture was then stirred for 30 minutes and washed with ethyl acetate.

The obtained aqueous solution layer was adjusted to pH 2.0 by adding hydrochloric acid. The resulting white suspension was extracted three times with 5 ml of ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, and then concentrated under reduced pressure to give a yellow oil. This product was placed in a column filled with silica gel 4.0 g% and eluted with chloroform. The syrup obtained was treated with chloroform-ethanol to give 30 mg of crystals. This crystal was identified as the target compound having the following physical properties. Yield 20.1%. Melting Point 181-183 ℃

:1775, 1690, 1650, 1615

: 1775, 1690, 1650, 1615

NMR (CD ₃ OD) δ (ppm): 7.16-6.88 (3H, m), 6.18 (1H, t), 5.16 (1H, d, J = 5Hz), 3.80 (1H, m), 3.37 (2H, s ), 2.5-1.30 (4H, m).

Reference Example 2

(±) -cis-2-carboxy-7- [2- (thiophen-2-yl) acetylamino] -1-azabicyclo [4,2,0] oct-2-ene obtained in Reference Example 1 The antimicrobial activity of -8-one is described below. It was performed by the regular agar dilution method at pH7.0.

Reference Example 3

(±) -cis-7- [2- (2-tritylamino-4-thiazolyl) -2-anti-methoxyiminoacetamido] -2-t-butyloxycarbonyl-1-azabi Preparation of Cyclo [4,2,0] oct-2-en-8-one.

Method a)

73 mg (0.307 mmol) of (±) -cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one obtained in Example 11 ) And 13 (5.9 mg (0.307 mmol) of 2- (2-tritylamino-4-thiazolyl) -2-anti-methoxyiminoacetic acid were dissolved in 2 ml of anhydrous methylene chloride, and dissolved in 1 ml of anhydrous methylene chloride. 69.6 mg (0.307 mmol) of cyclohexyl carbodiimide were added under ice cooling with stirring. The mixture was stirred for 3 hours and reacted overnight at 10 ° C. The reaction mixture was washed with an aqueous 1% phosphate solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dehydrated with magnesium sulfate and concentrated under reduced pressure to give 257 mg of crude product.

This product was purified by column chromatography using 12 g of sullica gel and solvent of n-hexane and ethyl acetate (1: 1) to give 73 mg (35.9%) of the title compound as light yellow glass.

: 1780, 1725, 1695(sh), 1690, 1635

: 1780, 1725, 1695 (sh), 1690, 1635

NMR (CDCl ₃ ) δ (ppm): 8.48 (d, 1H, J = 6Hz), 7.25 (s, 1.5H), 6.30 (t, 1H, J = 3.0Hz), 5.35 (t, 1H, J = 6.4 Hz), 4.05 (S, 3H), 2.5-1.6 (m, 4H), 1.52 (s, 9H).

Method b)

524.9 mg (1.18 mmol) of 2- (2-tritylamino-4-thiazolyl) -2-anti-methoxyiminoacetic acid was dissolved in 10 ml of anhydrous tetrahydrofuran. To this solution, 1.18 ml (1.18 mmol) of 1N-N-methylmorpholine tetrahydrofuran and 1,18 ml (1,18 mmol) of 1N-isobutylchloroformate tetrahydrofuran were added at -30 ° C and the mixture was added. Stir for 40 minutes. 235 mg (0.987) of (±) -cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one dissolved in 5 ml of anhydrous methylene chloride Mmol) was added dropwise to the mixture.

The mixture was reacted for 30 minutes and stirred at 0 ° C. for 2 hours. 10 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give 865 mg of crude product. Silica gel chromatography using 40 g of silica gel by method a) gave 580 mg (87.5%) of the title compound. The IR and NMR spectra of this product were consistent with that of the compound prepared in method a).

Reference Example 4

(±) -cis-7- [2- (2-amino-4-thiazolyl) -2-anti-methoxyimino-acetamido] -1-azabicyclo [4,2,0] oct-2 Preparation of -ene-8-silver-2-carboxylic acid

(±) -cis-7- [2- (2-tritylamino-4-thiazolyl) -2-anti-methoxyiminoacetamido] -2-t-butyloxycarb obtained in Reference Example 3 500 mg (0.754 mmol) of carbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one were dissolved in a mixture of 5 ml of trifluoroacetic acid, 2.5 ml of anhydrous methylene chloride and 2.5 ml of anisol. . The solution was left at 0 ° C. for 3 hours 40 minutes, concentrated under reduced pressure, and 5 ml of 50% acetic acid aqueous solution was added to the concentrate. The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure.

The concentrate was dissolved well with ether and filtered to give 244 mg of crude product. The product was purified by column chromatography using 10 ml of Diaion HP 10 and a solvent of methanol and water (2: 5) to give 90 mg (32.7%) of a pale yellow powder.

:1760, 1670, 1630

: 1760, 1670, 1630

NMR (CD ₃ OD) δ (ppm): 7.47 (s, 1H), 6.40 (m, 1H), 5.51 (d, 1H, J = 5.0Hz), 4.05 (s, 3H), 4.3-3.7 (m, 1H), 2.6-1.1 (m, 1H)

Reference Example 5

(±) -cis-7-[(R) -2-phenyl-2-t-butyloxycarbonyl-aminoacetamido] -2-t-butyloxycarbonyl-1-azabicyclo [4,2 , 0] Preparation of Oct-2-en-8-one.

Method a)

81 mg (0.34 mmol) of (±) -cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one and (R)- 94.0 mg (0.34 mmol) of Nt-butyloxycarbonylphenylglycine was dissolved in 2 ml of anhydrous methylene chloride. To this solution was added together with sodium chloride under ice cooling of 77 mg (0.34 mmol) of dicyclohexyl carbodiimide dissolved in 1 ml of anhydrous methylene chloride.

The mixture was reacted under ice-cooling for 2 hours, and thereto was added 2 drops of acetic acid. The mixture was stirred for 20 minutes and then filtered under reduced pressure. The cake was washed with 20 ml of ethyl acetate and 20 ml of ether was added to the combined washes. The mixture was washed with an aqueous 1% phosphoric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to give 187 mg of crude product. The product was purified by silica gel chromatography with 9 g of silica gel and a solvent of n-hexane and ethyl acetate (1: 1) to give 104 mg (64.9%) of the title compound as a colorless glass.

:1770, 1750, 1750, 1720, 1630

: 1770, 1750, 1750, 1720, 1630

NMR (CDCl ₃ ) δ (ppm): 7.32 (s, 5H), 6.31 (m, 1H), 5.90 (m, 1H), 2.50-1.70 (m, 4H), 1.50 (s, 9H), 1.46 (s , 9H)

Method b)

297.3 mg (1.18 mmol) of (R) -Nt-butyloxycarbonylphenylglycine was dissolved in 5 ml of anhydrous tetrahydrofuran, and 1.18 ml (1.18 mmol) and 1N of 1N, N-methylmorpholine-tetrahydrofuran were added thereto. 1.18 ml (1.18 mmol) of isobutylchloroformate / tetralahydrofuran were added at -30 ° C. The mixture was stirred for 30 minutes and dissolved in 5 ml of anhydrous methylene chloride (±) -cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct A 234 mg (0.983 mmol) solution of 2-en-8-one was added. The mixture was reacted at −30 ° C. for 45 minutes and at 0 ° C. for 4 hours 15 minutes.

The reaction mixture was diluted with 15 ml of methylene chloride, washed successively with water 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, then dehydrated with anhydrous sodium sulfate and concentrated to give 588 mg of crude acyl compound. Silica gel chromatography purification with 28 g of silica gel was carried out by method a) to give 322 mg (69.4%) of the title compound as a colorless glass. The IR and NMR spectra of the product were consistent with that of the compound prepared in method a).

Reference Example 6

(±) -cis-7-[(R) -2-phenyl-2-aminoacetamido] -1-azabicyclo [4,2,0] oct-2-en-8-one-2-car Preparation of Acids.

(±) -cis-7-[(R) -2-phenyl-2-t-butyloxycarbonylaminoacetamide] -2-t-butyloxycarbonyl-1-azabicyclo obtained in Reference Example 5 280 mg (0.59 mmol) of [4,2,0] oct-2-en-8-one were dissolved in 2,5 ml of anhydrous methylene chloride and 2.5 ml of annisol, and 5.0 ml of trifluoroacetic acid was added thereto under ice cooling. The mixture was left under ice cooling for 4 hours and 50 minutes, and then concentrated. 10 ml of ether was added thereto, and the mixture was stirred for 1 hour at room temperature to precipitate. The precipitate was collected by filtration to give 202 mg (70.9%) of the title compound as a pale yellow powder.

:765,1680,1630

: 765,1680,1630

NMR (DSS based on D ₂ O internal) δ (ppm): 7.5 (d, 5H), 6.31 (m, 1H), 4.95 (d, 1H), 3.8-3.5 (m, 1H), 2.6-2.9 (m , 4H)

(±) -cis-7-[(R) -2-phenyl-2-t-aminoacetamido] -1-azabicyclo [4,2,0] oct-2-en-8-one-2 Separation of non-isomers of carboxylic acids.

The compound (50 mg) obtained in the above method was dissolved in 150 ml of water, and this solution was used as a carrier, using Bondapak C-18 (manufactured by Waters Co.), 7% methanol and 0.2 N phosphoric acid. The solvent of sodium hydrogen was eluted eight times and subjected to high performance liquid chromatography.

Isolation of the two fractions was adjusted by absorbance analysis at 254 nm wavelength. After removing methanol under reduced pressure, each fraction was lyophilized, dissolved in water, and adsorbed onto a column filled with 20 ml of Diaion HP-10 (manufactured by Mitsubishi Chemical Co., Ltd.). The column was washed with 200 ml of water and eluted with 20% ethanol. Fractions positive for the ninhydrin test were collected and lyophilized to give 14.0 mg of A-isomer and 24.6 mg of B-isomer as white powder. These are potassium salts of the target compound.

A: Polarity sort

:-74.2°

: -74.2 °

:1750,1690,1640

: 1750,1690,1640

PMR (D ₂ O) δ (ppm): 7.51 (5H, s), 6.15 (1H, t, J = 3.9Hz), 5.20 (1H, t, J = 4.9Hz), 5.19 (1H, s), 3.88 (1H, Octet J = 8.6, 3.7, 4.9 Hz), 2.41-1.41 (H, m)

B: Less polar fraction

(물, C=0.5) : +57.2°

(Water, C = 0.5): + 57.2 °

:1750,1690,1640

: 1750,1690,1640

PMR (D ₂ O) δ (ppm): 7.51 (5H, s), 6.08 (1H, J = 4.2 Hz), 5.41 (1H, J = 4.9 Hz), 3.83 (1H, octet J = 8.6, 3.7, 4.9 Hz)), 2.28-1.01 (4H, m)

Given the structural activity relationship of cephalosporins, isomers with less polarity than those with higher polarity are identified as having 6 (R) m 7 (S) absolute configuration, as shown in the table below.

Reference Example 7

(±) -cis-7-[(R) -2-phenyl-2- (4-ethyl-2,3-dioxo-1-piperadinylcarbonylamino) -acetamido] -2-t- Preparation of Butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one

Method a)

68 mg (0.286 mmol) of (±) -cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one and (R)- 100.4 mg (0.286 mmol) of 2-phenyl-2- (4-ethyl-2,3-dioxo-1-piperadinylcarbonylamino) acetic acid are dissolved in 2 ml of anhydrous methylene chloride, and in 1 ml of anhydrous methylene chloride. A solution of 70 mg (0.315 mmol) of dicyclohexylcarbodiimide dissolved was added under ice cooling. The mixture is filtered and the cake is washed with methylene chloride. The filtrate and washings were combined and washed successively in the order of 1% phosphoric acid and saturated aqueous sodium bicarbonate solution. This wash was dehydrated with anhydrous sodium sulfate and then concentrated to give 189 mg of crude acyl compound. The product was purified by silica gel chromatography using 9 g of silica gel and a solvent of n-hexane and ethyl acetate (1: 2) to give 43 mg of a highly polar isomer, 20 mg of a less polar isomer and 11.1 mg of a mixture of two isomers. . The total yield was 54.1%.

Polar isomers

:1780, 1695(),1685, 1620

1780, 1695 (), 1685, 1620

NMR (CDCl ₃ ) δ (ppm): 7.73 (d, 1H, J = 7.0Hz), 7.37 (s, 5H), 6.25 (m, 1H), 5.7-5.0 (m, 2H), 4.3-3.0 (m , 7H), 2.6-0.7 (m, 4H), 1.50 (s, 9H), 1.20 (t, 3H)

Less polar isomers

:1780,1720,1695(sh),1685

: 1780,1720,1695 (sh), 1685

NMR (CDCl ₃ ) δ (ppm): 7.77 (d, 1H, J = 8.0Hz), 7.30 (m, 5H), 6.21 (m, 1H), 5.67-5.33 (m, 2H), 4.5-3.2 (m , 7H), 3.5-1.0 (m, 4H), 1.50 (s, 9H), 1.20 (t, 3H)

Method b)

428.5 mg (1.13 mmol) of (R) -2-phenyl-2- (4-ethyl-2,3-dioxo-1-piperadinylcarbonylamino) acetic acid are dissolved in 10 ml of anhydrous tetrahydrofuran, and 1.25 ml (1.25 mmol) of 1N, N-methylmorpholine tetrahydrofuran and 1.25 ml (1.25 mmol) of 1N-isobutylchloroformate-tetrahydro fuman were added at -30 ° C.

The mixture was stirred for 30 minutes and dissolved in 5 ml of anhydrous methylene chloride (±) -cis-7-amino-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct A solution of 238 mg (1.13 mmol) of 2-en-8-one was added. The mixture was reacted for 1 hour and then stirred overnight at 10 ° C. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with saturated aqueous 0.1N-zHCl sodium bicarbonate water and water. The washing solution was dehydrated with anhydrous sodium sulfate and concentrated to give 570 mg of crude acyl compound. This product was purified and separated by method a) to yield 73 mg of the highly polar isomer and 6.1 mg of the less polar isomer (total yield 65.4%) using 27 g of silica gel with exception. The IR and NMR spectra of the isomers were consistent with those of the isomers obtained in method a).

Reference Example 8

(±) -cis-7-[(R) -2-phenyl-2- (4-ethyl-2,3-dioxo-1-piperadinylcarbonylamino) acetamido] -1-azabicyclo Preparation of [4,2,0] oct-2-ene-8-one-2-carboxylic acid.

(±) -cis-7-[(R) -2-phenyl-2- (4-ethyl-2,3-dioxo-1-piperidinylcarbonylamino) acetamido obtained in Reference Example 7] 103 mg (0.248 mmol) of 2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one was added to 5 ml of trifluoroacetic acid, 5 ml of methylene chloride, and anisol 2 It was dissolved in an enemy mixture. The mixture was reacted at 0. C for 2 hours and concentrated under reduced pressure. Dry benzene was added to the concentrate, and the mixture was concentrated again to give an oil. Ether was added to the product and the mixture was stirred at room temperature to give a yellow precipitate. The crude product (104 mg) was collected by filtration to obtain a yellow powder. The crude product was dissolved in ethyl acetate, extracted three times with 5 ml of saturated aqueous sodium bicarbonate solution, and washed with ethyl acetate. 0.5 N-HCl was added to this wash solution under ice-cooling, the pH was adjusted to 2.5, and extracted three times with 5 ml of ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dehydrated with magnesium sulfate and concentrated under reduced pressure to yield 41 mg (46.0%) of a pale yellow powder.

:1775, 1720, 1685, 1620(sh)

1775, 1720, 1685, 1620 (sh)

NMR (CD ₃ OD) δ (ppm): 7.31 (s.5H), 6.33 (t, 1H, J = 4.0Hz), 5.40 (m, 2H), 4.30-3.10 (m, 7H), 2.40-0.7 ( m, 4H), 1.27 (t, 3H)

From the strong antimicrobial activity as shown in the table below, this compound was identified as having 6 (R), 7 (S) absolute configuration.

Reference Example 9

-[(R)-2-페닐-2-t-부틸옥시카 르보닐아미노아세트아미도]-4

-메틸-2-t-부틸-옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조.(±) -cis-7

-[(R) -2-phenyl-2-t-butyloxycarbonylaminoacetamido] -4

Preparation of -methyl-2-t-butyl-oxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one.

-아미노-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 하이드로클로라이드 1.44mg(0.5밀리몰)을 가하고, 이 혼합물을 0℃에서 1시간 동안 교반시킨 다음에 5-10℃에서 철야 교반시켰다.132 mg (0.53 mmol) of (R) -Nt-butyloxycarbonylglycine are dissolved in 5 ml of anhydrous tetrahydrofuran, and 0.53 ml (0.53 mmol) of 1N-N-methylmorpholine and 0.53 of 1N-isobutylchloroformate ml (0.53 mmol) was added at 0 ° C. The mixture was stirred for 15 minutes, to which 0.07 ml (0.5 mmol) triethylamine and (±) -cis-7 obtained in Example 14

-Amino-4

1.44 mg (0.5 mmol) of hydrochloride of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one were added and the mixture was heated to 0 ° C. After stirring for 1 hour at 5-10 ° C overnight.

The reaction mixture was diluted with 10 ml of ethyl acetate and washed successively in the order of 10% citric acid, sodium bicarbonate [saturated aqueous solution and saturated aqueous sodium chloride solution]. This wash was dehydrated with anhydrous sodium sulfate and concentrated to afford crude acyl compound. The product was purified by column chromatography using silica gel 30 g, a solvent of n-hexane and ethyl acetate (3: 1, by volume) to give 150 mg (61.7%) of the title compound as a powder.

:3290,1780,1685,1665

: 3290,1780,1685,1665

NMR (CDCl ₃ ) δ (ppm): 7.34 (5H, s), 6.60, 6.49 (1H, d, J = 7Hz respectively), 6.11, 6.04 (1H, d, J = 2Hz each), 5.66, 5.60 (1H , d, J = 7Hz), 5.18 (2H, m), 3.86 (1H, m), 2.46 (1H, m), 1.75 (2H, br), 1.51 (9H, s), 1.42 (9H, s) 1.15, 0.98 (3H, d, J = 7.5 Hz respectively)

Reference Example 10

-[(R)-2-페닐-2-아미노아세트아미도]-4

-메틸-2-카르복시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 트리플루오로아세테이트의 제조(±) -cis-7

-[(R) -2-phenyl-2-aminoacetamido] -4

Preparation of Trifluoroacetate of -methyl-2-carboxy-1-azabicyclo [4,2,0] oct-2-en-8-one

-[(R)-2-페닐-2-t-부틸옥시카르보닐아미노아세트아미도]-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 100mg(0.21밀리몰)을 무수 염화메틸렌 1ml에 용해시키고, 여기에 트리플루오로초산 1ml를 빙욕 냉각하에 가했다. 이 혼합물을 0-5℃에서 가끔 흔들어 주면서 3,5시간동안 방치한 후 감압하에서 농축시켰다. 이 농축액을 무수 에틸에테르 5ml에 용해시키고, 에테르층을 경사시켜 제거했다. 이 처리를 3회 반복하고, 생성 케이크를 감압하여 건조시켜 분말상 목적 화합물 70mg(75%)을 얻었다.(±) -cis-7 obtained in Reference Example 9

-[(R) -2-phenyl-2-t-butyloxycarbonylaminoacetamido] -4

100 mg (0.21 mmol) of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one is dissolved in 1 ml of anhydrous methylene chloride, and 1 ml of fluoroacetic acid was added under ice bath cooling. The mixture was left for 3 to 5 hours with occasional shaking at 0-5 ° C. and then concentrated under reduced pressure. This concentrated solution was dissolved in 5 ml of anhydrous ethyl ether, and the ether layer was decanted to remove. This treatment was repeated three times, and the resulting cake was dried under reduced pressure to obtain 70 mg (75%) of the target compound in powder form.

:3450(sh), 3230(sh), 3060, 2960-2800, 1769, 1695(sh), 1681(sh), 1673

3450 (sh), 3230 (sh), 3060, 2960-2800, 1769, 1695 (sh), 1681 (sh), 1673

NMR (DMSO-d ₆ ) δ (ppm): 9.29 (1H, t, J = 8 Hz), 7.49 (5H, s), 6.11, 6.04 (1H, d, respectively, J = 2 Hz), 5.30 (1H, m ), 4.79 (1H, d, J = 4 Hz), 3.82 (1H, br), 2.44 (br, display and partial overlap of DMSO-d ₆ ), 1.82 (2H, br), 1.14, 0.91 (3H, d, J = 7.5 Hz each)

Reference Example 11

-[(R)-2-페닐-2-t-부틸옥시카르보닐-아세트 아미도]-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조(±) -cis-7

-[(R) -2-phenyl-2-t-butyloxycarbonyl-acetamido] -4

Preparation of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one

-아미노-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 144mg을 원료로서 사용하는 것을 제외하고 참고예 9의 방법과 동일하게 수행하여 목적화합물 140mg(57.6%)을 수득했다.(±) -cis-7 obtained in Example 13

-Amino-4

In the same manner as in Reference Example 9, except that 144 mg of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one was used as a raw material. This gave 140 mg (57.6%) of the title compound.

: 3330,1792(sh), 1782, 1730, 1692, 1975

3330, 1792 (sh), 1782, 1730, 1692, 1975

NMR (CDCl ₃ ) δ (ppm): 7.34 (2H, s), 6.73, 6.60 (1H, d, J = 7Hz respectively), 6.28 (1H, d, J = 7Hz), 5.60 (1H, m), 5.43 -5.18 (2H, m), 3.82 (1H, m), 2.55 (1H, m), 1.69 (2H, m), 1.51 (9H, s), 1.41 (9H, s), 1.09, 1.03 (3H, d J = 7 Hz each)

Reference Example 12

-[(R)-2-페닐-2-아세트아미도]-4

-메틸-2-카르복시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조(±) -cis-7

-[(R) -2-phenyl-2-acetamido] -4

Preparation of -methyl-2-carboxy-1-azabicyclo [4,2,0] oct-2-en-8-one

-[(R)-2-페닐-2-t-부틸옥시카르보닐-아세트아미도]4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 80mg을 원료로서 사용하는 것을 제외하고, 참고예 10의 방법과 동일하게 수행하여 목적화합물 73mg(100%)을 수득했다.(±) -cis-7 obtained in Reference Example 11

-[(R) -2-phenyl-2-t-butyloxycarbonyl-acetamido] 4

-Methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one 80 mg is the same as the method of Reference Example 10, except that it is used as a raw material. To give 73 mg (100%) of the title compound.

:3430, 3200, 3060, 2960-2650, 1780(sh), 1770, 1695(sh), 1680

3430, 3200, 3060, 2960-2650, 1780 (sh), 1770, 1695 (sh), 1680

NMR (DMSO-d ₆ ) δ (ppm): 9.36 (1H, d, J = 8 Hz), 7.47 (5H, s), 6.28 (1H, d, J = 6 Hz), 5.40 (1H, m), 4.98 ( 1H, m), 3.70 (1H, br), 2.45 (br, indication and partial polymerization of DMSO-d ₆ ), 1.80 (2H, m), 1.06, 0.95 (3H, d, respectively J = 7.5 Hz)

Reference Example 13

-메틸-2-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조(±) -cis-7 [2- (2-tritylamino-4-thiazolyl-2-methoxy aminoacet amido] -4

Preparation of -methyl-2-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one

Method A

-아미노-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 88mg(0.35밀리몰)을 무수염화메틸렌 1.5ml에 용해시키고, 여기에 2-(2-트리틸아미노-4-티아졸릴)-2-안티-메톡시아미노초산 155mg(0.35 밀리몰)을 가한후 이 혼합물에 무수디옥산 1.5ml를 가하여 이 혼합물을 더 균일하게 만들었다. 이 혼합물에 디옥산 1ml에 용해시킨 디사이클로헥실카르보디이미드 80mg(0.39밀리몰)을 가하고, 생성되는 혼합물을 5-10℃에서 철야 교반시켰다. 석출된 백색 침전물을 여거시킨 후 이 여액에 초산에틸 10ml 및 에테르 5ml를 가했다. 이 혼합물을 1% 냉인산으로 3회 그리고, 중탄산나트륨 포화수용액으로 세척했다.(±) -cis-7

-Amino-4

88 mg (0.35 mmol) of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one are dissolved in 1.5 ml of anhydrous methylene chloride, and 155 mg (0.35 mmol) of 2- (2-tritylamino-4-thiazolyl) -2-anti-methoxyaminoacetic acid were added and 1.5 ml of dioxane anhydride was added to the mixture to make the mixture more uniform. 80 mg (0.39 mmol) of dicyclohexylcarbodiimide dissolved in 1 ml of dioxane was added to the mixture, and the resulting mixture was stirred overnight at 5-10 ° C. The precipitated white precipitate was filtered off and 10 ml of ethyl acetate and 5 ml of ether were added to the filtrate. The mixture was washed three times with 1% cold phosphoric acid and with saturated aqueous sodium bicarbonate solution.

The washed solution was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to yield 290 mg of the crude target compound as a semisolid. The compound was placed in a column filled with 27 g of silica gel, and eluted with a solvent of n-hexane and ethyl acetate (2: 1). The eluate was concentrated under reduced pressure to give 170 mg (72%) of the title compound.

Melting Point (Recrystallized from n-hexane and ethyl acetate) 214.5-215.5 ° C

: 3240, 1780(sh), 1762, 1730, 1665, 1636

: 3240, 1780 (sh), 1762, 1730, 1665, 1636

NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 7.30 (15HHs), 6.64 (HHs), 6.34 (1H, d, J = 7Hz), 5.48 (HHd, J = 5.5Hz) , 5.43 (⅓H, d, J = 5.5 Hz), 4.08 (1H, s), 4.01 (2H, s), 3.90 (1H, m), 2.66 (1H, m), 1.75 (2H, m), 1.54 ( 3H, s), 1.53 (6H, s), 1.14 (3H, d, J = 7 Hz)

Method B

-아미도-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 염화수소물 144mg(0.5밀리몰)을 가했다. 이 혼합물을 5-10℃에서 철야 교반시킨 뒤 감압하에서 농축시킨 후 초산에틸(10ml)을 이 농축액에서 가하고, 생성혼합물을 5% 염산, 염화나트륨 포화수용액, 탄산나트륨 포화수용액 및 염화나트륨 포화수용액으로 세척한 후 무수 황산나트륨으로 탈수 하고, 감압하에서 농축시켜 조생성물을 얻었다.243.9 mg (0.05 mmol) of 2- (2-tritylamino-4-thiazolyl) -2-anti-methoxyiminoacetic acid are dissolved in 5 ml of anhydrous tetrahydrofuran, and 1N-N-methylmorpholine 0.55 ml (0.55 mmol) was added. To the mixture was added dropwise at 0 ° C while stirring 0.55 ml (0.55 mmol) of 1N-i-butylchloroformate-tetrahydrofuran. After stirring the mixture for 15 more minutes, 0.11 ml (0.5 mmol) of triethylamine was added, followed by (±) -cis-7

Amido-4

144 mg (0.5 mmol) of hydrogen chloride of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one were added. The mixture was stirred at 5-10 ° C. overnight, concentrated under reduced pressure, ethyl acetate (10 ml) was added to the concentrate, and the resulting mixture was washed with 5% hydrochloric acid, saturated aqueous sodium chloride solution, saturated aqueous sodium carbonate solution and saturated aqueous sodium chloride solution. Dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product.

This product was placed in a column filled with 25 g of salica gel, and eluted with a solvent of n-hexane and ethyl acetate (5: 3).

The eluate was concentrated under reduced pressure to give 250 mg (74.0%) of the title compound. The physical properties of this compound were consistent with that of the compound prepared in Method A.

Reference Example 14

-[2-(2-아미노-4-티아졸릴)-2-안티-메톡시아미노아세트아미도]-4

-메틸-2-카르복시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조(±) -cis-7

-[2- (2-amino-4-thiazolyl) -2-anti-methoxyaminoacetamido] -4

Preparation of -methyl-2-carboxy-1-azabicyclo [4,2,0] oct-2-en-8-one

-[2-(2-트리틸아미노-4-티아졸릴-2-안티-메톡시아미노아세트아미도]-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 70mg(0.103밀리몰)을 무수 염화메틸렌 0.5ml 및 아니졸 0.1ml에 용해시키고, 이 혼합물을 0℃까지 냉각시킨 다음에 트리플루오로초산 0.5ml를 가했다. 생성 혼합물을 빙욕에서 3.5시간동안 방치시킨 후 감압하에서 농축시켰다. 이 농축물을 무수 에틸에테르로 용해시키고, 여과시켜 백색 분말을 얻었다. 이 분말을 50% 초산 2ml에 용해시키고, 이 용액을 실온에서 2.5시간동안 방치시킨 다음에 5-10℃에서 철야 방치시켰다.(±) -cis-7 obtained in Reference Example 13

-[2- (2-tritylamino-4-thiazolyl-2-anti-methoxyaminoacetamido] -4

70 mg (0.103 mmol) of methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one in 0.5 ml of anhydrous methylene chloride and 0.1 ml of anisol After dissolving, the mixture was cooled to 0 DEG C and 0.5 ml of trifluoroacetic acid was added thereto. The resulting mixture was left for 3.5 h in an ice bath and then concentrated under reduced pressure. This concentrate was dissolved in anhydrous ethyl ether and filtered to give a white powder. The powder was dissolved in 2 ml of 50% acetic acid and the solution was left at room temperature for 2.5 hours and then at 5-10 ° C. overnight.

The solution was left at room temperature (25 ° C.) for 6 hours and then concentrated under reduced pressure to give a glassy product. The glassy product was dissolved well with ether, filtered and dried to give 20 mg (51%) of the title compound.

:3480, 3300, 1770, 1680, 1635

: 3480, 3300, 1770, 1680, 1635

NMR (DMSO-d ₆ ) δ (ppm): 9.17 (1H, d, J = 8Hz), 7.50 (1H, s), 7.24 (2H, m), 6.31 (1H, d, J = 6Hz), 5.52 ( 1H, m), 4.00 (3H, s), 2.65 (br, display and partial overlap of DMSO-d ₆ ), 1.70 (2H, m), 1.06 (3H, d, J = 7.5 Hz)

Reference Example 15

-[-(2-트리틸아미노-4-티아졸릴)-2-메톡시이미노아세트아미도]-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조(±) -cis-7

-[-(2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido] -4

Preparation of -methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one

-아미노-4

-메틸-2-t-부틸옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 202mg(0.7밀리몰)을 원료로서 사용하는 것을 제외하고 참고예 13의 방법과 동일하게 수행하여 목적화합물 251mg(53%)을 수득했다.(±) -cis-7

-Amino-4

Reference Example 13 except that 202 mg (0.7 mmol) of methyl-2-t-butyloxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one was used as a raw material. 251 mg (53%) of the title compound was obtained in the same manner as the method.

Melting Point 201.0-202.0 ℃

: 3225, 1780(sh), 1760, 1725, 1668, 1635

: 3225, 1780 (sh), 1760, 1725, 1668, 1635

NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 7.35 (1 / 2H, s), 7.30 (15H, s), 6.65 (1 / 2H, s), 6.14 (1H, d, J = 2Hz), 5.38 (1H, dd, J = 5Hz), 4.09 (3 / 2H, s), 4.01 (3 / 2H, s), 3.96 (1H, m), 2.45 (1H, m), 2.05 (2H, m), 1.53 (9 / 2H, s), 1.52 (9 / 2H, s), 1.16 (3H, dd, J = 7.5 Hz)

Reference Example 16

-[2-(2-아미노-4-티아졸릴)-2-메톡시이미노 아세트아미도]-4

-메틸-2-카르복시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조(±) -cis-7

-[2- (2-amino-4-thiazolyl) -2-methoxyimino acetamido] -4

Preparation of -methyl-2-carboxy-1-azabicyclo [4,2,0] oct-2-en-8-one

-[2-(2-트리틸아미노-4-티아졸릴)-2-메톡시아미노아세트아미도]-4

-메틸-2-t-부톡옥시카르보닐-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온 70mg을 원료로서 사용하는 것을 제외하고 참고예 14의 방법과 동일하게 수행하여 목적화합물 22mg(56%)을 수득했다.(±) -cis-7 obtained in Reference Example 15

-[2- (2-tritylamino-4-thiazolyl) -2-methoxyaminoacetamido] -4

In the same manner as in Reference Example 14, except that 70 mg of -methyl-2-t-butoxyoxycarbonyl-1-azabicyclo [4,2,0] oct-2-en-8-one was used as a raw material. This gave 22 mg (56%) of the title compound.

:3460, 3280, 1780(sh), 1770, 1670, 1630

: 3460, 3280, 1780 (sh), 1770, 1670, 1630

NMR (DMSO-d ₆ ) δ (ppm): 9.24 (1 / 2H, d, J = 8Hz), 9.17 (1 / 2H, d, J = 8Hz), 7.50 (1 / 2H, s), 7.25 (2H , m), 6.78 (1 / 2H, s), 6.10 (1H, d, J = 2Hz), 5.47 (1H, m), 4.00 (3 / 2H, s), 3.85 (3 / 2H, s), 2.60 (br, display and partial overlap of DMSO-d ₆ ), 1.91 (2H, m), 1.12 (2H, dd, J = 7.5Hz)

Reference Example 17

-[2-(2-클로로아세틸아미노-4-티아졸릴)-2-신-메톡시이미노 아세트아미도]-4

-메틸-2-카르복시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 제조(±) -cis-7

-[2- (2-Chloroacetylamino-4-thiazolyl) -2-cin-methoxyimino acetamido] -4

Preparation of -methyl-2-carboxy-1-azabicyclo [4,2,0] oct-2-en-8-one

172 mg (0.62 mmol) of (2-chloroacetylamino-4-thiazolyl) -2-cin-methoxyaminoacetic acid were dissolved in 3.6 ml of anhydrous dichloromethane, and 68.9 mg (0.68 mmol) of triethylamine was added thereto to give a solution. Was made uniform. While drying over an sodium chloride ice bath, 129 mg (0.62 mmol) of phosphorus pentachloride was added to the mixture with stirring, and the resulting mixture was stirred for 1.5 hours. n-hexane (13.8 ml) was added to this mixture to remove the supernatant by decantation.

The residue was added with anhydrous techrahydrofuran (1.3 ml) to obtain an acid chloride solution.

-아미노-4

-메틸-2-카르복시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온의 트리플루오로아세테이트 160mg(0.52밀리몰)을 50% 테트라하이드로푸란-물 1ml에 용해시키고, 이어서, 여기에 트리에틸아민 209mg(2.06)밀리몰을 가했다. 이 혼합물을 빙냉하에 교반시키면서 산염화물 용액에 가했다. 이 온도에서 1.5시간동안 교반시킨 후에 , 이 혼합물에 1N 염산을 가하여 pH 4-5로 조정하고, 초산에틸 10ml를 가하여 3회 추출했다.On the other hand, (±) -cis-7 obtained in Example 15

-Amino-4

160 mg (0.52 mmol) of trifluoroacetate of -methyl-2-carboxy-1-azabicyclo [4,2,0] oct-2-en-8-one are dissolved in 1 ml of 50% tetrahydrofuran-water. Subsequently, 209 mg (2.06) mmol of triethylamine was added thereto. This mixture was added to the acid chloride solution while stirring under ice cooling. After stirring at this temperature for 1.5 hours, 1N hydrochloric acid was added to the mixture to adjust the pH to 4-5, and 10 ml of ethyl acetate was added and extracted three times.

The ethyl acetate extract was washed with sodium chloride sap, dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure to yield 147 mg (52.1%) of the title compound.

:1765, 1680

1765, 1680

PMR (DMSO-d ₆ ) δ (ppm): 7.40 (1H, s), 6.32 (1H, d, J = 5.2Hz), 5.53 (1H, m), 4.35 (2H, s), 3.90 (3H, s ), 2.50 (1H, m), 1.90-1.27 (2H, m), 1.10 (3H, d, J = 7.5 Hz)

Reference Example 18

-[2-(2-아미노-4-티아졸릴)-2-신-메톡시이미노아세트아미도]-4

-메틸-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온-2-카르복실산의 제조(±) -cis-7

-[2- (2-amino-4-thiazolyl) -2-cin-methoxyiminoacetamido] -4

Preparation of -methyl-1-azabicyclo [4,2,0] oct-2-ene-8-one-2-carboxylic acid

147 mg (0.321 mmol) of the chloroacetyl compound obtained in Reference Example 17 were dissolved in 0.5 ml of dimethyl sulfoxide and 2.5 ml of dimethylformamide, and 47 mg (0.64 mmol) of thiourea was added thereto while stirring at room temperature.

The mixture was stirred for 14 hours. After ether addition, the supernatant was adsorbed onto a column filled with 10 ml of Diaion HP-10. The column was washed with 240 ml of water and eluted with a solvent of methanol and water (1:10 to 1 ... 2). The eluate was collected and methanol was removed under reduced pressure. The residue was again adsorbed onto a column filled with 10 ml of diion HP-10, the column was washed with 500 ml of water, eluted with a solvent of methanol and water (1: 1), the eluates were collected and concentrated under reduced pressure. 50.2 mg (41.1%) of the title compound were obtained.

:1760, 1680, 1655

1760, 1680, 1655

PMR (DMSO-d ₆ ) δ (ppm): 9.27 (1H, d, J = 9.0Hz), 7.15 (2H, br), 6.75 (1H, s), 6.31 (1H, d, J = 4.2Hz), 5.58 (1H, br), 3.85 (3H, s) 2.60 (1H, m), 1.67 (2H, br), 1.08 (3H, d, J = 8Hz)

Reference Example 19

(±) -cis-7- [2- (2-chloroacetylamino-4-thiazolyl) -2-cin-methoxyaminoacetamido] -1-azabicyclo [4,2,0] oct- Preparation of 2-ene-8-one-2-carboxylic acid

54.2 mg (0.195 mmol) of 2-chloroacetylamino-4-thiazolyl-2-cinmethoxyiminoacetic acid (symmetric) was suspended in 0.98 ml of anhydrous methylene chloride, and 23.48 mg (0.195 mmol) of triethylamine was added thereto. To the reaction mixture, 40.8 mg (0.195 mmol) of phosphorus contaminants were added under ice cooling.

After stirring for 20 minutes, 3.92 ml of n-hexane was added to the mixture, the supernatant was decanted, and the residue was dissolved in 1.96 ml of tetrahydrofuran to obtain an acid chloride solution.

On the other hand, 45.9 mg 10.155 mmol of (±) -cis-7-amido-2-carboxy-1-azabicyclo [4,2,0] oct-2-en-8-one obtained in Example 10 was added. It was dissolved in 2 ml of 50% tetrahydrofuran-water- and 47.4 mg (0.469 mmol) of triethylamine were added thereto. The above acid chloride solution was added to this solution under ice cooling, and the mixture was stirred for 2 hours, and then adjusted to pH 2.0 by addition of 10% hydrochloric acid, and extracted three times with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the washed solution was dehydrated with anhydrous sodium sulfate and concentrated to give 80 mg of the target compound as a pale yellow powder.

: 1760, 1710, 1660

: 1760, 1710, 1660

PMR (DMSO-d ₆ ) δ (ppm): 16.64 (2H, br), 9.39 (1H, d, J = 8.8Hz), 7.47 (1H, s), 6.31 (1H, t), 5.51 (1H, dd , J = 5.5,8.8Hz), 4.38 (2H, s), 3.89 (3H, s), 2.54-0.8 (4H, m)

Reference Example 20

(±) -cis-7- [2- (2-amino-4-thiazolyl) -2-cin-methoxyaminoacetamido] -1-azabicyclo [4,2,0] oct-2- Preparation of En-8-one-2-carboxylic Acid

80 mg of the compound obtained in Reference Example 19 was dissolved in 0.99 ml of dimethylacetamide, and then 27.5 mg of thiourea was added while stirring at room temperature, and the mixture was stirred for 14 hours. After ether was added, the supernatant was decanted to obtain a red oil. The residue was purified by silica gel chromatography using diion HP-10 to give 19.2 mg of the target compound.

: 1760, 1670, 1630

: 1760, 1670, 1630

PMR (DMSO-d ₆ ) δ (ppm): 9.6 (1H, d, J = 8.6Hz), 7.11 (2H, br), 6.75 (1H, s), 6.30 (1H, t), 5.47 (1H, dd , J = 5.4,8.8Hz), 3.89 (3H, s), 2.5-1.0 (4H, m)

Reference Example 21

-(2-티에닐아세트아미도)-4

-아세톡시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온-2-카르복실산의 제조(±) -cis-7

-(2-thienylacetamido) -4

Preparation of Acetoxy-1-azabicyclo [4,2,0] oct-2-ene-8-one-2-carboxylic acid

-아미노-4

-아세톡시-1-아자바이사이클로[4,2,0]옥트-2-엔-8-온-2-카르복실산 126mg을 디옥산 3.0ml 및 물 4.0ml에 용해시켰다. 이 용액을 염화나트륨 빙욕상에서 냉각시켰다. 이 용액에 중탄산나트륨 105mg과 디옥산 1ml에 용해시킨 2-티에닐아세틸클로라이드 84mg을 가한 후 1시간동안 교반하고, 반응혼합물에 1N-염산을 가하여 pH2.0으로 조정하고, 초산에틸로 3회 추출시켰다. 추출물을 합하고, 염화나트륨 포화수용액으로 세척한 후 무수 황산나트륨으로 탈수한 후 여과시켰다. 여액을 농축시키고, 농축액을 실리카겔 20g을 넣은 컬럼에 넣었다.(±) -cis-7 obtained in Example 16

-Amino-4

126 mg of acetoxy-1-azabicyclo [4,2,0] oct-2-ene-8-one-2-carboxylic acid was dissolved in 3.0 ml of dioxane and 4.0 ml of water. This solution was cooled on a sodium chloride ice bath. 105 mg of sodium bicarbonate and 84 mg of 2-thienylacetyl chloride dissolved in 1 ml of dioxane were added to the solution, followed by stirring for 1 hour. The reaction mixture was adjusted to pH 2.0 by adding 1N hydrochloric acid, and extracted three times with ethyl acetate. I was. The extracts were combined, washed with saturated aqueous sodium chloride solution, dehydrated with anhydrous sodium sulfate and filtered. The filtrate was concentrated and the concentrate was placed in a column containing 20 g of silica gel.

Eluted with a mixture of chloroform and ethanol (20: 1 volume ratio). Fractions containing the target compound were combined and concentrated to dryness to give 89.1 ml of the target compound as a pale yellow powder. Yield 47%.

The physical properties of this compound are as follows.

; 1780, 1745, 1660

; 1780, 1745, 1660

NMR (CDCl ₃ + CD ₃ OD) δ (ppm); 7.27-6.93 (3H, m), 6.39 (1H, d, J = 5.4 Hz), 5.43 (1H, d, J = 4.9 Hz), 5.40 (1H, m), 3.79 (2H, s), 2.10-1.26 (3H, s)

The antibacterial activity of the compounds obtained in Reference Examples 4,6,8,10,12,14,16,18,20 and 21 was measured by Hert Infusion Agar Dilution (pH 7.2). The results are shown in the following table. Sephazoline was used as a reference.

Reference Example 22

Preparation of (±) -cis-2-t-butyloxycarbonyl-7-azido-1-azabicyclo [4,2,0] oct-2,4-diene-8-one of the formula

The sheath then relates to the arrangement of both at the 6- and 7-positions of the 1-azibacyclo [4,2,0] octane ring.

1) (±) -cis-2-t-butyloxycarbonyl-5-phenylsulfinyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one A (The sulfinyl group in its 5-position has the same arrangement as that of the proton in the 6- and 7-positions, which is a novel compound prepared in Example 9 above) 960 mg (2.47 mmol) were dissolved in 50 ml of toluene The solution was stirred at 105-110 ° C. for 3.5 hours. This solution was distilled off under reduced pressure to obtain a crude product. The product was poured into a column filled with 50 g of silica gel, eluted with a mixture of n-hexane and ethyl acetate (8: 1), and concentrated under reduced pressure to give 330 mg of a colorless, transparent oil. Yield 50.9%

The physical properties of the product are as follows.

NMR δ (CDCl ₃ ): 6.64 (d, 1H, J = 6Hz), 6.24 (ddd, 1H, J = 2.5,6.0Hz), 6.04 (dd, 1H, J = 2.0,10.0Hz), 5.26 (d, 1H, 5.0Hz), 4.64 (m, 1H), 1.50 (s, 9H)

: 2130, 1790, 1720, 1630

: 2130, 1790, 1720, 1630

2) (±) -cis-2-t-butyloxycarbonyl-5-phenylsulfinyl-7-azido-1-azabicyclo [4,2,0] oct-2-en-8-one B (The phenyl group at its 5-position has the arrangement opposite to that of the protons at the 6- and 7-positions, which is a novel compound prepared by a similar method as described in Example 9 using the raw materials described in Example 8) Was dissolved in 50 ml of carbon tetrachloride and the solution was stirred at 80 ° C. for 1.5 h. The solvent was distilled off under reduced pressure to give the crude product. This product was purified in the same manner as described in Example 1-1) to give 449 mg of the target compound. Yield 74.3%. The physical properties of this compound were consistent with those obtained in Example 1-1).

Reference Example 23

Preparation of (±) -cis-2-carboxy-7-azido-1-azabicyclo [4,2,0] oct-2,4-diene-8-one of the general formula

290 mg (1.1 mmol) of (±) -cis-2-t-butyloxycarbonyl-7-azido-1-azabicyclo [4,2,0] oct-2,4-diene-one obtained in Example 1 ) Was dissolved in a mixture of 6 ml of trifluoroacetic acid and 6 ml of methylene chloride, and the solution was stirred for 1 hour and 40 minutes under ice-cooling, and then stirred for 30 minutes at room temperature, and then the solvent was distilled off under reduced pressure. After adding ethyl acetate, the residue was extracted three times with 5 ml of 10% potassium carbonate. About 15 ml of the extracted aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid, and extracted twice with 10 ml of ethyl acetate. The extract was dehydrated with sodium sulfate and the solvent was distilled off under reduced pressure to yield 156 mg of the target compound as crystals. Yield 68.4%. The physical properties of this compound are as follows.

NMR δ (CD ₃ OD): 6.77 (d, 1H, J = 6.0Hz), 6.33 (m, 1H) 6.13 (dd, 1H, J = 2.0, 10.0Hz), 5.48 (d, 1H, J = 5.0Hz )

:2130, 1780, 1700, 1620

: 2130, 1780, 1700, 1620

Melting point 125-126 ℃

Mass M ⁺ (m / e) 206

Reference Example 24

Preparation of the following general formula (±) -cis-2-carboxy-7-amino-1-azabicyclo [4,2,0] oct-2,4-diene-8-one

39 mg (0.19 mmol) of (±) -cis-2-carboxy-7-azido-1-azabicyclo [4,2,0] oct-2,4-diene-8-one obtained in Example 2 It was dissolved in 3 ml of ethanol, and 22 mg of 5% palladium-calcium carbonate (catalyst) was added thereto, followed by stirring for 5 hours and 45 minutes in a hydrogen stream at atmospheric pressure.

The catalyst was filtered off, washed with 3 ml of ethanol and 3 ml of water, then the filtrate and wash were combined and concentrated under reduced pressure.

After adding 3 ml of ethyl acetate, the concentrate was extracted with 5 ml of water. The aqueous layer was concentrated to dryness under reduced pressure to give 35.4 mg of the target compound. Yield 100%

:3430, 1785, 1645, 1615

: 3430, 1785, 1645, 1615

메르크 회사제)를 충전한 실리카겔상에 전개제로 n-부탄올, 초산 및 물(4:1:1)의 혼합물을 사용하여 컬럼크로마토그라피 Rf치 :0.09Kieselgel 60 # 5719

Column chromatography Rf value: 0.09 using a mixture of n-butanol, acetic acid and water (4: 1: 1) as a developing agent on silica gel filled with

Reference Example 25

(±) -cis-2-carboxy-7- [2- (defenen-2-yl) acetylamino] -1-azabicyclo [4,2,0] oct-2,4-diene of the formula Preparation of 8-one

50 mg of (±) -cis-2-carboxy-7-amino-1-azabicyclo [4,2,0] oct-2,4-diene-8-one obtained in Example 3 was diluted with 2.4 ml of water and 2.4 with acetone. It was dissolved in ml, and 76 mg of sodium bicarbonate was added thereto. 44 mg of thienylacetyl chloride dissolved in 0.2 ml of acetone was added to the mixture under ice cooling.

After insoluble matter was produced within 5 minutes, 2 ml of acetone was further added to make the mixture uniform, and the resulting mixture was stirred for 1 hour and 50 minutes under ice cooling. The reaction mixture was adjusted to pH 2.0 by adding 3 ml of 1N hydrochloric acid, and the solvent was distilled off under reduced pressure to give 60 mg of crude product.

The product was dissolved in 1 ml of ether and filtered to give 23 mg of the desired product. Yield 27.2%.

The physical properties of the product are as follows.

:1790, 1780, 1695, 1655, 1630

: 1790, 1780, 1695, 1655, 1630

NMR δ (CD ₃ OD): 7.2-7.3 (m, 1H), 6.93-6.97 (m, 2H), 6.27 (d, 1H, J = 5.8Hz), 6.21 (ddd, 1H, J = 2.2,5.8, 9.8 Hz), 5.89 (dd, 1H, J = 1.5, 9.8 Hz), 5.72 (d, 1H, 4.6 Hz), 4.67-4.73 (m, 1H), 3.80 (s, 2H)

The antibacterial activity of the product obtained in Reference Example was measured by Hert Infusion Agar Dilution (pH 7.0). The results are described below.

Claims (1)

A general formula characterized by converting the X ₁ group of the compound of formula (I-1) to an amino group, and when R ₃ is an alkyl group, an aryl group, an aralkyl group or a silyl group, converts the COOR ₃ group to a COOH group by a known method. A method for producing the cephalosporin flexible body of I-2).

Where R ₁ represents a hydrogen atom, a halogen group, a hydroxyl group, a lower alkoxy group, an aryloxy group, an aralkyloxy group, an acyloxy group, a sulfonyloxy group, a lower alkylthio group, an arylthio group, an aralkylthio group, a lower alkyl sulfinyl group , Arsulfinyl group, aralkylsulfinyl group, sulfo represented by the general formula-S ⁺ R ₄ R ₅ (wherein R ₄ and R ₅ may be the same as or different from each other and are a lower alkyl group, an aryl group, or an aralkyl group) Nium group, lower alkyl sulfonyl group, aralsulfonyl group, aralkylsulfonyl group, general formula N ⁺ R _6, R ₇ R ₈ (wherein R ₆ R ₇ and R ₈ may be the same as or different from each other and lower alkyl group, aryl Quaternary ammonium group, arylselinyl group or allyl seleninyl group, R ₂ has the same meaning as R ₁ or lower alkyl group, halogen substituted lower alkyl group, azido group, nitrile group or general formula NR ₉ R ₁₀ , wherein R ₉ and R ₁₀ may be the same as or different from each other. A hydrogen atom, a lower alkyl group, an aryl group, or an aralkyl group). R ₃ is a hydrogen atom, substituted or unsubstituted alkyl, aryl, aralkyl or silyl group, X ₁ is an azido group.