JPH0586023A - Beta lactam antibiotic intermediate - Google Patents

Abstract

PURPOSE: To obtain a compound which is useful as intermediate of a new β- lactam antibiotic having antimicrobial activity for microorganisms of both region of Gram negative and Gram position, and useful as antimicrobial agent.

CONSTITUTION: The compound of formula I, for example, (S)-3-amino-2-oxo-1- azetidinesulfonic acid is obtained by sulfonating a compound of formula II, deprotecting the obtained compound and treating the resultant compound of formula III (M⁺ is H, cation) with an acid such as formic acid. In the formula I, R₂ is H, a 1-4C alkoxy; R₃, R₄ are each H, an alkyl, cycloalkyl, phenyl, substituted phenyl, one of R₃ and R₄ is H, the other is an alkoxycarbonyl, alken-1-yl, alkyl-1-yl, 2-phenyl-ethenyl, 2-phenyl-ethynyl. The compound is useful for treatment of fungus infectious disease (urethra and respiratory tract infection) of the mammals containing human, and dosage is 1.4-350 mg/kg/day, preferably about 14-100 mg/kg/day.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a beta-lactam antibiotic intermediate, more specifically an intermediate for producing a novel 3- (substituted or unsubstituted) amino-2-oxo-1-azetidine sulfonic acid derivative having antibacterial activity. Regarding

[0002]

INDUSTRIAL APPLICABILITY The present invention has an activity against microorganisms in both Gram-negative and Gram-positive regions, and is useful as an antimicrobial agent in the 1-position sulfonate (including inner salt). Β having a substituent and an acylamino group at the 3-position
-Lactams, preferably a compound useful as an intermediate for producing a novel β-lactam antibiotic represented by the following formula:

[0003]

[Chemical 2]

In addition to the above β-lactam [I] having a sulfonate substituent at the 1-position and an acylamino substituent at the 3-position, the present invention includes a sulfonate (intramolecular salt) at the 1-position. ) Β-lactams having a substituent and an amino group at the 3-position are included. Preferred compounds of such β-lactams can be represented by the formula:

[Chemical 3] This compound [Ia] is a useful intermediate for the preparation of the corresponding 3-acylamino compound [I].

As will be understood from the compounds [I] and [Ia] of the present invention, the term "amino substituent on the 3-position" means an amino group substituted with an amino group and an acyl group (or substituted with a protecting group). Includes.

Each symbol in formulas [I] and [Ia] has the following meaning throughout the specification. R ₁ is acyl; R ₂ is hydrogen or alkoxy having 1 to 4 carbon atoms; R ₃ and R ₄ are the same or different and each represents hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or R ₃ and R ₄ are One of them is hydrogen, the other is alkoxycarbonyl, alkene-1-yl, alkyn-1-yl, 2-
It can be phenylethenyl or 2-phenylethynyl. M ⁺ can represent hydrogen or a cation.

Alkyl and alkoxy include both straight chain and branched groups. Alkyl or alkoxy having 1 to 10 carbon atoms is preferable.

Cycloalkyl and cycloalkenyl include cycloalkyl and cycloalkenyl having 3, 4, 5, 6 or 7 carbon atoms, respectively.

Alkenyl includes both straight-chain and branched groups, with groups having 1 to 10 carbon atoms being preferred.

Halogen includes fluoro, chloro, bromo and iodo. Substituted phenyl is 1-3 amino,
Included is phenyl substituted with halogen, hydroxy, trifluoromethyl, lower alkyl or lower alkoxy.

Protected carboxyl includes carboxyl groups esterified with conventional ester protecting groups.
Such groups are well known in the art (see, for example, US Pat. No. 4,144,333 (patent date: March 13, 1979)). Carboxyl protecting groups are preferably benzyl, benzhydryl and t-butyl ester groups.

Acyl includes all organic groups derived from an organic acid (ie, a carboxylic acid) by removing the hydroxyl group. Of course, this should not be explained by the examples of acyl groups which limit the scope of the invention, but certain acyl groups are preferred. This acyl group is 6-
Preferred are acyl groups as conventionally used to acylate β-lactam antibiotics, including aminopenicillanic acid and its derivatives and 7-aminocephalosporanic acid and its derivatives [such acyl groups are exemplified in the following references: Have been done: Flynn, for example: Cephalosporins and p.
enicillins) (published by Academic Fress (1972)), West German Patent Publication No. 2,716,677 (published date: 197)
October 10, 1998), Belgian Patent No. 867,994
(Publication date: December 11, 1978), US Pat. No. 4,15
No. 2,432 (patent date: May 1, 1979), No. 3,9
No. 71,778 (patent date: July 27, 1976) and No. 4,172,199 (patent date: October 23, 1979).
Sun), British Patent No. 1,348,894 (Publication Date: 1974
(March 27, 2013)]. Some of the various acyl groups described in the above documents are also cited in the acyl group of the present invention.

As used herein, the term cation means a positively charged atom or group of such atoms. Β of the present invention
- -SO ₃ on the nitrogen atom of the lactam ^- M ⁺ substituents encompass all sulfonic acid salts. Of course, the salt is preferably a pharmacologically acceptable salt, but other salts are also useful for purifying the product of the present invention or as an intermediate for producing a pharmacologically acceptable salt. The cation portion of the sulfonates of the present invention can be obtained from either organic or inorganic bases. Such cation moieties include, but are not limited to, the following ions: ammonium ion; alkylammonium (eg, tetra-n-butylammonium (hereinafter tetrabutylammonium)). Substituted ammonium ions such as; alkali metal ions such as lithium, sodium and potassium; alkaline earth metal ions such as calcium and magnesium; pyridinium ions; dicyclohexylammonium ions: hydrabaminium ions: benzathinium ions, N-methyl- D-glucaminium ion and the like.

M ⁺ can be hydrogen, as described for the meaning of the formula [1] and the symbols therein.

The β-lactams of the present invention can be produced by various synthetic methods as described below. Non-alkoxylated 4-unsubstituted β-lactams [I] (ie compound [I] which is R ₂ , R ₃ and hydrogen) uses 6-aminopenicillanic acid or 6-acylaminopenicillanic acid as starting material. Can be manufactured. Β-lactams [I] in which R ₂ is alkoxy can be prepared from the corresponding non-alkoxylated β-lactams. Some of the compounds of the present invention can be crystallized or recrystallized from a solvent containing water. In this case, hydration water can be constituted. The present invention can be directed to stoichiometric hydrates and compounds containing varying amounts of water, which can be obtained by methods such as lyophilization.

The β-lactams having a sulfonate substituent at the 1-position and an amino group or an acylamino group at the 3-position have at least one chiral center, that is, the carbon atom to which the amino group or the acylamino group is bonded (β -Containing the 3rd carbon atom of the lactam nucleus). The present invention is directed to β-lactams as described above, and the stereochemistry of the bond center at the 3-position of this β-lactam nucleus is determined by the 6-position of naturally-occurring penicillins (eg penicillin G). Is similar to the configuration of the carbon atom of and the configuration of the carbon atom at the 7-position of naturally occurring cephamycins (eg, cefamycin C).

Preferred β-lactams [I] and [I
With respect to a], these formulas are structurally described so as to show the stereochemistry of the bond center at the 3-position. For the usual notation, compounds [I] and [Ia] in which R ₂ is hydrogen have the S configuration and compounds [I] and [Ia] in which R ₂ is alkoxy have the R configuration. Racemic mixtures containing β-lactams as described above are also included within the scope of the invention.

The β-lactams having a sulfonate substituent at the 1-position of the β-lactam nucleus and an amino group or an acylamino group at the 3-position have activity against gram-negative and gram-positive microorganisms. .. The sulfonate substituent is an essential group for the activity of the compound of the present invention. The compounds of the present invention in which R ₃ and / or R ₄ are hydrogen or alkyl (especially methyl) exhibit particularly useful activity.

The compounds according to the invention can be used as medicaments for treating bacterial infections (urethra and respiratory infections) in mammals and humans, for example in livestock (eg dogs, cats, cows, horses etc.). ..

In order to treat bacterial infections in mammals (including human), the compound of the present invention is administered to mammals in need thereof at about 1.4-350 mg / kg / day (preferably about 14-100 m).
g / kg / day). All the administration methods conventionally used for supplying penicillins and cephalosporins to the site of infection can be used for the administration method of the novel β-lactams of the present invention. Such administration methods include oral, intravenous, intramuscular and suppository administration methods.

The β-lactam product of the present invention has a sulfonic acid group (sulfo group: —S) on the nitrogen atom at the 1-position of the β-lactam nucleus.
It can be produced by introducing O ₃ −). This sulfonation reaction involves converting the β-lactam to a sulfur trioxide complex or equivalent sulfonating agent (e.g., chlorosulfonate).
It can be easily progressed by treating with.

The most commonly used sulfur trioxide complexes are pyridine-sulfur trioxide; lutidine, sulfur trioxide; dimethylformamide-sulfur trioxide and picoline-sulfur trioxide. Instead of using the complex formed in advance, chlorosulfonyl-trimethylsilyl ester and pyridine may be used as reagents to form the complex in the reaction system. In the sulfonation reaction, for example, the nitrogen atom of the β-lactam nucleus is silylated, and the silylated compound is subjected to a silyl exchange reaction with trimethylsilyl chlorosulfonate or a similar reagent to obtain the sulfonation reaction through an intermediate obtained. be able to. Illustrative silylating agents are monosilyl trifluoroacetamide, trimethylsilyl chloride / triethylamine and bis-trimethylsilyl trifluoroacetamide.

The sulfonation reaction can generally be carried out in the presence of pyridine or a mixture of organic solvents, preferably a polar solvent such as dimethylformamide and a mixture of halogenated hydrocarbons such as dichloromethane.

The product initially obtained by the sulfonation reaction is a sulfonated β-lactam salt. When the sulfonated complex is pyridine-sulfur trioxide, the resulting product has the formula:

[Chemical 4] (In the formula, M ⁺ is as defined above)
Lactam β-lactam-sulfonated pyridinium salt
(Salt in which M ⁺ is a pyridinium ion). Such a complex compound can be converted into another sulfonate by a conventional method (for example, a method using an ion exchange resin, crystallization or an ion pair extraction method). This conversion method is also useful for purifying the target compound. Method for converting pyridine salt into potassium salt with potassium phosphate or potassium ethylhexanoate, method for converting tetrabutylammonium salt with sulfur hydrogen tetrabutylammonium, method for converting zwitterionic compound (M ⁺ is hydrogen) with formic acid Is particularly useful.

The sulfonation reaction in which a sulfo group is introduced onto the nitrogen atom of the β-lactam nucleus is carried out at various synthetic steps including a method of introducing the β-lactam nucleus prior to its formation (this method will be described later). be able to. The sulfonation reaction can usually proceed at room temperature in the presence of the solvent. If an amino group is present, the sulfonation reaction is preferably carried out with the amino group protected.

For example, the formula of the sulfonation reaction using a benzyloxycarbonyl protecting group is as follows.

[Chemical 5] (In the formula, R ₂ , R ₃ , R ₄ and M ⁺ are as defined above)

To protect the amino group, other protective groups such as t-butyloxycarbonyl group, acyl groups such as acetyl, benzoyl and phenylacetyl, triphenylmethyl group are used, or azido group-type amino groups are used. The group can be retained. The desired acyl can then be attached by conventional acylation reactions.

Carboxylic Acids as a Method Included in Acylation to Convert Compound [III] into Product [I]
The method of reacting with (R ₁ —OH), the corresponding carboxylic acid halide or carboxylic acid anhydride can be exemplified. When R ₂ is alkoxy, acylation can be most effectively performed by using acid chloride or acid bromide as the acylating agent. The reaction with a carboxylic acid can be most easily proceeded in the presence of a carbodiimide such as dicyclohexylcarbodiimide or a substance capable of forming an active ester form in the reaction system (for example, N-hydroxybenzotriazole). In this example, when an acyl group; R ₁ contains a reactive functional group (for example, an amino group or a carboxyl group), such reactive functional group is protected, and then an acylation operation is performed, followed by deprotection of the obtained compound. It may be necessary to perform basic treatment. Alternatively, the desired compound [V] can be obtained by appropriately acylating the compound [IV] having an acyl group as shown in the following formula:

[Chemical 6] (Wherein R ₁ , R ₂ , R ₃ , R ₄ and M ⁺ have the same meanings as described above)

In order to obtain a product in which R ₂ is lower alkoxy, the acylated nitrogen atom at the 3-position is halogenated by a conventional method after or before sulfonating a compound in which R ₂ is hydrogen. The R ₂ group (lower alkoxy) can be introduced by (for example chlorination) and then reacting it with a lower alkoxide as shown in the following formula:

[Chemical 7] (In the formula, R ₃ , R ₄ and M ⁺ have the same meanings as above)

The acylating agent used in the acylation reaction functions as a protecting group and can be eliminated after the reaction to give a deacylated product (compound having --NH ₂ at the 3-position), which can be easily removed. Including a group to be released.

Further, as shown in the following formula, β-
A lactam ring can be formed. The sulfonation reaction can be carried out before or after carrying out the ring closure treatment:

[Chemical 8] (In the formula, V represents a group capable of leaving. R ₃ , R ₄ and M ⁺ have the same meanings as described above.) The acyl group in this reaction functions as a protecting group, which is released to produce NH _2-. It can be an easily removable group from which a product can be obtained.

An azetidinone starting material in which R ₂ is hydrogen and at least one of R ₃ and R ₄ is hydrogen has the formula:

[Chemical 9] It can be produced from the amino acid represented by (wherein at least one of R ₃ and R ₄ is hydrogen) by the method described below. For example, the amino group of the starting material [XII] is protected with a protecting group (eg, classical t-butoxycarbonyl (hereinafter abbreviated as Boc)), and the carboxyl group of this protected amino acid and the formula:

[Chemical 10] (Wherein Y represents alkyl or benzyl) is reacted in the presence of a carbodiimide compound to give a compound of the formula:

[Chemical 11] (Wherein Y is as defined above) (wherein R ₃
And R ₄ at least one of which is hydrogen). This compound [XIV] and a classical reagent such as methanesulfonyl chloride (hereinafter, methanesulfonyl group is abbreviated as Ms)
Is converted into a group capable of eliminating hydroxy of compound [XIV]: V, and a compound of the formula:

[Chemical formula 12] (Wherein V and Y are as defined above), a protected compound (wherein at least one of R ₃ and R ₄ is hydrogen) is obtained.

Other removable groups that can be used: V include benzenesulfonyl, toluenesulfonyl, chloro, bromo and iodo.

The fully protected compound [XV] above is ring-closed by treatment with a base (eg potassium carbonate) to give the formula:

[Chemical 13] (Wherein Y is as defined above) (wherein R ₃
And R ₄ at least one of which is hydrogen). This reaction operation is preferably carried out under reflux conditions in an organic solvent such as acetone.

The compound [XVI] can also be obtained by directly ring-closing without converting the hydroxy group of the compound [XIV] into a group capable of leaving. This ring closure is a compound [X
IV] is treated with triphenylphosphine and ethyl azodicarboxylate to give compound [XVI] (wherein R ₃ and R _3
4 is at least one of which is hydrogen).

When Y of the obtained azetidinone [XVI] is alkyl, the protecting group at the 1-position is eliminated by sodium reduction to give the formula:

[Chemical 14] To obtain an intermediate represented by (at least one of R ₃ and R ₄ is hydrogen). When Y is benzyl, the azetidinone [XVI] is for example catalytically (eg palladium / carbon) hydrogenated to give the corresponding N-hydroxy compound, which is treated with titanium trichloride to give the above intermediate [XVII] ( At least one of R ₃ and R ₄ is hydrogen).

The configurational conversion of the R ₃ group and the R ₄ group occurs by the synthetic method including the ring closure reaction as described above.

Obtained azetidinone intermediate [XVII]
By sulfonation as above, the formula:

[Chemical 15] (Wherein, M ⁺ is as defined above) (wherein R is
₃ and R ₄ are at least one of which is hydrogen).

The compound [I] of the present invention in which R ₂ is hydrogen and at least one of R ₃ and R ₄ is hydrogen can be produced by the following method using the following amino acid amide [XIX] as a starting material. .. Ie the formula:

[Chemical 16] After protecting the amino group of the amino acid amide represented by (wherein at least one of R ₃ and R ₄ is hydrogen) with a protecting group such as classical benzyloxycarbonyl (hereinafter abbreviated as Z) or Boc , Hydroxy is converted to a eliminable group such as Ms group: V to obtain the formula:

[Chemical 17] (Wherein A represents a protecting group) (wherein at least one of R ₃ and R ₄ is hydrogen),
This compound [XX] is sulfonated to give a compound of the formula

[Chemical 18] (Wherein, M ⁺ and A have the same meanings as described above)
(Wherein at least one of R ₃ and R ₄ is hydrogen).

This compound [XXI] is cyclized with a base (eg potassium carbonate) to give the following compound [XXI]
I] is obtained. This reaction is carried out using water and an organic solvent (eg 1,
It is preferably carried out under reflux conditions in a mixture of halogenated hydrocarbons such as 2-dichloroethane). This operation gives the formula:

[Chemical 19] (In the formula, M ⁺ and A have the same meanings as described above)
(Wherein at least one of R ₃ and R ₄ is hydrogen) can be obtained.

This sulfonated azetidinone [XXII]
(Protecting group: a compound having A) and the relative compound (for example, compound [V ′] or compound [VIII] in which R ₂ is alkoxy) are eliminated by, for example, catalytic hydrogenation. With the formula:

[Chemical 20] (In the formula, R ₂ represents hydrogen or alkoxy. M ⁺ is as defined above) (wherein at least one of R ₃ and R ₄ is hydrogen).

Also this compound

By treating [XXIII] with an acid such as formic acid, the formula:

[Chemical 21] A corresponding zwitterionic compound represented by the formula (wherein R ₂ is as defined above) (wherein at least one of R ₃ and R ₄ is hydrogen) can be obtained.

The corresponding zwitterionic compound [XXIV] can be obtained by treating the sulfonated azetidinone [XXII] in which A is a protecting group: Boc with a deprotecting group under acidic conditions (for example, using formic acid).

As an excellent source of the β-lactam starting material in the present invention, 6-aminopenicillanic acid or 7-aminocephalosporanic acid represented by the following formula and 6-alkoxy-substituted or 7-alkoxy-substituted if necessary, respectively. Examples of penicillins or cephalosporins having groups are:

[Chemical formula 22] (In the formula, R ′ ₁ represents hydrogen or acyl, and R ₂ represents hydrogen or alkoxy)

The 3-amino-2-azetidinone starting material can be prepared by applying the methods described in various publications [eg Chem. Soc. Special Publication No. 2888. Page (1977), The Chemistry of Penicillins
257 (Princeton University Press) and Synthesis, page 494 (1977)].

When 6-aminopenicillanic acid or 7-aminocephalosporanic acid is used, it is first reduced with Raney-nickel and desulfurized to give the following compound [XX:
VI] is obtained. This reaction can proceed in water under reflux conditions.

[Chemical formula 23] (In the formula, R ′ ₁ and R ₂ are as defined above)

By substituting the carboxyl group of this compound [XXVI] with an acetate group and then hydrolyzing it, R ₁ is hydrogen or acyl, R ₂ is hydrogen or lower alkoxy, and R ₃ and R ₄ are hydrogen. A compound [I
V] (3-amino-3-alkoxy-2-azetidinone)
Can be obtained. That is, compound [XXVI] is treated with cupric acetate and lead tetraacetate in an organic solvent (for example, acetonitrile) to substitute the carboxyl group with an acetate group. Hydrolysis of the resulting compound can be accomplished using potassium carbonate in the presence of sodium borohydride. Introduction of the sulfo group at the 1-position of the 3-amino-3-alkoxy-2-azetidinone compound can be achieved by reacting this intermediate with a mixture of dimethylformamide and sulfur trioxide.

The 3-azido-2-azetidinone starting material can be prepared by the following method. Ie the formula: (In the formula, R ₃ and R ₄ have the same meanings as described above) and an halosulfonyl isocyanate (preferably chlorosulfonyl isocyanate) represented by the formula: O═C═N—SO ₂ -halogen [XXVII]. Reacting formula:

[Chemical formula 24] (Wherein R ₃ and R ₄ have the same meanings as described above), and azetidinone is produced.

The resulting azetidinone [XXIX] was reductively hydrolyzed to give the formula:

[Chemical 25] (In the formula, R ₃ and R ₄ have the same meanings as described above) to obtain an N-unsubstituted β-lactam. The above series of reaction examples are described in various documents [eg Chem. Soc. Rev. Vol. 5, p. 181 (1976), The Journal of Organic Chemistry (J. Org. Chem.) No. 35.
Vol. 2043 (1970)].

The resulting azetidinone [XXX] (or the corresponding sulfonated compound) is reacted with an arylsulfonyl azide (eg toluenesulfonyl azide) to give the formula:

[Chemical formula 26] (In the formula, R ₃ and R ₄ have the same meaning as above), an azide starting material (including a sulfonated compound) can be obtained. This reaction involves protecting the nitrogen of azetidinone [XXX] with a silyl group (eg t-butyldimethylsilyl or t-butyldiphenylsilyl) and treating it with a strong organic base (eg lithium diisopropylamine) at low temperature to form a lactam nucleus. After forming the anion at the 3-position, the anion is treated with toluenesulfonyl azide. The resulting intermediate is treated with trimethylsilyl chloride, then N-
The compound [XXXI] can be obtained by acid hydrolysis or solvolysis with fluorine of the protecting group.

The azide starting material [XXXI] can be prepared by an alternative method described below. That is, the formula:

[Chemical 27] By reacting a primary amine represented by with an aldehyde represented by the formula: R ₃ CH═O to obtain a corresponding Schiff salt. This Schiff salt and activated azidoacetic acid were subjected to a [2 + 2] cycloaddition reaction, and the formula:

[Chemical 28] (Where Q is

[Chemical 29] Represents. R ₃ and R ₄ are as defined above)
-Azido-2-azetidinone is obtained. The azide starting material [XXXI] can be obtained by oxidatively eliminating the substituent: Q of this compound.

The 3-acylamino-2-azetidinone starting material is obtained by reducing 3-azido-2-azetidinone [XXXI] to produce the corresponding 3-amino-2-azetidinone and acylating the product. You can

As before, the products where R ₂ is lower alkoxy can be prepared from the corresponding compounds where R ₂ is hydrogen. That is, by chlorinating the nitrogen atom of the amide group of the non-alkoxy compound, the formula:

[Chemical 30] (Wherein R ₁ , R ₃ , R ₄ and M ⁺ have the same meanings as described above) are obtained. Reagents and methods for N-chlorination of amide groups are well known in the art. Examples of the reagent include t-butyl hypozincate, sodium hypozincate, chlorine and the like. Reaction operation is an organic solvent
It can be carried out (for example in a lower alkanol such as methanol) or in a two-phase solvent system (for example water / methylene chloride) in the presence of a base such as sodium borate decahydrate. The reaction is preferably allowed to proceed at cold temperature.

By reacting the resulting intermediate [XXXII] with an alkoxylating agent (for example, an alkali metal alkoxide), a product [I] (enantiomeric mixture) in which R ₂ is alkoxy can be obtained. This reaction can proceed in an organic solvent (for example, a polar organic solvent such as dimethylformamide) at a cold temperature.

The compound [I] of the present invention in which R ₂ is alkoxy is an intermediate [I] in which R ₁ -NH- is a carbamate (for example, R ₁ is benzyloxycarbonyl) and R ₂ is hydrogen.
V] can be alkoxylated and a sulfo group can be introduced into the 1-position of the resulting compound to produce the compound. The compound [VI] is halogenated (for example, chlorinated) by the method described above (a method of chlorinating a non-alkoxy compound [I] to obtain a compound [XXXII]) to give a compound of formula:

[Chemical 31] (In the formula, R ₃ and R ₄ are as defined above). This is alkoxylated by the same method as the above (operation for converting the compound [XXXII] into the target compound [I]), and then a reducing agent such as trimethyl phosphite is added to obtain the compound represented by the formula:

[Chemical 32] (Wherein R ₃ and R ₄ are as defined above)
(Enantiomeric mixture) is obtained. The product [I] can then be obtained by sulfonating it as described above.

The product [I] obtained by the above method in which R ₂ is alkoxy is obtained as a racemic mixture. The enantiomer with the R configuration is isolated from the racemic mixture by conventional methods such as fractional crystallization of the appropriate salt with an optically active organic amine or ion pair chromatography using an optically active cation as desired. be able to.

Next, the production method of the preferred compound of the present invention will be specifically described with reference to examples. Example 1 (S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinecarboxylic acid pyridine salt (1:
Preparation of 1):-Method I: A.A. 1-[(1R) -carboxy-2-methyl (propyl)]
Preparation of 2-oxo- (3S)-[[(phenylmethoxy) carbonyl] amino] azetidine: 12.98 g (0.06 mol) 6-aminopenicillanic acid and sodium hydrogen carbonate 5.
A slurry of 18 g of water in 140 ml of water (stirring for about 10 minutes, but not completely) is a well stirred (mechanical stirring) Raney nickel (washed with water of pH 8.0) suspension (260 ml = 130 g). , 70 ° C. in an oil bath). 15
After minutes, the slurry was cooled and filtered, and the filtrate was 5.18 g sodium hydrogen carbonate and benzyl chloroformate 11.9.
It is treated with a solution of 4 g (0.07 mol) in 12 ml of acetone.
After 30 minutes, the solution is adjusted to pH 2.5 and extracted with methylene chloride. The organic layer is dried, evaporated and treated with ether-hexane to give a total of 6.83 g of the title compound.

B. 1-[(acetyloxy) -2-methyl
Production of (propyl)]-2-oxo- (3S)-[[(phenylmethoxy) carbonyl] amino] azetidine:-A solution of 6.83 g (0.0213 mol) of the acid obtained in A above in 213 ml of acetonitrile was added to acetic acid. Cupric monohydrate 1.
95 g (0.0107 mol) and lead tetraacetate 9.5 g (0.02
13 mol). The slurry is immersed in an oil bath at 65 ° C., and a nitrogen stream is bubbled through the slurry until the starting material is digested and stirred. Filter the slurry and wash the solids with ethyl acetate. The filtrate and washings are combined, evaporated under reduced pressure, the residue is dissolved in 100 ml of ethyl acetate and 100 ml of water and adjusted to pH 7. The ethyl acetate layer was separated and dried,
Evaporate to give 6.235 g of the title compound.

C. Preparation of (S)-(2-oxo-3-azetidinyl) carbamic acid phenylmethyl ester: -3.12 g (0.0093 mol) of the acetate obtained in B above was dissolved in 70 ml of methanol and 7 ml of water and this solution Is cooled to -15 ° C, 1.33 g of potassium carbonate and 0.349 g of sodium borohydride are added, and the mixture is -15 to 15
Stir at 0 ° C. After the reaction was completed (about 2 hours), the mixture was mixed with 2N.
Adjust to pH 7 with hydrochloric acid and concentrate under reduced pressure. PH of concentrate
Adjust to 5.8, saturate with salt and extract 3 times with ethyl acetate. The organic layer is dried, evaporated under reduced pressure and the residue is combined with a similar material obtained by treatment of another lot and treated with ether to give 3.30 g of the title compound.

D. Preparation of (S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid pyridine salt: -Method I: in a nitrogen atmosphere in 2 ml of dry methylene chloride and 2 ml of dry dimethylformamide. A solution of 0.440 g (0.002 mol) of azetidinone obtained in C above is stirred with 0.350 g (0.022 mol) of pyridine-sulfur trioxide complex for 2 hours. Most of the solvent was removed under reduced pressure and the residue was treated with ethyl acetate to give the title compound as a solid.
758 g were obtained. _{NMR (D 20 -CD 30 D)} : 3.63 (1H, d of d, j = 6.
4) 3.90 (1H, t, j = 6), 4.85 (1H, d d, j
= 6.4), 5.10 (2H, S), 7.27 (5H, S),
8.0-9.0 ppm (m, 5H).

Method II: Under nitrogen atmosphere, with stirring 7.9 g of anhydrous pyridine at -20 ° C, 18.87 g of chlorosulfonyltrimethylsilyl ester are added dropwise. After completion of the dropwise addition, stirring is continued for 30 minutes at room temperature, and then trimethylchlorosilane is removed under reduced pressure. The above method IC in 120 ml of dimethylformamide and 120 ml of methylene chloride
A solution of 20 g of the azetidinone obtained in 1. is added and stirring is continued for 3.5 hours at ambient temperature. The solvent was distilled off under reduced pressure,
The oily residue was crystallized by adding ethyl acetate to obtain 31 g of the title compound. The NMR data for this product can be found in Method I above.
Matches that of the product of.

Example 2 Preparation of (S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt: -Method I: (S) -2-oxo- 3-[[(phenylmethoxy)
Carbonyl] amino] -azetidine sulfonic acid pyridine salt
(See Example 1) 0.135 g is dissolved in 2 ml of 0.5M potassium phosphate monobasic (adjusted to pH 5.5 with 2N potassium hydroxide) and applied to a 25 ml HP-20AG column. The column was eluted with 100 ml buffer, 200 ml water and 100 ml acetone-water (1: 1), fractionation (25 ml) 14-
Evaporation of 15 (indicating high Rydon positivity) yielded 0.080 g of the title compound (spectral data for this product is consistent with that of the next product).

Method II: (S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid pyridine salt (see Example 1) 0.600 g in water 2 m.
Dissolve in 1 l potassium phosphate monobasic buffer (pH 5.5) 1
Mix with 5 ml. The resulting solid-containing slurry is cooled to 0 ° C., the solid is filtered off and washed with cold buffer, cold 50% ethanol, ethanol and ether to give the title compound.
(Substance containing excess potassium ion by analysis) 0.37
Get 0 g. A solution of 0.280 g of salt product in 10 ml of water was added to 10
Apply to a 0 ml HP-20 column. 200m column
Elute with 1 then water-acetone (9: 1). Each fraction (5
0 ml) is collected and fraction 7 is evaporated to give a solid. Treated with acetone, filtered and dried under reduced pressure to give the title compound.
164 g were obtained. Melting point 193-196 [deg.] C. Elemental analysis, calculated as C ₁₁ H ₁₁ N ₂ O ₆ SK · 1 / 2H ₂ O: C, 38.02%; H, 3.48%; N, 8.06
%; S, 9.23%; K, 11.25%, actual value: C, 38.19%; H, 3.24%; N, 8.15
%; S, 9.12%; K, 11.53%. _{NMR (D 20): 3.69 (} 1H, d of d, j = 6.4), 3.9
1 (1H, t, j = 6), 4.76 (1H, m), 5.16 (2H,
S), 7.43 ppm (5H, S).

(S)-(2-oxo-3-acetylidinyl) carbamic acid phenyl methyl ester (see Example 1C) 2
Suspending 0.0 g in 200 ml of acetonitrile, 21.6 ml of monotrimethylsilyltrifluoroacetamide (2
5.3 g) is added and the mixture is heated to 50 ° C. with stirring for 1 hour. After cooling to 0 ° C. on an ice bath, 17.2 g of trimethylsilyl chlorosulfonate are added dropwise and the solution is stirred at ambient temperature for 6 hours. A mixture of 24.2 g of potassium ethylhexanoate and 100 ml of butanol was added to this solution, and stirring was continued for another hour. The slurry is poured onto 1000 ml of dry diethyl ether, the precipitate is filtered off and dried under reduced pressure. This compound is dissolved in 500 ml of water, adjusted to pH 5.0 with potassium carbonate, the insoluble material is filtered off and the mother liquor is freeze-dried to give 19.4 g of crude product. A small amount of potassium chloride was removed by chromatography to obtain the product. The spectral data of the product is in agreement with that of the product of Method II.

Example 3 Preparation of (S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid tetrabutylammonium salt (1: 1):-Method I :( S) -2-oxo-3-[[(phenylmethoxy)
34.3 g of carbonyl] amino] -1-azetidinesulfonic acid pyridine salt (1: 1) [see Example 1] is dissolved in 800 ml of water. The solution is clarified with activated charcoal, a mixture of 30.7 g of tetrabutylammonium hydrogensulfate and 80 ml of water is added and the pH is adjusted to 5.5 with 1N potassium hydroxide. The solvent is removed under reduced pressure to a volume of about 200 ml, the precipitated tetrabutylammonium salt product is filtered off and dried under reduced pressure. Although this compound may be recrystallized from water, it was dissolved in methylene chloride, filtered, and ether was added to cause precipitation to obtain 34.3 g of the title compound. Melting point 108-110 [deg.] C.

Method II: (S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt (1: 1) [see Example 2] 20.2 g
Was dissolved in 500 ml of water, filtered, and a mixture of 20.3 g of tetrabutylammonium hydrogensulfate and 100 ml of water was added.
Adjust to pH 5.5 with N-potassium hydroxide. The volume is reduced to about 100 ml under reduced pressure and the precipitated tetrabutylammonium salt product is filtered off. This compound was dissolved in 30 ml of methylene chloride, filtered, and ether was added to precipitate the product to obtain 21 g of the title compound. Melting point 109-111
° C.

Example 4 Preparation of (3S) -α-[[(2-oxo-1-sulfo-3-azetidinyl) amino] carbonyl] benzeneacetic acid phenylmethyl ester potassium salt (1: 1):-A. Preparation of (S) -3-Amino-2-azetidinone :-( S)-(2-oxo-3-azetidinyl) carbamic acid phenylmethyl ester (Example 1C) in 100 ml of methanol in the presence of 1 g of palladium / activated carbon catalyst. Hydrogenate 3 g. When the theoretical amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated to dryness. After standing, crystallization gives 1.1 g of the title compound.

B. Production of (3S) -α-[[(2-oxo-3-azetidinyl) amino] carbonyl] benzeneacetic acid phenylmethyl ester: -Dissolve 3.0 g of the azetidinone compound obtained in A above in 100 ml of dimethylformamide, The solution was cooled to 0 ° C., 4.5 g of N-methylmorpholine was added, and then α-
A mixture of 10.8 g of (chlorocarbonyl) benzeneacetic acid phenylmethyl ester and 50 ml of acetonitrile is added dropwise with stirring. The mixture is stirred at 5 ° C. for about 16 hours, the solvent is distilled off under reduced pressure and 100 ml of water are added to the residue. This aqueous suspension is extracted twice with 100 ml portions of methylene chloride. The organic layers are combined, washed with sodium hydrogen carbonate, 2N phosphoric acid and water, dried over sodium sulfate, filtered and evaporated to dryness. The residue is crystallized from ethyl acetate and petroleum ether to give 3.7 g of product. Melting point 164-166 [deg.] C.

C. Preparation of (3S) -α-[[(2-oxo-1-sulfo-3-azetidinyl) amino] carbonyl] benzeneacetic acid phenylmethyl ester potassium salt (1: 1):-6.9 g of the above B product Is suspended in 150 ml of acetonitrile. 5.7 g of monotrimethylsilyl trifluoroacetamide was added and the solution was stirred at 50 ° C. for 3 hours.
Warm for 0 minutes. The solution is cooled to 0 ° C. and 3.9 g of trimethylsilyl chlorosulfonate are added dropwise. After the addition is complete,
The mixture is warmed at 50 ° C. for 5 hours. After cooling to 20 ° C, 7.6 g of potassium ethylhexanoate and 1 of butanol
Add 0 ml of the mixture and continue stirring for 30 minutes. 300 ml of ether are added to precipitate the title compound, which is filtered off. The crude product was mixed with 100 ml of dry acetonitrile 3
Stir for 0 minutes and filter to obtain 4.5 g of the title compound. Melting point 118-120 [deg.] C. The crude product was further purified by HP20 chromatography followed by lyophilization to give the title compound. Melting point 188-190 [deg.] C.

Example 5 (S) -3-[[(2-amino-4-thiazolyl) acetyl]
Preparation of Amino] -2-oxo-1-azetidinesulfonic acid potassium salt: -A. Preparation of (S) -3-amino-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt :-( S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azeti 2 g of tetrabutylammonium ginsulfonate (see Example 3) was dissolved in 100 ml of dimethylformamide and palladium / activated carbon was used as a catalyst.
Add 1 g (10%) and hydrogenate for about 30 minutes. The catalyst is filtered off and dimethylformamide is removed to give the title compound as an oily residue. NMR (CDCl ₃ ): 3.82 (1H, t, j = 5.5), 4.
05 (d, 1H, d d, j = 5.5,2.5 cps).

B. Preparation of (S) -3-[[(2-amino-4-thiazolyl) acetyl] amino] -2-oxo-1-azetidinesulfonic acid potassium salt: -2 g of the product of A above in 100 ml of dry dimethylformamide. A solution of 0.7 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide was added dropwise to 0.5 g of aminothiazoleacetic acid and 0.4 g of hydroxybenzotriazole, and the mixture was stirred at 0 ° C. After the addition, add 1 at 20 ℃
Continue stirring for 2 hours. The insoluble urea body is filtered off and the solvent is evaporated under reduced pressure. The oily residue is treated at room temperature for 15 minutes with a solution of potassium perfluorobutanesulfonate in 20 ml of acetone. After adding 200 ml of dimethyl ether, the precipitated title compound was collected by filtration and dried to 300
Purify by passing through a mlHP-20 chromatography column using water as eluent to give 0.850 g of the title compound. Melting point> 300 ° C.

Example 6 Preparation of (S) -3- (acetylamino) -2-oxo-1-azetidinesulfonic acid potassium salt: -Method I: A. Production of (S) -3-amino-2-oxo-1-azetidinesulfonic acid potassium salt :-( S) -3- (benzyloxycarbonylamino) -2-oxo-1-azetidinesulfonic acid potassium salt ( Example 2
0.169 g) are dissolved in 4.0 ml of water and hydrogenated on 0.037 g of 10% palladium / activated carbon for 1 hour 40 minutes. The catalyst is filtered off and washed with 1 ml of 50% aqueous acetone.

B. Preparation of (S) -3- (acetylamino) -2-oxo-1-azetidinesulfonic acid potassium salt:-A solution of the free amine product of A above was diluted with 3.5 ml of acetone and stirred on an ice bath. To do. 0.320 ml of acetyl chloride are added in small portions over a period of about 15 minutes, during which solid potassium hydrogen carbonate is alternately added and maintained at a pH of 6.5 to 7.2. After 30 minutes, run on silica gel TLC in acetone: acetic acid (19: 1) and make sure the reaction is substantially complete by the Rydon test. 6 ml of 0.5 M monobasic potassium phosphate buffer (pH 5.5) was added, and the solution was adjusted to 2N.
Adjust to pH 4.8 with hydrochloric acid. Acetone was removed under reduced pressure and the resulting aqueous solution was passed through a 50 ml HP-20AG column to obtain 2.197 g of solid. This is dissolved in methanol to give 0.282 g of a substance which still contains some salt which can be extracted. The product is further purified by passing through an IRC-50 column, adjusted to pH 3.8 and then evaporated to dryness under reduced pressure. Treatment with acetone gives 0.064 g of the desired product containing about 0.5 equivalents of inorganic potassium salt. Finally 20
After passing through a 0 ml HP-20AG column and freeze-drying from 0.5 ml of water, 0.022 g of the product was obtained as an amorphous powder, which was dried under reduced pressure at 50 ° C. for 2 hours to obtain the title compound. Melting point 170-180 ° C (softening at 100 ° C). Elemental analysis, calculated as C ₅ H ₇ O ₅ N ₂ SK: C, 24.38%; H, 2.87%; N, 11.37
%; K, 15.9%. Found: C, 26.06%; H, 3.14%; N, 9.96.
%; K, 18.04%.

Method II: (S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid pyridine salt (see Example 1) 2.0 g water 25 ml
The solution is hydrogenated over 0.500 g of 10% palladium / activated carbon. After 2 hours, the solution is filtered, cooled to 0 ° C. and 40 ml of acetone are added. At the same time, add acetyl chloride and cold 10% potassium hydrogen carbonate solution to the solution to adjust the pH.
Hold at 5.2-5.8. Of the solution with acetyl chloride
The pH is adjusted to 4.2 and the solution is concentrated on a rotary evaporator, excluding its acetone. 300 ml HP-2
Chromatography on 0AG column (eluent:
0.900 g of product are obtained in water, fraction 25 ml), fractions 13 and 14 contaminated with some potassium acetate. HP
Purified by re-chromatography on -20AG
The title compound was obtained. Melting point 205-210 ° C. Elemental analysis, calculated as C ₅ H ₇ N ₂ O ₅ SK: C, 24.38%; H, 2.86%; N, 11.38
%; S, 13.02%; K, 15.88%. Found: C, 24.23%; H, 2.81%; N, 11.25.
%; S, 12.86%; K, 15.74%.

Example 7 3- (Acetylamino) -3-methoxy-2-oxo-1
-Preparation of azetidine sulfonic acid potassium salt: -Method I: A. Preparation of 3-[(N-acetyl-N-chloro) amino] -2-oxo-1-azetidinesulfonic acid mixed sodium and potassium salts: Methanol 1 containing 4% sodium borate decahydrate
7 ml was cooled to −15 to −10 ° C., and 0.172 g of 3- (acetylamino) -2-oxo-1-azetidinesulfonic acid potassium salt (see Example 6) was dissolved therein, and this solution was Add 0.110 ml of t-butyl chlorate. The mixture is stirred for 1 hour and 45 minutes in the cold, poured into 50 ml of 0.5M monobasic potassium phosphate solution and the pH is lowered to 5.5. Remove the solvent under reduced pressure, dissolve the residue in a minimum amount of water and add HP
Elution with water over 140 ml of -20AG (100-200 mesh) and 0.063 g of the oil obtained is left to crystallize. Treatment with methanol / ether then ether gives 0.053 g of the title compound as a solid. Melting point 124 ° C (slow decomposition).

B. Preparation of 3- (acetylamino) -3-methoxy-2-oxo-1-azetidinesulfonic acid potassium salt: -3-[(N-acetyl-N-chloro) amino] -2-oxo-1-azetidine 0.037 g of sulfonic acid / mixed salt is dissolved in 1.5 ml of dry dimethylformamide, and this solution is dissolved in 0.050 g of lithium methoxide in 1 ml of methanol
(-78 ° C). After stirring at −78 ° C. for 15 minutes,
A 10 ml solution of 0.5M monobasic potassium phosphate is added and the solution is adjusted to pH 4 with 1N hydrochloric acid. To this solution is added 0.070 g of tetrabutylammonium hydrogensulfate and the solution is extracted 4 times with methylene chloride. The extracts are combined and dried over sodium sulfate, and the solvent is removed under reduced pressure to give 55 mg of an oil. Chromatography on 5.5 g of silica gel with 8% methanol: 92% methylene chloride as eluent gives the oily product 0.041 as the tetrabutylammonium salt.
get g. 0.031 g of oily product was dissolved in water and
0W-X2K ⁺ type (200-400 mesh, 0.6me
q / ml) Ion exchange column (5 ml). Water is removed under reduced pressure to give an oil that crystallizes from methanol-ether.
Treated twice with ether to give the product as colorless powder 0.01
Obtained 1 g, mp 182-183 ° C (decomposition).

Method II: A. Preparation of 3-amino-3-methoxy-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt:
-10% Palladium / activated carbon 0.030 g methanol 2 m
l Sodium borate 4% methanol solution in suspension
100 ml are added and the mixture is stirred under a hydrogen atmosphere for 15 minutes. A mixture of 0.060 g of 3-methoxy-2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid tetrabutylammonium salt and 2 ml of methanol was added thereto, and the mixture was placed under a hydrogen atmosphere. 1
Stir vigorously for 5 minutes. Micropore filter (0.5mμ)
The catalyst is filtered off through celite, the solvent is removed from the filtrate under reduced pressure, and the residue is extracted with methylene chloride. The solvent was removed under reduced pressure to give 0.035 g of the title compound as an oil.

B. Preparation of 3- (acetylamino) -3-methoxy-2-oxo-1-azetidinesulfonic acid potassium salt: -3-Amino-3-methoxy-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt 0 0.035 g
10 ml of methylene chloride solution (0 ° C.) with propylene oxide 2
ml and 0.074 ml of acetyl chloride are added. After 2 hours, the solvent was removed under reduced pressure and the oily residue was treated with 4 g of silica gel.
Chromatography on 6-8 in methylene chloride
Elution with% methanol gave 0.018 g of an oil. The oily substance was dissolved in water and the ion exchange resin (AG50W-X2
・ Pass through K ⁺ type 3ml ・ 0.6meq / ml). Water was removed from the eluate under reduced pressure to give 0.010 g of the desired product.

Example 8 3-Methoxy-2-oxo-3-[[(phenylmethoxy)
Carbonyl] amino] -1-azetidinesulfonic acid potassium salt preparation: -Method I: A. Preparation of 2-oxo-3- [N-chloro-N-[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt:-(S) -2-oxo-3-[[(phenylmethoxy ) Carbonyl] amino] -1-azetidinesulfonic acid potassium salt (see Example 2) (1.00 g) was dissolved in 90 ml methanol containing 4% sodium borate decahydrate, and the solution (-10
C.) 0.420 ml of t-butyl hypochlorite are added. -1
After stirring for 2 hours at 0 ° C., 100 ml of 0.5M potassium phosphate monobasic solution is added and the pH is adjusted to 6 with 1N hydrochloric acid.
Concentrate the solvent under reduced pressure to a volume of 30 ml and add the aqueous solution to HP.
Chromatograph on 200 ml of -20AG (100-200 mesh). After passing 50 g of monobasic potassium phosphate in 1000 ml of water and then 2000 ml of water, 1
Elute the product with 0% acetone-90% water. The solvent was removed under reduced pressure and the product was crystallized from water to give 0.530 g of the title compound as a solid. Melting point 173-175 [deg.] C.

B. 3-methoxy-2-oxo-3-
[[(Phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt preparation: -Lithium methoxide 0.874 g dry methanol 10 m
2-oxo-3- [N-chloro-N] in a solution (-78 ° C)
A mixture of 0.857 g of-[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt and 13 ml of dry dimethylformamide is added. 1 at -78 ° C
After 5 minutes, the mixture is treated with 0.5M monobasic potassium phosphate solution 2
Pour to 00 ml and adjust to pH 5.5 with 1N hydrochloric acid. The aqueous mixture is washed with methylene chloride (3 x 100 ml) and 1.169 g of tetrabutylammonium hydrogensulfate is added. Extract the product with methylene chloride (3 x 200 ml), dry over sodium sulfate, filter and concentrate under reduced pressure. The oily residue was chromatographed on 150 g of silica gel, eluting the product with 2-4% methanol in methylene chloride and the tetrabutylammonium salt of the product as an oil.
Obtained as 701 g. A part of the oily substance (0.051 g) was dissolved in water, and an ion conversion column (AG50W-X2 (200 ~
400 mesh) K ⁺ type 3 ml, 0.6 meq / ml). The eluate was concentrated under reduced pressure to obtain 0.030 g of an oily substance, which was treated with acetone to crystallize to obtain the title compound. νmax
(KBr): 1760, 1725 cm ^-1 . NMR (D ₂ O): δ
_{3.48 (s, 3H, OCH 3} ), 3.92 (s, 2H, H 4),
_{5.20 (s, 2H, CH 2} ), 7.42 (s, 5H, aromatic).
Melting point 196-198 [deg.] C.

Method II: A. Preparation of 1-chloro-3- [N-chloro-N-[(phenylmethoxy) carbonyl] -2-azetidinone: -3-[[(phenylmethoxy) carbonyl] amino] -2-azetidinone (see Example 1C). 0.440 g of methanolic 4% borax solution is cooled to 0 ° C. and t-butyl hypochlorite is added. After 30 minutes at 0 ° C., the solution is poured into 200 ml of cold water and extracted with ethyl acetate (100 ml × 2). The ethyl acetate layers were combined, washed with water, dried and evaporated under reduced pressure to give 0.546 g of the title compound as an oil.

B. Preparation of 3-methoxy-3-[[(phenylmethoxy) carbonyl] amino] -2-azetidinone: -1-chloro-3- [N-chloro-N-[(phenylmethoxy) carbonyl] amino] -2-azetidinone 0.730g
A solution of (0.0025 mol) in 5 ml of tetrahydrofuran-
Cool to 78 ° C. and add 4 ml methanol containing 0.285 g lithium methoxide. After 20 minutes at -78 ° C, 0.6 ml acetic acid and 0.6 ml trimethyl phosphite are added. The solution is stirred at −78 ° C. for 5 minutes, warmed to room temperature and stirred for another 30 minutes. The solution is diluted with ethyl acetate, washed with 5% sodium hydrogen carbonate, water, 5% potassium hydrogen sulfate, water, saturated salt solution and dried. The solvent was removed to give an oil, which was applied to four 20 cm x 20 cm x 1 mm silica gel plates. Developing with benzene-ethyl acetate (1: 1), Rf =
The major UV-active band at 0.25 was isolated to give an oil of 0.
091 g are obtained, which is crystallized from ether to give a solid. This is recrystallized from ether to give the title compound. Melting point 1
12-114 ° C.

C. 3-methoxy-2-oxo-3-
Preparation of [[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt: -Dichloromethane and dimethylformamide 0.1 each
A solution of 0.025 g of 3-methoxy-3-[[(phenylmethoxy) carbonyl] amino] -2-azetidinone in 75 ml is stirred with 0.0554 g of pyridine-sulfur trioxide complex for 24 hours. The slurry is diluted with 5 ml of 0.5 M cold monobasic potassium phosphate (adjusted to pH 4.5) and extracted with ethyl acetate. The aqueous layer is applied to a 40 ml HP-20AG column. Buffer as above, water and water-acetone
Elution with (9: 1) gave 0.032 g of product as an oil. This one gradually solidifies. This was crystallized from acetone to obtain the title compound. Melting point 196-198 ° C (decomposition).

Example 9 Preparation of 3-methoxy-2-oxo-3-[(2-thienylacetyl) amino] -1-azetidinesulfonic acid potassium salt: -A. Preparation of 3-amino-3-methoxy-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt:
0.143 g of (±) -3-methoxy-3-[[(phenylmethoxy) carbonyl] amino] -2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt is dissolved in 15 ml of dry methanol. This borax _{(Na 2 B 4 O 7 ·} 1
0H ₂ O) 0.012 g (0.1 eq), then 10% palladium on carbon 0.072 g, and the mixture at 1 atm.
Hydrogenate for 5 minutes. The catalyst is filtered off and the filtrate is evaporated under reduced pressure to give 0.114 g of the title compound.

B. 3-methoxy-2-oxo-3-[(2
-Thienylacetyl) amino] -1-azetidinesulfonic acid tetrabutylammonium salt preparation: -3-methoxy-3-amino-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt 0.102 g
Is dissolved in 10 ml of dry acetonitrile. 0.0565 ml of dry pyridine was added, and the solution was placed under a dry nitrogen atmosphere at -1
Stir well at 0 ° C. To this is added dropwise a mixture of 0.044 ml of thienylacetyl chloride and 1 ml of dry acetonitrile. The reaction is complete in 15 minutes as evidenced by thin layer chromatography. 0.5M potassium phosphate buffer
4.2 ml (pH 5.5) and 0.0085 g (0.1 equiv.) tetrabutylammonium sulphate are added and most of the acetonitrile is removed under reduced pressure. The residue is diluted with water and extracted with methylene chloride (20 ml x 3 times). The extract is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a gum, 0.107 g. Purify the crude product by chromatography on silica gel with methylene chloride-methanol to give 0.066 g of the title compound.

C. 3-methoxy-2-oxo-3-[(2
Preparation of -thienylacetyl) amino] -1-azetidinesulfonic acid potassium salt: -3-methoxy-2-oxo-3-[(2-thienylacetyl) amino] -1-azetidinesulfonic acid tetrabutylammonium salt 0 154 g was dissolved in 3 ml of 30% acetone-water, passed through a Dowex 50W-X2 (K ⁺ type) column and eluted with the same solvent. The entire eluate is evaporated under reduced pressure to give 0.095 g of product, which is lyophilized to give the title compound as an amorphous powder. Melting point 120-135
° C. Elemental analysis, calculated as C ₁₀ H ₁₁ N ₂ O ₆ S ₂ K, calculated value: C, 33.51%; H, 3.09%; N, 7.82
%; S, 17.89%, measured value: C, 33.46%; H, 3.08%; N, 7.92
%; S, 17.64%.

Example 10 Preparation of (±) -3-butoxy-2-oxo-3-[(phenylacetyl) amino] -1-azetidinesulfonic acid potassium salt: -A. Preparation of 3- [chloro (phenylacetyl) amino] -2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt: -5.25 ml of sodium hypochlorite 4.72 ml and water 20 ml
% Sodium borate 1.27 g was suspended in this solution, and (S) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidine sulfone was added to this suspension (0 ° C.). Acid tetrabutylammonium salt (see Example 3) 0.3
A solution of 50 g of methylene chloride in 3 ml is added. One hour later,
25 ml 0.5 M monobasic potassium phosphate was added, the mixture was extracted with methylene chloride (50 ml x 3 times), the organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.344 g of the title compound. obtain.

B. (±) -3-Butoxy-2-oxo-3
-[(Phenylacetyl) amino] -1-azetidinesulfonic acid tetrabutylammonium salt preparation: -0.73N n-lithium butoxide (-7 in 6 ml of n-butanol and 1 ml of dimethylformamide under an inert atmosphere)
8 [deg.] C., 3-[[chloro (phenylmethoxy) carbonyl]
A solution of 0.344 g of amino] -1-azetidinesulfonic acid tetrabutylammonium salt in 5 ml of dimethylformamide is added. After 10 minutes, the mixture is diluted with 175 ml of 0.5M potassium phosphate monobasic solution. After extraction with methylene chloride three times, the organic layer is dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue is silica gel (SilicA
R. Purify by eluting 4-8% methanol in methylene chloride over 80 g of CC-4) to give 0.130 g of the title compound.

C. (±) -3-Butoxy-2-oxo-3
Preparation of potassium salt of-[(phenylacetyl) amino] -1-azetidinesulfonic acid:-(±) -3-butoxy-2-oxo-3-[(phenylacetyl) amino] -1-azetidinesulfonic acid tetra Butyl ammonium salt (0.043 g) was dissolved in a water-acetone (9: 1) mixture and a cation exchange column (Dowex AGM) was used.
P50W-X2 ・ K ⁺ type (100-200 mesh)) 5g
Apply to. The product was eluted with water and the eluate was concentrated under reduced pressure to give 0.020 g of the title compound. Melting point 122-1
25 ° C. Elemental analysis, calculated as C ₁₅ H ₁₉ N ₂ O ₆ SK · 1 / 2H ₂ O, calculated value: C, 44.66%; H, 4.96%; N, 6.95
%; S, 7.94%. Found: C, 44.77%; H, 4.76%; N, 6.76.
%; S, 7.75%.

Example 11 Preparation of (± -cis) -4-methyl-2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt: -A. Preparation of N-benzyloxy-t-boc-allothreonine amide (where boc is used as an abbreviation for butoxycarbonyl, and so on): -d, l-t-boc-allothreonine 6.9 g, and o-benzylhydroxylamine A solution of about 0.033 mol of a free amine (ethyl acetate-sodium bicarbonate dehydrochlorinated) obtained from 5.3 g of hydrochloride in 80 ml of tetrahydrofuran was added to N-.
It is treated with a mixture of 4.82 g of hydroxybenzotriazole, 6.5 g of dicyclohexylcarbodiimide and 20 ml of tetrahydrofuran. After stirring at room temperature for about 16 hours, the slurry was filtered, concentrated under reduced pressure, chromatographed on a silica gel column 400 ml, eluting with 5-10% ethyl acetate in chloroform, fractionated (200 m each).
l) 6.8 g of the title compound are obtained in 7-22.

B. (± -cis) -N-benzyloxy-3
Preparation of -t-butoxycarbonylamino-4-methylazetidinone: A solution of 6.8 g of N-benzyloxy-t-boc-allothreonine amide in 200 ml of tetrahydrofuran was treated with 5.24 g of triphenylphosphine and diethyl azodicarboxylate. Stir with 2 ml for about 16 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed on a 500 ml silica gel column, eluting with methylene chloride and crystallized from ether to give a total azetidinone product of 2.65.
get g. The mother liquor and mixed fractions are rechromatographed to give an additional 0.6 g of product. A part of the product was crystallized twice from ether (-20 ° C) to obtain a pure product of the title compound. Melting point 140-142 [deg.] C.

C. Preparation of (± -cis) -3-t-butoxycarbonylamino-1-hydroxy-4-methylazetidinone: -cis-N-benzyloxy-3-t-butoxycarbonylamino-4-methylazetidinone 3.2 g 200% 95% ethanol solution of 10% palladium / carbon 0.7
Stir in a hydrogen atmosphere with g. After 40 minutes the slurry is filtered (filtrate 249 ml), the filtrate evaporated and treated with ether to give 2.05 g of solid as the product of the two treatments. Melting point 134-136 [deg.] C.

D. Production of (± -cis) -3-t-butoxycarbonylamino-4-methylazetidinone: -cis-3-t-butyloxycarbonylamino-1-hydroxy-4-methylazetidinone 2.05 g solution in methanol 60 ml 4.5M ammonium acetate 4 each
0 ml, 20 ml, 30 ml (90 ml total) and 20 ml, 1.5 ml titanium trichloride, 10 ml, 15 ml (45 ml total) are added (second addition after 15 minutes, third addition after 120 minutes). After 135 minutes, the solution is diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate (300 ml x 3 times). The organic layers are combined, washed with a mixture of 100 ml of 5% sodium hydrogen carbonate and 100 ml of saturated salt, dried and evaporated. The residue is treated with ether to give a total of 1.65 g of solid as the product twice. A portion of the first crop is recrystallized from ether to give pure product. Melting point 176-178.
5 ° C.

E. Preparation of (± -cis) -3-benzyloxycarbonylamino-4-methylazetidinone: -cis-3-t-butoxycarbonylamino-4-methylazetidinone 1.55 g methylene chloride 4 ml and anisole 4 ml solution 0. Cool to 0 ° C and add 50 ml of cold trifluoroacetic acid. After 90 minutes the solvent is evaporated under reduced pressure (benzene is added and evaporated 3 times). 25m acetone in the residue
Dissolve in l and add the first pH with 5% sodium bicarbonate
Increase (2.5) to 7 and add 2 ml of benzyl chloroformate. The solution is kept at 0 ° C., pH 7 for 4 hours, the acetone is removed under reduced pressure and the resulting slurry is filtered. The filtrate is saturated with sodium chloride and extracted with methylene chloride. The solid obtained is further dissolved in methylene chloride and dried. The organic layers were combined and concentrated, and the residue was put on a 200 ml silica gel column.
Subject to chromatography. Chloroform: Ethyl acetate
Elution with (3: 1) gives 0.850 g of product in fractions 4-11 (100 ml of each fraction). Part of the product is crystallized from ether to give the pure title compound. Melting point 165-16
6 ° C.

F. (± -cis) -4-Methyl-2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-
Production of azetidine sulfonic acid potassium salt: -cis-3-benzyloxycarbonylamino-4-methylazetidinone 0.75 g, dimethylformamide (dried by 4Å sieve activated at 320 ° C. for 15 hours under argon stream) 7 ml To a suspension of 7 mL of methylene chloride and methylene chloride (dried through basic aluminum oxide), 1.66 g of pyridine-sulfur trioxide complex is added. After stirring for 3 hours at room temperature under a nitrogen atmosphere, 1.66 g of pyridine-sulfur trioxide complex was added. The mixture is stirred under a nitrogen atmosphere at room temperature for about 16 hours. Dimethylformamide is removed under reduced pressure and 4.6 g of the residue obtained are dissolved in 300 ml of a 0.5 M potassium phosphate monobasic solution (40 ° C.) in 10 to 15 minutes. The solution was cooled and HP-20 resin column (3 cm x 60 c) with 400 ml of 0.5 M monobasic potassium phosphate.
m) through 1000 ml of distilled water and water: acetone (14:
Using 1) 0.280 g of product is obtained in fractions 13-26 (100 ml each). This was crystallized from methanol: petroleum ether to give 0.7575 g of the title compound. Melting point 2
14-215.5 (decomposition). Elemental analysis, C ₁₂ H ₁₃ N ₂ S
Calculated as O ₆ K: C, 40.90%; H, 3.72%; N, 7.95
%; S, 9.10%; K, 11.10% Actual value: C, 40.43%; H, 3.60%; N, 7.89
%; S, 8.69%; K, 10.82%.

Example 12 Preparation of (3S-trans) -4-methoxy-2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt: -d, lt Substituting 1-t-boc-threonine for -boc-allothreonine and treating according to Example 11, the title compound was obtained. Melting point 133-135 [deg.] C. Elemental analysis, calculated as C ₁₂ H ₁₃ N ₂ O ₆ SK, calculated: C, 40.90%; H, 3.72%; N, 7.95
%; S, 9.10%; K, 11.10%, actual value: C, 40.72%; H, 3.60%; N, 7.99
%; S, 8.80%; K, 10.82%.

Example 13 Preparation of (3S-trans) -4-methyl-2-oxo-3-[(phenylacetyl) amino] -1-azetidinesulfonic acid potassium salt: -A. (3S) -3-amino-4-methyl-2-oxo-1
-Preparation of azetidinesulfonic acid tetrabutylammonium salt :-( 4S-trans) -4-methyl-2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid potassium salt (implementation (See Example 12) 0.3524 g is dissolved in 20 ml of distilled water and treated with 0.3735 g (1 mmol) of tetrabutylammonium hydrogensulfate. 1 at room temperature
After stirring for 0 minutes, the solution is saturated with sodium chloride and extracted with methylene chloride (10 ml x 3 times). The methylene chloride extract was dried over sodium sulfate and evaporated under reduced pressure to give 0.536 g of the corresponding tetrabutylammonium salt,
This is hydrogenated with 0.270 g of 10% palladium on carbon in 25 ml of dimethylformamide. The mixture is filtered through Celite and washed twice with 2.5 ml of dimethylformamide to give the title compound in solution.

B. Preparation of (3S-trans) -4-methyl-2-oxo-3-[(phenylacetyl) amino] -1-azetidinesulfonic acid potassium salt: -crude (3S) -3-amino-4-methyl-2 -Oxo-1-
Azetidine sulfonic acid tetrabutylammonium salt (the total amount of the filtrate obtained in the above A and the washing solution) was added with 0.206 g of disilochhexylcarbodiimide, 0.153 g of N-hydroxybenzotriazole and 0.138 g of phenylacetic acid.
Is added at 0 ° C. The mixture is stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. The precipitate formed is filtered off, the filtrate is evaporated under reduced pressure, the residue is taken up in 10 ml of acetone and filtered. 25 m of acetone saturated with potassium iodide
0.752 g of solid obtained after treatment with 200 ml of ether and 200 ml of ether are a mixture of potassium and tetrabutylammonium salts of the title compound. This solid was
It is dissolved in 50 ml of 5M monobasic potassium phosphate and HP-20
Apply to column. The several fractions obtained, eluting with water and then with water-acetone, are combined and evaporated to give the pure tetrabutylammonium salt. An aqueous solution of this substance is added to Dowex 5
0W-X2 (K ⁺ type) to give potassium salt product 0.12
14 g are obtained. This was treated with acetone-hexane to give 0.1046 g of the title compound. Melting point 211-213
° C. Elemental analysis, calculated as C ₁₂ H ₁₃ N ₂ O ₅ SK · 1 / 2H ₂ O, calculated value: C, 41.72%; H, 4.09%; N, 8.11
%, S, 9.28%; K, 11.32% Actual value: C, 41.70%; H, 4.01%; N, 8.07
%; S, 9.01%; K, 11.02%.

Example 14 [3S- [3α (Z), 4β]]-3-[[(2-amino-4-thiazolyl) [1-carboxy-1-methylethoxy) imino] acetyl] amino] -4 -Methyl-2-oxo-1-
Preparation of azetidine sulfonic acid dipotassium salt: -A. Preparation of N-benzyloxy-t-boc-threonine amide: The corresponding free amine (ethyl acetate-sodium bicarbonate with 8.76 g of t-boc-threonine and 6.4 g of O-benzylhydroxyamine hydrochloride) (Remove hydrochloric acid)
In 100 ml of tetrahydrofuran was added to 6.12 g of N-hydroxybenzotriazole, 8.24 g of dicyclohexylcarbodiimide and 20 ml of tetrahydrofuran.
Is treated with a mixture of. The mixture is stirred under a nitrogen atmosphere for 26 hours, filtered and evaporated under reduced pressure. 300 residue
Chromatography on a silica gel column eluting with chloroform and chloroform-ethyl acetate (3: 1) gives 7.2 g of product. This was crystallized from ether-hexane to give 4.18 g of the title compound.

B. Production of (3S-trans) -N-benzyloxy-3-t-butoxycarbonylamino-4-methylazetidinone: 12.67 g of N-benzyloxy-t-boc-threonine amide, triphenylphosphine under nitrogen atmosphere Tetrahydrofuran 38 of 11.5 g and diethyl azodicarboxylate 6.23 ml
The 0 ml solution is stirred for about 16 hours. Evaporate the solution to 90
Chromatograph on a 0 ml silica gel column,
Elute with chloroform-ethyl acetate (3: 1) to give product 1
Crystallization of 3.69 g from ether-hexane gives 9.18 g of the title compound.

C. Preparation of (3S-trans) -3-t-butoxycarbonylamino-1-hydroxy-4-methylazetidinone :-( 3S-trans) -N-benzyloxy-3-t-butoxycarbonylamino-4-methylazeti 9.18 g of dinone
A 300 ml solution of 95% ethanol in 10% is stirred with 1.85 g of 10% palladium on carbon under a hydrogen atmosphere. 14
After 1 minute, the slurry is filtered and evaporated under reduced pressure.
The residue is recrystallized from ether-hexane to give 5.12 g of the title compound.

D. Preparation of (3S-trans) -3-t-butoxycarbonylamino-4-methylazetidinone:-(3S-trans) -3-t-butoxycarbonylamino-1
A solution of 4.98 g of 4-hydroxy-4-methylazetidinone in 200 ml of methanol was mixed with 1 M of 4.5 M ammonium acetate.
32 ml, then treated with 66 ml of 1.5M titanium trichloride,
Stir for 4.5 hours. This aqueous solution was diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate to obtain a crude product of 3.48.
get g. Recrystallize from ether-hexane to give 3.3 g of the title compound.

E. Preparation of (3S-trans) -3-benzyloxycarbonylamino-4-methylazetidinone:-(3S-trans) -3-t-butoxycarbonylamino-4
A solution of methylazetidinone in 10 ml of dichloromethane and 10 ml of anisole was cooled to 0 ° C. and trifluoroacetic acid 11
Add 2 ml. The solution is stirred for 90 minutes and evaporated under reduced pressure (3 times with benzene). The residue is dissolved in 70 ml of acetone and the solution is adjusted to pH 7 with 5% sodium hydrogen carbonate solution. A total of 5.33 g of benzyl chloroformate is added to the solution having a pH of 6.5 to 7.5 over 1 hour.
The mixture is stirred at pH 7 for 30 minutes, diluted with 100 ml saturated sodium chloride and extracted with ethyl acetate (400 ml x 3 times). The residue obtained by evaporation is chromatographed on a 1 l silica gel column, eluting with chloroform-ethyl acetate (4: 1) to give 2.19 g of product. This was crystallized from ether-hexane to give the title compound 1.12.
5 g are obtained.

F. (3S-trans) -4-methyl-2-oxo-3-[[(phenylmethoxy) carbonyl] amino]-
Preparation of 1-azetidinesulfonic acid tetrabutylammonium salt :-( 3S-trans) -3-benzyloxycarbonylamino-4-methylazetidinone 0.600 g of dimethylformamide in 2 ml of solution was cooled to 0 ° C. Add 4 ml of 8M sulfur trioxide solution. The solution is stirred for 1 hour at room temperature under a nitrogen atmosphere and poured into 80 ml of cold 0.5M-basic potassium phosphate (adjusted to pH 5.5). This solution was extracted with methylene chloride (50 ml × 3 times) (the extract was discarded) and tetrabutylammonium hydrogensulfate 0.8.
Add 68 g. This solution was added with methylene chloride (75 ml x 4).
Times) to extract. The organic layers are combined, washed with an aqueous solution of 8% sodium chloride, dried and evaporated under reduced pressure to give 1.54 g of the title compound.

G. [3S- [3α (Z), 4β]]-3-[[(2
-Amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid potassium salt :-( 3S- trans) -4-Methyl-2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid tetrabutylammonium salt in 45 ml of dimethylformamide was added to 10% palladium / carbon 0.80.
Stir with 0 g in hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was (Z) -2-amino-α-[(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] -4-.
Stir with 1.24 g of thiazole acetic acid, 0.4 g of N-hydroxybenzotriazole and 0.580 g of dicyclohexylcarbodiimide for about 16 hours. The slurry is evaporated under reduced pressure, the residue is treated with 20 ml of acetone and filtered. The filtrate (and the wash 2 ml) is treated with a mixture of potassium perfluorobutanesulfonate 0.868 g and acetone 3 ml. Dilute with 75 ml of ether, decant the mother liquor to isolate a solid product, treat with ether and filter to give 0.91 g of the title compound. Mother liquor 100m ether
Diluted with l to give 0.45 g of the title compound (second product)
To get

H. [3S- [3α (Z), 4β]]-3-[[(2
-Amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4-methyl-
Preparation of 2-oxo-1-azetidine sulfonic acid dipotassium salt:-[3S- [3α (Z), 4β]]-3-[[(2-
Amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid potassium salt (1 obtained in G above) Second product) 0.
A slurry of 140 g and 0.5 ml of anisole is stirred at 12 ° C and 2.5 ml of cold (-10 ° C) trifluoroacetic acid is added. After 10 minutes, add 10 ml of ether and 5 ml of hexane,
The slurry is stirred at -12 ° C for 5 minutes and then warmed to room temperature. The solid is centrifuged and washed twice with ether. A 5 ml solution of this solid in cold water was promptly adjusted to pH 5.5 with 0.4N potassium hydroxide and applied to an 80 ml HP-20AG column. Elute with water, evaporate (3x with acetonitrile) and treat with ether before fractionation (10 times each).
ml) 7-11 to give 0.072 g of the title compound. Melting point about 250 ° C (decomposition). Elemental analysis, calculated as C ₁₃ H ₁₅ N ₅ O ₈ S ₂ K ₂ ; calculated value; C, 30.51%; H, 2.95%; N, 13.69
%; S, 12.53%; K, 15.28%, measured value: C, 29.63%; H, 3.20%; N, 12.96
%; S, 11.94%; K, 12.78%. NMR (D ₂₀ ): 1.46 (s, 6H), 1.58 (1H, d, j =
7), 4.28 (1H, q d, j = 7,2.5), 4.67 (1
H, d, j = 2), 6.95 ppm (s, 1H). [3S- [3α (Z), 4β]]-3-[[(2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-
Methyl ethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidine sulfonic acid potassium salt 1.22 g (the remainder of the total of the first and second products in the above G) was added in the same manner as above. Treatment (with 4.2 ml of anisole and 16 ml of trifluoroacetic acid, treated at -15 ° C for 13 minutes)
To do. This was chromatographed on a 300 ml HP-20AG column, treated as above, and fractionated.
0.694 g of the title compound was obtained in 6-9 (60 ml each).

Example 15 (3S-cis) -3-amino-4-methyl-2-oxo-
Preparation of 1-azetidine sulfonic acid: -A. Preparation of t-boc-1-allothreonine: A suspension of 6.72 g of 1-allothreonine and 70 ml of 50% aqueous dioxane is treated with 9.45 ml of triethylamine and 18.1 g of t-butyl pyrocarbonate. The mixture is stirred at room temperature for 4 hours and diluted with 70 ml of water and 140 ml of ethyl acetate. After shaking thoroughly, the layers were separated and the organic layer was washed with water:
Wash with 30 ml of brine (2: 1), combine the aqueous layers and back extract with 70 ml of ethyl acetate. Cool the water layer on an ice bath for 10
% Potassium bisulfite solution is added to adjust the pH to 2.3. The acidic solution is extracted with ethyl acetate (150 ml x 4 times). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was removed to obtain 9.13 g of the title compound.

B. Preparation of N-methoxy-t-boc-1-allothreonine amide: t-boc-1-allothreonine (9.13 g) in water (85 ml) and 1
Dissolve in 41 ml of N potassium hydroxide solution. To this is added 5.22 g of methoxyamine hydrochloride and 8.67 g of 1-ethyl-3,3- (dimethylaminopropyl) carbodiimide hydrochloride. The mixture is stirred at room temperature for 4 hours and then saturated with potassium sodium tartrate. This mixture was extracted with ethyl acetate (150 ml × 4 times), the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the title compound 7.3 was obtained as a solid.
8 g are obtained.

C. Preparation of O-methanesulfonyl-N-methoxy-t-boc-1-arothreoninamide: -N-methoxy-t-boc-1-allothreoninamide 7.
32 g was dissolved in 40 ml of pyridine, and under a nitrogen atmosphere, -2.
Cool to 0 ° C. Using a syringe, add 3 ml of methanesulfonyl chloride dropwise over 5 minutes. The mixture is slowly warmed to 0 ° C. and stirred at this temperature for 3 hours. To this, 500 ml of ethyl acetate was added, and the solution was ice-cooled, 250 ml of 3N hydrochloric acid solution, and then 100 ml of 5% sodium hydrogen carbonate solution.
Wash with. The ethyl acetate layer was dried over anhydrous sodium sulfate,
The solvent was removed to give 8.64 g of the title compound as a white solid.

D. Preparation of (3-cis) -3-t-butoxycarbonylamino-1-methoxy-4-methylazetidinone: --O-methanesulfonyl-N-methoxy-t-boc-1-alothreonine amide 8.64 g in acetone Dissolve in 530 ml and add 11 g of solid potassium carbonate. The mixture is slowly heated to 65 ° C. under nitrogen atmosphere and stirred at this temperature for 1 hour. The reaction mixture is filtered through Celite and the filter cake is washed with ethyl acetate. The filtrate is concentrated and the residue is dissolved in 250 ml of ethyl acetate. Ethyl acetate solution is 100 ml of 1N hydrochloric acid solution and 100 ml of 5% sodium hydrogen carbonate solution.
Wash with. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was removed to obtain 6.63 g of a crude product.

E. Production of (3S-cis) -3-t-butoxycarbonylamino-4-methylazetidinone: -Sodium 1.35g was dissolved in liquid ammonia about 300ml at -50 ° C to give (3S-cis) -3-t. A mixture of 5.87 g of butoxycarbonylamino-1-methoxy-4-methylazetidinone and 35 ml of tetrahydrofuran is added dropwise with a syringe. An additional 10 ml of tetrahydrofuran is used for washing. Near the end of the addition, add another 0.100 g of sodium. The mixture is stirred for a further 5 minutes and 3.35 g of solid ammonium chloride are added in one portion to quench the reaction. Ammonia is expelled through a nitrogen stream,
250 ml of ethyl acetate are added to the residue. Filter this,
The solid is washed with ethyl acetate and the filtrates are combined and the solvent is removed to give 4.82 g of the title compound.

F. Preparation of (3S-cis) -3-t-butoxycarbonylamino-4-methyl-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt:-[3S, 4R] -3-t-butoxycarbonylamino- 4-
4.98 g of methylazetidinone are dissolved in 30 ml of dimethylformamide. Pyridine-sulfur trioxide complex 11.
9 g are added and the mixture is stirred at room temperature under a nitrogen atmosphere.
After stirring for 14 hours, the pyridine-sulfur trioxide complex 1.
Add 8 g and continue stirring for 80 hours. The reaction mixture was charged to 0.
Pour into 700 ml of 5M potassium phosphate monobasic solution and wash with methylene chloride (300 ml x 3 times). To this aqueous solution was added 8.45 g of tetra-n-butylammonium hydrogensulfate and the mixture was extracted with methylene chloride (300 ml x 4). The methylene chloride layers were combined and dried over anhydrous sodium sulfate to remove the solvent to give 10.76 g of the title compound as a gum.

G. Production of (3S-cis) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid :-( 3S-cis) -3-t-butoxycarbonylamino-4-methyl-under a nitrogen atmosphere. 2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt 10.76 g
Dissolve in 50 ml of 5-97% formic acid and stir for 4 hours. Add a small amount of the product from the previous reaction as a seed crystal,
The mixture is stirred for another hour. The mixture is left in the freezer for about 16 hours, the frozen mixture is warmed to room temperature and stirred for 1 hour. The solid formed was collected by filtration and washed with methylene chloride to obtain 0.982 g of the title compound. The filtrate is diluted with 1000 ml of methylene chloride and kept at -20 ° C for 4 hours. The formed precipitate was recrystallized from water-methanol-acetone to obtain 0.167 g of the title compound. _{NMR (D 20): 1.63 (} 3H, d, j = 6.5cps). IR
(Nujol): 1775 cm ^-1 .

Example 16 Preparation of (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid: -A. Production of threonine methyl ester hydrochloride: -In a nitrogen atmosphere, put a flask containing 500 ml of methanol at -5 ° C.
Cool to (ice / salt) and add thionyl chloride 130 ml (excess) at such a rate as to maintain a reaction temperature of 0-10 ° C.
Recool to -5 ° C, add 59.5 g of 1-threonine, bring the mixture to room temperature and stir for 16 hours. The mixture is concentrated and depressurized (10 ^-1 torr) for 2 hours to give a viscous oil. This material is used directly in the next step.

B. Preparation of threoninamide: -The crude product obtained in A above is dissolved in 2500 ml of methanol and cooled to -5 ° C (ice / saline). The solution is saturated with ammonia gas, the cold bath is removed, the vessel is sealed and left for 3 days. After removing most of unreacted ammonia with an aspirator, 100 g of sodium hydrogen carbonate and 50 ml of water were added,
The mixture is evaporated to give a viscous oil.

C. Preparation of benzyloxycarbonyl threonine amide: -The crude product from B above (already containing the required amount of sodium hydrogen carbonate) is diluted with water to a volume of 1000 ml. With rapid stirring of this solution, 94 g of benzyloxycarbonyl chloride are added as a solution of its tetrahydrofuran in 80 ml (88 ml containing 90% pure) over 1 hour. The mixture is stirred for another 16 hours and then with ethyl acetate.
Extract (500 ml x 1 then 250 ml x 2). The extracts are combined, dried over magnesium sulfate and concentrated. The crystalline residue was dissolved in 250 ml of hot ethyl acetate and mixed with hexane 3
Add 00 ml and boil until clear solution. This is cooled and the crystalline mass is filtered off and dried, then the title compound 10
Get 4g.

D. Preparation of benzyloxycarbonylthreonineamide O-mesylate: -Under an argon atmosphere, 100 g of benzyloxycarbonylthreonineamide are dissolved in 400 ml of anhydrous pyridine and cooled on an ice / saline bath. While stirring the solution, 36.8 ml (54.5 g) of methanesulfonyl chloride are added thereto over 15 minutes. After stirring for 2 hours, another 0.3 equivalents of methanesulfonyl chloride are added. The mixture is stirred for 1 hour and poured into a mixture of 1500 ml of ice and 2000 ml of water. The slurry was stirred for about 30 minutes and filtered, and the crude product was dried under reduced pressure at 60 ° C. for about 16 hours to give the title compound 1
09 g are obtained.

E. Preparation of N-sulfonylbenzyloxycarbonyl threonine amide O-mesylate tetrabutylammonium salt: -A solution of 2-picoline 17.8 ml in methylene chloride 90 ml-
Cool to 5 ° C (ice-saline) and add 5.97 ml of chlorosulfonic acid at a rate such that the internal temperature is kept below 5 ° C.
This solution is cannulated into a suspension of 7.56 g of benzyloxycarbonylthreonine amide O-mesylate and 120 ml of methylene chloride. The resulting heterogeneous mixture is refluxed for about 16 hours to give a clear solution. This solution is pH
4.5 Pour into 500 ml of phosphate buffer (0.5 M) and further dilute with 120 ml of methylene chloride. The separated organic layer was washed once with 100 ml of buffer solution, the aqueous layers were combined, treated with 10.2 g of tetra-n-butylammonium hydrogensulfate and extracted with methylene chloride (300 ml x 1 time, then 150 ml x 2 times). To do. After combining the organic extracts and drying over sodium sulfate,
The solution is concentrated to give 12.7 g of a foamy product.

F. Preparation of (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid:
Start a reflux of a mixture of 5.52 g of potassium carbonate in 20 ml of water and 160 ml of 1,2-dichloroethane,
15.5 mmol of N-sulfonylbenzyloxycarbonylthreonamide amide O-mesylate tetrabutylammonium salt in 20 ml of dichloroethane (20 ml of which is used as detergent) are added. After refluxing for 30 minutes, the mixture is placed in a separating funnel, diluted with 50 ml of water and 100 ml of methylene chloride, and the layers are separated. The organic layer obtained was dried over sodium sulfate and concentrated to give crude (3S-tran
s) -3-Benzyloxycarbonylamino-4-methyl-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt is obtained. This crude azetidinone intermediate was added to 5% palladium / carbon catalyst 0.8% in 250 ml ethanol.
Treat with g and bubble hydrogen through the solution. 90
After minutes, the reaction mixture is filtered through Celite, using 50 ml of ethanol as a washing agent. To this filtrate was further added 1.2 ml of formic acid, and the mixture was stirred for 1 hour to promptly precipitate the zwitterionic compound of the title compound.
After drying at 0 ^-1 torr for 1 hour, 1.1 g of product was obtained.
The filtrate was concentrated, and formic acid was added to precipitate the product to obtain 1.3 g of the zwitterionic compound of the title compound. Melting point> 218 ° C (decomposition). [α] D = -41.1 ° (in water, concentration
c = 1). _{NMR (D 20): 1.58 (} 3H, d, j = 7), 4.
80 (2H, m).

Example 17 (±) -3-amino-4,4-dimethyl-2-oxo-1
-Production of azetidine sulfonic acid: -A. Preparation of (±) -4,4-dimethyl-2-oxo-1-azetidine-t-butyldiphenylsilane: A solution of 40.5 ml of t-butylchlorodiphenylsilane in 112 ml of dimethylformamide was cooled to 0 ° C. and triethylamine was added thereto. Add 22 ml. To this cold triethylamine solution was added 4,4-dimethyl-2-azetidinone 12.8.
A solution of 7 g of 25 ml of dimethylformamide is added dropwise over a period of 10 minutes. The resulting cloudy solution is stirred at 5 ° C for 18 hours under an argon atmosphere. Add this mixture to ice water 40
Pour into 0 ml, ether: ethyl acetate (2: 1) (150 ml)
Extract 3 times. The extracts were combined, and 0.5 M monobasic potassium phosphate buffer (100 ml x 4 times), sodium hydrogen carbonate solution (150 ml x 1 time), water (150 ml x 2 times), saturated sodium chloride solution (150 ml x 1) Wash). The solution is dried over sodium sulfate and concentrated under reduced pressure to give 33.03 g of the title compound as a solid.

B. Preparation of (±) -3-azido-4,4-dimethyl-2-oxo-1-azetidine-t-butyldiphenylsilane: -100 ml three-necked flask under argon atmosphere at -50 ° C.
1.6M (in hexane) 4.25 ml of n-butyllithium
And a solution of dry tetrahydrofuran 11 ml is prepared. Triphenylmethane 0.083 g tetrahydrofuran 1 ml
The solution was added, the resulting solution was cooled to -60 ° C, and 1.0 ml of diisopropylamine was added dropwise with a syringe.
After stirring for 5 minutes, cool to -78 ° C. (±) -4,4-
A solution of 2.3 g of dimethyl-2-oxo-1-azetidine-t-butyldiphenylsilane in 8 ml of tetrahydrofuran is slowly added with a syringe. This solution at -78 ° C for 20
Stir for a minute, during which heavy precipitation occurs, making uniform stirring difficult. A solution of 1.33 g of P-toluenesulfonyl azide in 5 ml of tetrahydrofuran was added dropwise, and the mixture was added to
Stir at 78 ° C for 20 minutes and then add trimethylsilyl chloride 2
Add ml dropwise. The mixture is warmed to ambient temperature and stirred for 1 hour. The mixture was then cooled to 0 ° C. and ethyl acetate (0
(.Degree. C.) 150 ml and add sufficient 0.5 M monobasic potassium phosphate buffer to clear both the aqueous and organic layers in the mixture. The two layers were separated, and the organic layer was 0.5M monobasic potassium phosphate solution (150 ml x 3 times), sodium chloride solution (150 ml x 1 time) and saturated sodium chloride solution.
Wash with (150 ml x 1) and dry over sodium sulfate. 2.83 g of an oily product obtained by concentrating the solution under reduced pressure.
Is treated with hexane to give 1.67 g of the title compound as a solid.
To get

C. Production of (±) -3-azido-4,4-dimethyl-2-oxo-1-azetidine: (±) -3-azido-4,4-dimethyl-2-oxo-1 in a 50 ml three-necked flask. 1.52 g of azetidine-t-butyldiphenylsilane are dissolved in 25 ml of acetonitrile. While stirring the solution, 0.25 ml of 48% hydrofluoric acid is added thereto. Stir this at ambient temperature and
8% hydrofluoric acid every 60 minutes in an amount of 0.5 ml of 6.5
Add over time (this adds a total of 3.25 ml of 48% hydrofluoric acid). The mixture is cooled to 0 ° C., neutralized with saturated sodium hydrogen carbonate and 120 ml of ethyl acetate.
To extract. The organic layer is washed with 100 ml of water and 100 ml of saturated sodium chloride solution, dried over sodium sulphate and the dried solution is concentrated under reduced pressure to give 1.34 g of an oil. The crude oil was chromatographed on 27 g of silica gel with hexane and then 33% acetic acid in hexane,
0.358 g of the title compound is obtained as a solid.

D. Preparation of (±) -3-azido-4,4-dimethyl-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt :-( ±) -3-azido-4,4-dimethyl-under argon atmosphere 2-oxo-1-azetidine 0.100 g (0 ° C)
To this is added 2.8 ml of 0.5M dimethylformamide-sulfur trioxide complex. Warm the mixture to ambient temperature and 45
Stir for 1 minute and pour this solution into 20 ml of 0.5 M monobasic potassium phosphate buffer (pH 5.5). This is washed with methylene chloride (20 ml × 3 times) (washing liquid is discarded), and 0.237 g of tetrabutylammonium hydrogen sulfate is added to this aqueous solution. It is extracted with methylene chloride (4 times 20 ml) and the combined organic extracts are washed with 20 ml of 8% sodium chloride solution. The methylene chloride solution is dried over sodium sulfate,
Concentration under reduced pressure gives 0.31 g of an oil containing 50% of dimethylformamide and 50% of the title compound (determined by NMR).

E. Preparation of (±) -3-amino-4,4-dimethyl-2-oxo-1-azetidinesulfonic acid :-( ±) -3-azido-4,4-dimethyl-2-oxo-1
Tetrabutylammonium azetidine sulfonate
A solution of 155 g in 0.6 ml of methanol is hydrogenated over 10% palladium on carbon for 20 minutes at 1 atmosphere. The catalyst was filtered off, washed with methylene chloride, washed with methanol solution.
Combine (filtrate). 0.123 ml of 97% formic acid in a clear solution
Is added. Upon addition of acid, the solution immediately becomes cloudy. After standing at 5 ° C. for 1 hour, the solid was collected by filtration to obtain 0.0664 g of the title compound. Melting point 200-202 ° C (decomposition). NMR (D ₂₀ ): 1.64 (3H, s), 1.68 (3H, s),
4.42 (1H, s). IR (KBr): 1765 cm ^-1 .

Example 18 (3S-Trans) -3-methoxy-4-methyl-2-oxo-3-[[(phenylmethoxy) carbonyl] amino] -1
-Preparation of azetidine sulfonic acid potassium salt: -A. (3S-trans) -4-methyl-3-methoxy-2-
Oxo-4-[[(phenylmethoxy) carbonyl] amino]
Preparation of azetidine:-(3R-trans) -4-methyl-2-oxo-3-[[(phenylmethoxy) carbonyl] amino] azetidine (d substantially as described for the racemic cis isomer in Example 11C). -It is obtained from threonine in 12.6% yield.)
2.5 g (0.0106 mol) are dissolved in 112 ml 4% borax in methanol, the solution is cooled to 0 ° C. and 3.5 ml t-butyl hypochlorite are added. After 20 minutes, pour the solution into 1000 ml cold water and with cold ethyl acetate (750 ml x 2).
Extract. The organic layer was washed with cold water (750 ml × 2 times), washed with saturated saline solution, dried and evaporated to obtain 3.05 g of crude N, N′-dichloroamide. Lithium methoxide 0.4
A solution of 26 g of dry methanol in 20 ml is cooled to -78 ° C and diluted with 40 ml of dry tetrahydrofuran. The above N, N'-dichloroamide of tetrahydrofuran 20
Add ml solution (-78 ° C) by syringe over 30 seconds. After 20 minutes at -78 ° C, 2 ml acetic acid and 2 ml trimethyl phosphite are added. After 40 minutes at room temperature, the solution is poured into 500 ml of water and extracted with ethyl acetate (300 ml x 2). The organic layer is washed with water, dried and evaporated to give an oil. The oil was chromatographed on a 200 ml silica gel column, eluting with chloroform-ethyl acetate (3: 1) to give the total title compound, 1.25 g.

B. (3S-trans) -3-methoxy-4-
Preparation of Methyl-2-oxo-3-[[(phenylmethoxy) carbonyl] amino-1-azetidinesulfonic acid potassium salt :-( 3S-trans) -4-methyl-3-methoxy-
A solution of 0.800 g (0.00303 mol) of 2-oxo-4-[[(phenylmethoxy) carbonyl] amino] azetidine in 2 ml of dimethylformamide is cooled to 0 ° C. and 4 ml of dimethylformamide-sulfur trioxide complex is added. After 1 hour at 0 ° C. and 4 hours at room temperature, the solution was poured into 80 ml of 0.5 M potassium phosphate monobasic (solution adjusted to pH 5.5) and extracted with methylene chloride (50 ml × 2 times) (the extract was extracted). throw away.). Aqueous solution of tetrabutylammonium sulfate 1.0
Treated with 4 g and extracted with dichloromethane to give an oil 1.4
2 g are obtained. This is dissolved in acetone and treated with a mixture of 1.04 g potassium perfluorobutanesulfonate and 10 ml acetone. Dilute with 250 ml of ether and grind the resulting oily solid to give 0.584 g of crude product. Chromatography on 200 ml HP-20AG, eluting with 1000 ml water and then water-acetone (9: 1) gives 0.418 g of pure product in fractions 13 to 16 (100 ml each). 0.114 g of this material was treated with ether to give 0.104 g of the pure title compound. Elemental analysis, calculated as C ₁₃ H ₁₄ N ₂ O ₇ SK · H ₂ O, calculated value: C, 39.06%; H, 4.04%; N, 7.01
%; S, 8.03%; K, 9.78%, actual value: C, 38.91%; H, 3.62%; N, 6.91
%; S, 8.06%; K, 9.51%. _{NMR (D 20): 1.33 (} 3H, d, j = 7), 3.46 (3
H, s), 4.22 (2H, d d, j = 6), 5.18 (2H,
s), 7.43 ppm (5H, s).

Example 19 Preparation of trans-3-amino-4-ethyl-2-oxo-1-azetidinesulfonic acid: -A. Preparation of t-boc-N-methoxy-β-threoethylserinamide: 1.33 g of threo-D, L-β-ethylserine is dissolved in 10 ml of 2N potassium hydroxide and 5 ml of t-butanol. After adding 2.46 g of di-t-butyl pyrocarbonate, the two-phase mixture is stirred for 4 hours at ambient temperature. Add 1.25 g of O-methylhydroxyammonium chloride and add 1N hydrochloric acid to adjust the pH.
Adjust to 4. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.92 g) was added, and the mixture was added again.
Adjust to pH4. After stirring for 1 hour, the mixture was saturated with sodium chloride, extracted with ethyl acetate (50 ml x 4 times), the ethyl acetate extracts were combined, dried over magnesium sulfate and the solvent removed under reduced pressure to give 1 g of the title compound. To get

B. t-boc-O-methanesulfonyl-N-
Preparation of methoxy-β-threopropionamide: -t-boc-N-methoxy-β-threoethylserinamide 10.5 g is dissolved in 65 ml pyridine. 4.65 ml of methanesulfonyl chloride was added at 0 ° C, and the mixture was mixed at ambient temperature for 3
After stirring for an hour, the reaction mixture was added with 200 g of ice and 1N hydrochloric acid 3
Pour to 00 ml. Adjust to pH 4 with concentrated hydrochloric acid and with ethyl acetate.
After extracting (85 ml x 3 times), the extracts are combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was treated with carbon tetrachloride and concentrated again, after stirring with ether,
Filter to obtain 6.9 g of the title compound.

C. Preparation of trans-3-t-butoxycarbonylamino-4-ethyl-1-methoxy-2-azetidinone: 4.15 g anhydrous potassium carbonate and 125 ml dry acetone begin to reflux and t-boc-O-methanesulfonyl-N A mixture of 3.4 g of -methoxy-β-threo-propionamide and 25 ml of acetone is added. After refluxing for 1 hour, the reaction mixture is cooled, filtered and the filtrate is concentrated under reduced pressure. The oily residue is stirred with hexane to give 2.2 g of the title compound.

E. Preparation of trans-3-t-butoxycarbonylamino-4-ethyl-2-azetidinone: -To a liquid ammonia 170 ml (-78 ° C) was added tr under nitrogen atmosphere.
ans-3-t-butoxycarbonylamino-4-ethyl-
3 g of 1-methoxy-2-azetidinone are added and 1.68 g of sodium are added in 5 portions with stirring over 5 minutes. After stirring for 30 minutes, ammonium chloride is slowly added until the blue color of the mixture disappears. After removing ammonia under a nitrogen atmosphere, the solid was washed with ethyl acetate.
Extract (100 ml x 2). The solvent was removed and the residue was dried under reduced pressure to obtain 2.7 g of the title compound.

E. Preparation of trans-3-t-butoxycarbonylamino-4-ethyl-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt: -a mixture of 2 ml of anhydrous pyridine and 20 ml of dry dichloromethane, 3.7 ml of trimethylsilylsulfonyl chloride. A mixture of 5 ml of dry dichloromethane is added. This addition is carried out under a nitrogen atmosphere at -30 ° C for 10 minutes. After stirring for 30 minutes at ambient temperature, the contents in the flask are removed to obtain the pyridine-sulfur trioxide complex. The contents of the flask were mixed with trans-3-t-butoxycarbonylamino-
2.67 g of 4-ethyl-2-azetidinone and 20 ml of dry pyridine are added and placed on an oil bath preheated to 90 ° C. After 15 minutes, the resulting clear solution is poured into 200 ml of 1M dibasic potassium phosphate solution. To this was added 27 g of dibasic potassium phosphate and 100 ml of water to give a clear solution.
This solution was extracted with ethyl acetate (60 ml x 2 times), tetrabutylammonium hydrogen sulfate was added to the aqueous layer, this aqueous solution was extracted with dichloromethane (100 ml x 3 times), the organic layers were combined and dried over magnesium sulfate. .. This is concentrated under reduced pressure to give 6.9 g of the title compound.

F. trans-3-amino-4-ethyl-2
Preparation of -oxo-1-azetidine sulphonic acid: -trans-3-t-butoxycarbonylamino-4-ethyl-2-oxo-1-azetidine sulphonic acid tetrabutylammonium salt 6.75 g in 40 ml of 98% formic acid. Is stirred at ambient temperature for 3 hours. 60 ml of dichloromethane in this
Is added and the mixture is refrigerated for about 16 hours. The formed precipitate was collected by filtration and dried under reduced pressure to obtain 0.85 g of the title compound. Melting point 185 [deg.] C (decomposition).

Example 20 [3S-trans] -3-amino-4-cyclohexyl-2
Preparation of -oxo-1-azetidine-sulphonic acid: -A) Preparation of α- (t-butoxycarbonylamino) -β-cyclohexyl-β-hydroxy-threo-propionic acid:
-Β-cyclohexyl-α-amino-β-hydroxy-th
Reo-propionic acid (15 g) is suspended in 150 ml acetonitrile and 70 ml water. Triethylamine (1
7.8 g) is added and the mixture is heated to 60 ° C. with stirring. At this temperature a clear solution was obtained, to which 21.0 g di-t
-Butyl pyrocarbonate was added and stirred at 60 ° C for 1.
Continue for 5 hours. The solvent is removed under reduced pressure and 50 ml of water are added. The aqueous layer was extracted with ethyl acetate at pH 2 and the pH
H is adjusted by the addition of 3N-HCl. Separate the organic layer,
Dry over Na ₂ SO ₄ and evaporate to dryness. The residual crystalline material was filtered off with petroleum ether to give 20.4 g of melting point 1
The title compound forms at 13-115 ° C.

B) α- (t-butoxycarbonylamino)-
β-cyclohexyl-β-hydroxy-N-methoxy-
Preparation of threo-propionamide: -α- (t-butoxycarbonylamino) -β-cyclohexyl-β-hydroxy-threo-propionic acid (20.2
g) and 7.6 g of O-methylhydroxylamine hydrochloride are suspended in 350 ml of water and 175 ml of t-butanol. The pH of the mixture is adjusted to 4 with potassium carbonate. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (16.4 g) is added and the pH is maintained at 4 with stirring for 1.5 hours. t-butanol was removed under reduced pressure,
The remaining aqueous solution is saturated with sodium chloride and extracted twice with 100 ml portions of ethyl acetate. The organic layers are collected and combined with Na ₂ SO
Dry at ₄ and evaporate to dryness. The remaining crystals are filtered off with petroleum ether, yielding 18.6 g of the title compound with a melting point of 125-127 ° C.

C) α- (t-Butoxycarbonylamino)-
β-cyclohexyl-β- (methanesulfonyloxy)-
Preparation of N-methoxy-threo-propionamide: -α- (t-butoxycarbonylamino) -β-cyclohexyl-β-hydroxy-N-methoxy-threo-propionamide (18.3 g) with stirring to 100 ml Dissolve in dry pyridine. The solution is cooled to 0 ° C. with stirring and 9.3 g of methanesulphonyl chloride are added dropwise.
After 1 hour, an additional 3.3 g of methanesulfonyl chloride is added at 0 ° C. and stirring is continued for another hour. 30 solution
Pour into 0 ml of ice water, add 200 ml of ethyl acetate and adjust the pH to 3 with dilute sulfuric acid. The organic layer was separated and Na ₂ SO ₄
And the solvent is removed under reduced pressure. The remaining solid was collected with petroleum ether to give 19.0 g, mp 150-152 ° C.
This produces the title compound of.

D) [3S-trans] -3- (t-butoxycarbonylamino) -4-cyclohexyl-1-methoxy-
Preparation of 2-azetidinone: -α- (t-butoxycarbonylamino) -β-cyclohexyl-β- (methanesulfonyloxy) -N-methoxy-
Threo-propionamide (18.7 g) is dissolved in 500 ml dry acetone. Potassium carbonate (9.8 g) is added and the suspension is heated to reflux temperature for 5 hours with stirring.
The insoluble inorganic material is filtered off, the solvent is removed under reduced pressure and the residual oil is dissolved in 30 ml of ethyl acetate. Addition of petroleum ether precipitates the title compound with a melting point of 110-112 ° C,
This is filtered off (12.9 g).

E) Preparation of [3S-trans] -3- (t-butoxycarbonylamino) -4-cyclohexyl-2-azetidinone:-[3S-trans] -3- (t-butoxycarbonylamino)-
4-cyclohexyl-1-methoxy-2-azetidinone
(1 g) is added with stirring to 50 ml of liquid ammonia. Sodium (0.154g) is added in 5-6 portions within 5 minutes. Then an additional amount of sodium 0.025
g and continue stirring for 5 minutes. Ammonium chloride
(0.89 g) is added and the ammonia is removed. The residue is extracted with warm ethyl acetate. The organic extract is evaporated to dryness and the remaining crystals of the title compound are filtered off with petroleum ether. Yield 0.5 g, melting point 130-132 ° C.

F) [3S-trans] -3- (t-butoxycarbonylamino) -4-cyclohexyl-2-oxo-1
-Preparation of azetidine sulfonic acid pyridine salt:-[3S-trans] -3- (t-butoxycarbonylamino)-
4-cyclohexyl-2-azetidinone (5.3 g),
Dissolve in 20 ml methylene chloride and 80 ml dimethylformamide. After addition of 60 mmol of pyridine-sulfur trioxide complex (complex), the solution is stirred at room temperature for 6 hours. Removal of the solvent under reduced pressure yields 11.3 g of the title compound as an oil.

G) [3S-trans] -3- (t-butoxycarbonylamino) -4-cyclohexyl-2-oxo-1
-Preparation of azetidine sulfonic acid tetrabutylammonium salt:-[3S-trans] -3- (t-butoxycarbonylamino)-
4-Cyclohexyl-2-oxo-1-azetidinesulfonic acid pyridine salt (11.3 g) is dissolved in 250 ml of water. Tetrabutylammonium acid sulfate (9.0 g) was added with stirring and the pH was adjusted to 6.5 with 1N potassium hydroxide.
Adjust to. The aqueous solution is extracted twice with 200 ml portions of methylene chloride. The organic portion is dried over Na ₂ SO ₄ , filtered and evaporated to yield 8 g of the title compound, mp 135-138 ° C.

H) Preparation of [3S-trans] -3-amino-4-cyclohexyl-2-oxo-1-azetidinesulfonic acid:-[3S-trans] -3- (t-butoxycarbonylamino)-
4-Cyclohexyl-2-oxo-1-azetidinesulfonic acid tetrabutylammonium salt (3.8 g) was added to 2
Stir in 0 ml of formic acid for 3 hours, then add 20 ml of methylene chloride. The precipitated title compound (1.0 g) is filtered off. Melting point 217-219 [deg.] C.

Example 21 Preparation of (±)-(trans) -3-amino-2-oxo-4-phenyl-1-azetidinesulfonic acid: --A) (±)-(trans) -2-oxo- Preparation of 4-phenyl-1-azetidine-tert-butyldiphenylsilane: -A solution of tert-butylchlorodiphenylsilane (20.56 g) in dimethylformamide (45 ml) was cooled to 0 ° C under argon, which was triethylamine. (10.
4 ml) and then (±) -2-oxo-4-phenyl-1-azetin. After several hours at 0 ° C., the resulting mixture is treated with additional triethylamine (1 ml) and tert-butylchlorodiphenylsilane (2.11 g) and allowed to stir at 5 ° C. for 65 hours. Reaction mixture with ice water
Pour into (300 ml) and extract with ether-ethyl acetate (3: 1) (125 ml portions, 3 times). The organic extracts were washed with pH 4.5 phosphate buffer (50 ml, 3 times), saturated sodium bicarbonate solution (50 ml), water (50 ml, 2 times), saturated sodium chloride solution and dried (Na). ₂ SO ₄ ). A solid is formed by filtration and concentration under reduced pressure, which is washed with hexane and dried (under high vacuum) to obtain 15 g of the title compound as a solid.

B) Preparation of (±)-(trans) -3-azido-2-oxo-4-phenyl-1-azetidine-tert-butyldiphenylsilane: For 50 ml equipped with stir bar, gas port and septum The flask was flame dried under argon and cooled to -40 ° C and charged with n-butyllithium (0.65 ml of a 1.65 molar hexane solution) dissolved in tetrahydrofuran (2 ml). Diisopropylamine (0.16 ml) is added dropwise and the resulting mixture is stirred for 30 minutes and cooled to -78 ° C. (±)-(trans) -2- in tetrahydrofuran (1.5 ml)
A solution of oxo-4-phenyl-1-azetidine-tert-butyldiphenylsilane (400 mg) is added dropwise over about 5 minutes. After stirring for an additional 20 minutes, the solution is treated with P-toluenesulfonyl azide (204 mg) in tetrahydrofuran (0.5 ml). The resulting mixture is -78 ° C.
Stir for 10 minutes and treat with chlorotrimethylsilane (0.4 ml) dropwise. After stirring for another 10 minutes, remove the cooling bath and
The reaction mixture is stirred at ambient temperature for 2.5 hours. Then 0
While cooling at ℃, add ethyl acetate (20 ml) and continue.
Add pH 4.5 phosphate buffer (8 ml). Add the organic layer to additional buffer (8 ml, twice), 5% sodium bicarbonate solution
(10 ml, 3 times), 50% sodium chloride solution (10 m
l), washed with saturated sodium chloride solution (10 ml) and dried (Na
₂ SO ₄ ). 500m by filtration and concentration under reduced pressure
g of an oil was formed which was flash chromatographed with 5% ethyl acetate-hexane to give the title compound (2
53 mg) is obtained.

C) Preparation of (±)-(trans) -3-azido-2-oxo-4-phenyl-1-azetidine: -17 g of crude (±)-(trans) -3-azido-2-oxo -4
A solution of -phenyl-1-azetidine-tertiarybutyldiphenylsilane is dissolved in methanol (240 ml) and treated dropwise with concentrated HCl (35 ml) at 0 ° C. The cooling bath is removed, the reaction is stirred at ambient temperature for 1 hour, recooled to 0 ° C. and neutralized by adding saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (300 ml part x 1 and 100 ml part x 4) and the organic extract was 5%.
Sodium bicarbonate and 50% sodium chloride solution (1:
1), washed with saturated sodium chloride solution and dried (Na ₂ SO ₄
(Above) Filtration and concentration under reduced pressure yielded 15 g of a heavy oil which was chromatographed on 100 g of silica gel with 20% ethyl acetate-hexane, 4
60 mg of the title compound are obtained.

D) Preparation of (±)-(trans) -3-azido-4-phenyl-1-azetidinesulfonic acid tetrabutylammonium salt :-( ±)-(trans)-in dimethylformamide (3 ml) 3-
Azido-2-oxo-4-phenyl-1-azetidine
A solution of (300 mg) is cooled to 0 ° C. under argon and treated dropwise with a complex of dimethylformamide and sulfur trioxide (4.78 ml of a 0.5M dimethylformamide solution). The cooling bath was removed, the reaction mixture was stirred at ambient temperature for 2 hours,
This was mixed with 80 ml of 0.5 M monobasic potassium phosphate (pH 5.
Pour into 5). The solution is extracted with dichloromethane (discarded) and 541 mg of tetrabutylammonium bisulfate are added. The resulting mixture was extracted with dichloromethane, the organic extracts were washed with 10% sodium chloride solution and dried (Na ₂ S
On O ₄ ). Filtration and concentration under reduced pressure gave 800 mg of oil, about 40% desired product, balance dimethylformamide. This mixture is used in the next step without purification.

E) Preparation of (±)-(trans) -3-amino-4-phenyl-1-azetidinesulfonic acid: (±)-(trans) -3-amino-4 in 4 ml of methanol.
A solution of -phenyl-1-azetidine sulfonic acid tetrabutylammonium salt is hydrogenated over 30 mg of platinum chloride at 1 atm and room temperature. After 15 minutes, the system is evacuated and fresh hydrogen is introduced. After an additional 45 minutes the reaction is complete and the system is flushed with nitrogen. After several days at room temperature, dichloromethane-methanol (4: 1, 200
catalyst aggregation is completed in (ml) and filtered. 18m of filtrate
Concentrate to l under reduced pressure and add 0.2 ml of 97% formic acid. 5 ° C
After cooling for several hours at 60 ° C., the solid formed is filtered off, washed with dichloromethane and, after drying, 150 mg of the title compound are applied as a solid. Calc'd for _{C 9 H 19 N 2 O 4} S: C44.62, H4.17,
N11.57, S13.23. Found: C43.36, H4.31, N11.09, S
13.02.

Example 22 Preparation of (cis) -3-amino-2-oxo-4- (2-phenylethenyl) -1-azetidinesulfonic acid: A) N- (3-phenyl-2-propenylidene) Preparation of 4-methoxyaniline: -P-anisidine (12.32 g) is dissolved in 160 ml methylene chloride and 20 g anhydrous magnesium sulfate are added.
The mixture is cooled in an ice bath and 13.22 g of trans-cinnamaldehyde is added. The mixture was stirred under nitrogen for 2 hours,
Then filter. The filtrate is evaporated to give a solid. The crude product was recrystallized from methylene chloride-petroleum ether to give 2
0.96 g of the title compound is obtained as a solid.

B) (±)-(cis) -3-azido-1- (4-
Preparation of methoxyphenyl) -2-oxo-4- (2-phenylethenyl) azetidine: 2-Azidoacetic acid (24.26 g) is dissolved in 100 ml methylene chloride and cooled in an ice bath. To this solution are added 48.57 g of triethylamine and 14.24 g of N- (3-phenyl-2-propenylidene) -4-methoxyaniline dissolved in 250 ml of methylene chloride. To the resulting solution, 50.41 g of trifluoroacetic anhydride are added dropwise over 1 hour. After stirring for 1 hour in an ice bath, the mixture is warmed to room temperature and stirred for about 16 hours. Then mix 25
Dilute with 0 ml methylene chloride, water (750 ml), 5% sodium bicarbonate solution (750 ml portions, 2 times) and 1N-HC.
l Wash with solution (750 ml). The organic layer is dried over anhydrous sodium sulfate and the solvent is removed to give a solid. The crude product is recrystallized from ethyl acetate to give 11.39 g of the title compound as a solid.

C) Preparation of (±)-(cis) -3-azido-2-oxo-4- (2-phenylethenyl) azetidine: A solution of 10.22 g of ceric ammonium nitrate in 13 ml of water. And 1.99 g of (±)-(cis) -3-at 0 ° C.
Azido-1- (4-methoxyphenyl) -2-oxo-4
Add-(2-phenylethenyl) azetidine and add 6
Dissolve in 5 ml of acetonitrile for 15 minutes (use an additional 10 ml of acetonitrile for rinsing). The mixture is stirred at 0 ° C. for a further 15 minutes, diluted with 750 ml of ethyl acetate, washed with water (600 ml portions, 6 times), dried over anhydrous sodium sulfate and the solvent is removed to give an oil. The crude product is chromatographed on 90 g of silica gel, first 2
50 ml of 30% ethyl acetate / petroleum ether, then 50
Elute with% ethyl acetate / petroleum ether. Fraction (each 50m
l) Collect 11-16 and evaporate to give 802 mg of the title compound as an oil.

D) Preparation of (±)-(cis) -3-azido-2-oxo-4- (2-phenylethenyl) -1-azetidinesulfonic acid tetra-n-butylammonium salt :-( ± )-(Cis) -3-Azido-2-oxo-4- (2-phenylethenyl) -azetidine (334 mg) is dissolved in 3 ml of dimethylformamide and 868 mg of pyridine-sulfur trioxide are added. The mixture is stirred under nitrogen at room temperature for 40 hours, then poured into 200 ml of 0.5M monobasic potassium phosphate solution and washed with 30 ml of methylene chloride. To the aqueous solution is added tetra-n-butylammonium bisulfate (530 mg) and the mixture is extracted with methylene chloride. (50 ml portion, 4
Times). The collected organic layer was back washed with water (100 ml portion, 2
Times), dried over anhydrous magnesium sulfate and the solvent removed to give 824 mg of the title compound as a gum.

E) Preparation of (±)-(cis) -3-azido-2-oxo-4- (2-phenylethenyl) -1-azetidinesulfonic acid :-( ±)-(cis) -3 -Azido-2-oxo-4- (2-phenylethenyl) -1-azetidinesulfonic acid tetra-n-
Butyl ammonium salt (300 mg) is dissolved in 4 ml of tetrahydrofuran and stirred rapidly. 600 mg in the mixture
Of zinc fines, followed by 0.8 ml of 1N-basic potassium phosphate solution. The mixture is heated to 45 ° C. and stirred at this temperature for 3 hours. Then the mixture is filtered and the filtrate is combined with 4
Take up in 0 ml methylene chloride and 10 ml water. The aqueous layer was further extracted with methylene chloride (40 ml portions, 3 times) and the combined methylene chloride layers were stripped of solvent to give 256 mg of foam. A small amount of this crude product, about 30% acetone /
Dissolve in water and add 7.5 ml of Dowex (K ⁺ ) resin (0.7 meq.
/ Ml) and elute with 40 ml of water. The eluent is evaporated to give 151 mg of foam, which is dissolved in 2 mg of water and acidified to pH 2 with 1N HCl solution. A small amount of acetonitrile is added to dissolve the precipitate, the resulting solution is applied to 15 ml HP-20 resin and eluted with 150 ml water, then 10% acetone / water. Fraction (1 each
50 ml) 2 to 13 are collected and evaporated to give 101 mg of the title compound in foam.

Example 23 (cis) -3-amino-4- (methoxycarbonyl) -2-
Preparation of oxo-1-azetidine sulphonic acid: -A) Preparation of [(4-methoxyphenyl) imino] acetic acid methyl ester: -In a dry flask for 3 liters 1 liter equipped with nitrogen port and stir bar, 56. 88 g of MgSO ₄ are subsequently charged, followed by a solution of recrystallized anisidine (19.43 g) in dichloromethane (250 ml). After cooling to 0 ° C, dichloromethane (25
Methylglyoxylate hemiacetal (1 ml in 0 ml)
A solution of 9.92 g) is added over 1.5 hours. 0
After stirring for a further 20 minutes at 0 ° C., the reaction mixture is suction filtered, dried over sodium sulphate, filtered and concentrated under reduced pressure to a quarter volume. Hexane (300 ml) was added and the solution was concentrated to an oil which semi-solidified on standing under high vacuum at 5 ° C.

B) (cis) -3- (1,3-dihydro-1,3
-Dioxo-2H-isoindol-2-yl) -4-
Manufacture of methoxycarbonyl-2-oxo-1- (4-methoxyphenyl) azetidine: -In a dry flask for 3 necks 500 ml equipped with stir bar, dropping funnel, septum and nitrogen port, dichloromethane (150 m
Charge a solution of [(4-methoxyphenyl) imino] acetic acid methyl ester (21.09g) in l) and cool to 0 ° C.
0.14 mol (19.2 ml) triethylamine is added dropwise, followed by a solution of (N-phthalimido) acetyl acid chloride (28.4 g) in dichloromethane (150 ml) over 1 hour. The resulting mixture is stirred for 1.5 hours at 0 ° C. and diluted with 2.5 l dichloromethane. P the organic solution
H4.5 monobasic potassium phosphate (500 ml, twice), 5
Wash with% sodium bicarbonate (500 ml, twice), saturated sodium chloride solution (500 ml) and dry over sodium sulfate. Filtration and concentration under reduced pressure produced a solid which was washed with ethyl acetate, cold acetone and hexanes.
65 g of product are obtained.

C) (cis) -4- (methoxycarbonyl) -1
Preparation of-(4-Methoxyphenyl) -2-oxo-3-[[(phenylmethoxy) carbonyl] amino] azetidine: -In a 500 ml dry flask equipped with a nitrogen port, stir bar and septum, 18.65 g of ( Charge cis) -3- (1,3-dioxo-2H-isoindol-2-yl) -4-methoxycarbonyl-2-oxo-1- (4-methoxyphenyl) azetidine and 325 ml of dichloromethane.
The resulting suspension was cooled to -30 ° C and methylhydrazine
(3.52 ml) is added dropwise. The reaction is warmed to 0 ° C. and stirred for 1 hour. Add 0.4 ml of methylhydrazine,
The mixture is stirred for 10 minutes. This procedure was repeated and a total of 2.9 equivalents of methylhydrazine (7.7 ml) was added.
The solvent is removed under reduced pressure, 200 ml of fresh dichloromethane are added and the mixture is concentrated again. This procedure is repeated twice more and the resulting foam is dried under high vacuum for 20 minutes and
Redissolve in 25 ml of dichloromethane, about 16 at ambient temperature
Allow to stand for a period of time, during which time a significant amount of solids precipitate.
The mixture was filtered under nitrogen, the filtrate cooled to 0 ° C. (nitrogen atmosphere) and treated with diisopropylethylamine (17 ml),
Then benzyl chloroformate (7 ml) is added dropwise. The reaction is stirred at 0 ° C. for 30 minutes then at ambient temperature for 1.5 hours. The mixture was adjusted to pH 4.5 with monobasic potassium phosphate buffer (300 ml, twice), 5% sodium bicarbonate (30 ml).
Wash with 0 ml portions (twice), saturated sodium chloride (300 ml), dry (over sodium sulfate) and filter. Concentration under reduced pressure produced a foam which was treated with ether to give 9.9 g of the title compound as a solid.

D) (cis) -4- (methoxycarbonyl) -2
Preparation of -oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidine: -60 ml of a solution of ceric ammonium nitrate (8.59 g) in acetonitrile-water (1: 1) was added to 50 ml. (Cis) -4- (methoxycarbonyl) -1 in acetonitrile
Treat with a slurry of 2 g of-(4-methoxyphenyl) -2-oxo-3 [[(phenylmethoxy) carbonyl] amino] azetidine over 10 minutes. The reaction mixture is stirred at ambient temperature for a further 10 minutes and diluted with ethyl acetate (100 ml). The separated aqueous layer was washed with ethyl acetate (40 ml, 3 times) and the combined organic extracts were washed with 50% sodium bicarbonate (70 m).
Wash with 1 part, 3 times). The basic washing solution was back-washed with ethyl acetate (50 ml), and the collected organic extracts were combined with aqueous sodium sulfite solution, 5% aqueous sodium carbonate solution (100 ml), 5% aqueous sodium chloride solution (100 ml, twice), saturated sodium chloride. Wash (50 ml, twice) and stir on Drago G-60 activated carbon for 30 minutes. Sodium sulphate was added and the mixture was filtered and concentrated under reduced pressure to give an oil which was treated with ether to give 685 mg of the title compound as a solid.

E) (cis) -4- (methoxycarbonyl) -2
Preparation of -oxo-3-[[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid tetrabutylammonium salt :-( cis) -4- (methoxycarbonyl) in 1 ml of pyridine.
-2-oxo-3-[[(phenylmethoxy) carbonyl]
A mixture of amino] -1-azetidine (100 mg) and 172 mg of a pyridine-sulfur trioxide complex was added under argon to 8%.
Stir at 0 ° C. for 3 hours. The reaction mixture is 70 ml of 0.5M
Pour into monobasic potassium phosphate (pH 5.5) and extract 4 times with 30 ml portions of dichloromethane (discard). To the aqueous layer was added tetrabutylammonium acid sulfate (122 mg), which was then extracted with dichloromethane (30 ml portions, 4 times). The organic extract is washed with 8% sodium chloride solution, dried over sodium sulfate and filtered. 1 by vacuum concentration
86 mg of the title compound are obtained as a viscous oil.

F) Preparation of (cis) -3-amino-4- (methoxycarbonyl) -2-oxo-1-azetidinesulfonic acid: 186 mg (cis) -4- (methoxycarbonyl) in 2 ml methanol. ) -2-Oxo-3-[[(phenylmethoxy)
A solution of carbonyl] amino] -1-azetidinesulfonic acid tetrabutylammonium salt is hydrogenated over 10% palladium / activated carbon (95 mg) at 1 atm for 1.5 hours. The catalyst is filtered off, rinsed with dichloromethane and the filtrate is 97%
Treat with formic acid and cool to -50 ° C (presence of seed crystals required at this stage to cause crystallization). The mixture is allowed to stand at 10 ° C. for about 16 hours after crystallization has started. The solid obtained is washed with dichloromethane, hexane and dried under reduced pressure to yield 50 mg of the title compound.

Example 24 Preparation of (S)-(trans) -3-amino-4-ethynyl-2-oxo-1-azetidinesulfonic acid: -A) Preparation of 2- (trimethylsilyl) ethynylmagnesium bromide;- To a 50 ml flame dried flask maintained under positive nitrogen pressure is added 20 ml of dry tetrahydrofuran, 2.20 ml of trimethylsilylacetylene and 5.05 ml of a 3.06M ether solution of methylmagnesium bromide. The mixture is stirred for 140 minutes to give the title compound.

B) Preparation of (S)-(trans) -4- [2- (trimethylsilyl) ethynyl] -2-oxo-3-[(triphenylmethyl) amino] azetidine: -flame dried 3 for 250 ml In a two-necked flask, 6.00
g of (S)-(cis) -4- (methylsulfonyl) -2-oxo-3-[(triphenylmethyl) amino] azetidine is added. The flask is flushed with nitrogen and then kept under positive nitrogen pressure. After cooling the reaction mixture in a dry ice / isopropanol bath, methylmagnesium bromide (3.06M) was added.
4.65 ml of ethereal solution are added dropwise via the Syringe with rapid stirring. The solution of 2- (trimethylsilyl) ethynylmagnesium bromide prepared in A) above is added via a Teflon tube under positive nitrogen pressure (rinse the flask containing the reactants with 7 ml of tetrahydrofuran).
At the end of the addition, remove the cold bath. After 45 minutes, a solution of 3.5 g potassium bisulfate in 20 ml water is added. Most of the tetrahydrofuran is removed with a rotary evaporator. The residue is transferred to a separating funnel with ether and water. Separate the aqueous layer and extract twice with ether. The combined ether layers are washed once with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered. Removal of the solvent gives a foam which is chromatographed on a silica gel column. Elution with 2 l dichloromethane, 1 l 1% ether / dichloromethane, 2 l 2% ether / dichloromethane and 1.5 l 10% ether / dichloromethane (fraction 1: 1000 ml, fractions 2,3: 500 ml, fraction 4
~ End: 250 ml), 1.3 in fractions 2-8
0 g of title compound, corresponding tra in fractions 12-19
1.80 g of the ns isomer are obtained. Fractions 9-11 contain 1.19 g of a mixture of cis and trans isomers.

C) Preparation of (S)-(trans) -4-ethynyl-2-oxo-3-[(triphenylmethyl) amino] azetidine:-(S)-(trans) -4- [2- ( Trimethylsilyl) ethynyl] -2-oxo-3-[[(triphenylmethyl) amino]
Azetidine (2.97 g) is dissolved in 30 ml dichloromethane and 330 mg tetrabutylammonium fluoride (containing 20-25% water) is added. After 20 minutes, the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and water. The organic layer is separated, washed once with water and once with saturated aqueous sodium chloride solution, dried over sodium sulphate,
Filter. Removal of the solvent gave an oil which was 60 ml.
Stir with pentane for 15 minutes to give 2.35 g of the title compound as a powder (after vacuum drying).

D) Preparation of (S)-(trans) -3-amino-4-ethynyl-2-oxo-1-azetidinesulfonic acid:
-(S)-(trans) -4-ethynyl-2-oxo-3-[(triphenylmethyl) amino] azetidine (404 mg) and 560 mg complex of pyridine and sulfur trioxide are added to a 25 ml flask. After flushing the flask with nitrogen, 4.
0 ml dry pyridine was added and the mixture was stirred at 80-85 ° C for 3 times.
Heat for hours. Such a mixture was added with 4.0 ml of concentrated hydrochloric acid, 5
0 ml water and 50 ml ethyl acetate are added to the rapidly stirred mixture. Adjust the pH to 3.15 with sodium carbonate. The aqueous layer is separated and extracted once with ethyl acetate. The combined organic layers are washed once with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered. Removal of the solvent under reduced pressure gives a foam which is taken up in 10 ml of dichloromethane. Formic acid (98%, 8 ml) is added and after 15 minutes the mixture is concentrated to 4 ml and 10 ml of dichloromethane are added to give a solid suspended in the solution. Filtration gives 100 ml of the title compound as a solid (melts at> 180 ° C. and a distinct color change).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location 7019-4C C07D 205/08 N (72) Inventor William L. Parker United States New Jersey, Pennington, Hale・ Street 216 (72) Inventor Christopher M. Simara Stay USA New Jersey, Pennington, Hugo Road 278 (72) Inventor William Eighth Coster United States New Jersey, Ringes, Werisewirts Road (No) (72) Inventor William A. Sursearch, USA New Jersey, Bell Mead, Sanset Road (No street address) (72) Alan Davryu Fritz United States New Jersey, Kendall Park, Betsk Court No. 9 (72) Inventor Devitt M Floyd United States New Jersey, Pennington, Earl Earl No. 1, Box No. 404 Em no display)

Claims (1)

[Claims] 1. The formula: (In the formula, R ₂ is hydrogen or alkoxy having 1 to 4 carbon atoms; R ₃
And R ₄ are the same or different and each represents hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R ₃ and R ₄ is hydrogen, the other is alkoxycarbonyl, alkene-1-yl, alkyne-
1-yl, 2-phenylethenyl or 2-phenylethynyl).