JPS59161384A - 6-beta-substituted penicillanic acid as beta-lactamase inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing a series of 6-β-substituted benidylanic acids and their esters that can be easily hydrolyzed in living organisms. It is a potent inhibitor and enhances the effectiveness of β-lactam antibiotics.

One of the best known and most commonly used classes of antibacterial agents are the so-called beta-lactam antibiotics. These compounds are characterized by having a core consisting of a 2-azetidinone (β-lactam) ring attached to a thiazolidine or dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are commonly referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring - the compounds are referred to as cef70sporins. Typical examples of penicillins commonly used in clinical practice are benzylpenicillin (Snigilan G), phenoxymethylpenicillin (penicillin V) - ampicillin and Cal (nigilin), which are typical of commonly used cephalosporins. Examples are cephalothin-cephalexin and cefazolin.

However, despite the versatility and widespread adoption of beta-lactam antibiotics as valuable chemotherapeutic agents, the acid compounds of these groups have suffered the reproach of being inactive against adult organisms. In many instances, this resistance of a particular microorganism to a given β-lactam antibiotic is believed to be the result of the microorganism producing a β-lactam degrading enzyme. The latter substances are enzymes that break down the β-lactam rings of penicillins and cephalosporins, rendering them devoid of antibacterial activity. However - certain substances have the ability to inhibit beta-lactamase and when beta-lactamase is used in combination with penicillins or cephalosporins - it is possible to It can increase the antibacterial effect on microorganisms or treat them. Increased antibacterial efficacy is considered to occur when the antibacterial activity in the combination of a β-lactamase inhibitor and a β-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.

6-substituted R-nidylanic acids and certain esters have been prepared via 6-diacibenisilanic acid (Helv, C
him, Acta, 50. 1ro 27 (1967)
), or the direction of the substituent is α-position. 6-alpha-no-idroxybenicilanic acid is also prepared from 6-diacibenicilanic acid and its esters'' (J, Org, C
hem-39, 1444 (1974)).

6-α-benzyloxy and nidylanic acid methyl ester are described by Manhas et al. (J, Heterocycle, Chem.
, 15.

601 (1978)).

Certain noro, 6-dino, and 6-no-nidylanic acids have been described by Harrision et al. (J, Chem, Soc.
, 1772 (1977)). A 6-α-epimer is described on each side of the mono-substituted dilanic acid.

More recently, Loosemore et al.
m, 43.

Ro 611 (1978), when -6-α-bromo is treated with nidillanic acid with a base to epimerize a part of the compound, 6-
It was reported to give a mixture of α- and 6-α-bromopenicillanic acids (12%). A similar mixture was obtained by hydrogenation of nidilanic acid to 6,6-dine lomo containing approximately 60% of the total β-epimer. 6-α- and 6
A report by Pratt et al. (Pr.
oc.

Natl, Acad, Sci, 75. 4145(
1978)). This finding of Pratt et al.
M. J., 177, 365 (1979)), 5
This was corroborated by the demonstration that a mixture of % 6-β-bromopenicillanic acid and 95% 6-α-bromopenicillanic acid inhibited β-lactum degrading enzymes, whereas the α-epimer alone was essentially inactive.

U.S. Pat. No. 4,093,625 claims a method for producing 6-β-mercaptopenicillanic acid and its derivatives as antibacterial agents.

Cartwrigbt et al. (Nature 278.36
0 (1979)) is -6α-chloro and nidillanic acid is β-
It has been reported that sulfone, which has a low inhibitory activity against Rakukum-degrading enzyme but exhibits a certain white color, is a fairly good inhibitor.
reactor.

Roets et al. (J, Chem, Soc, (Perkin
f) 704 (1976) identifies 6β-chloro R-nidylanic acid benzyl ester as a by-product of the reduction of 6-oxo-4-nidylanic acid henzyl ester and subsequent treatment of the product with hydrochloric acid.

Recently, John et al. (J, Chem, Soc, Ch6m,
Comm.

45 (1979)) used a complex hydride reduction method to produce 6β-
A method for producing noromobenicillanic acid hensyl ester was reported.

The 6-β-substituted derivatives obtained by the process of the invention or their pharmaceutically suitable basic salts.

(In the formula, R15 hafluoro, chloro-iodo8-fluoromethyl-chloromethyl-bromomethyl, alkoxy of 1 to 4 carbon atoms or alkylthio group of 1 to 4 carbon atoms; n is an integer from D to 2: R13 is hydrogen or an ester-forming residue that can be easily dissolved in vivo).

A suitable group for a β-lactum degrading enzyme inhibitor is when n is 0 and R1 is hydrogen. Within this group, those compounds in which R15 is chloro or iodo are particularly preferred.

A second group of preferred compounds are those in which n is 1-Rl3 is hydrogen. Particular preference within this group is given to compounds in which R1 is chloro or iodo9.

A sixth group of preferred compounds is 0 and R13 is R
Nidyline carboxy protecting group - This is a compound in which the protective group consists of the following.

a) -PR2R3 [wherein R2 and R3 are 1 to 6
each of alkyl having 5 carbon atoms, alkoxy having 1 to 6 carbon atoms, or phenyl] b> 3.5-di-
t-cutyl-4-hydroxybenzyl, c) -0H:z Y - where Y is 10(0)R4
[In the formula, R4 is phenyl or alkyl of 1 to 6 carbon atoms, cyanogen or carbalkoxy of 2 to 4 carbon atoms] a) -N2CHR5= [In the formula, R5 is phenyl or alkyl of 1 to 6 carbon atoms] Phenyl or alkyl group] e) CH(GOCI43)G○2R6 [In the formula, R6 is an alkyl group of 1 to 4 carbon atoms] - f) -Cf (voice, R9 [In the formula, R7 and U=R8 are each hydrogen phenyl or methyl, and R9 is phenyl/
I/-4-methoxyphenyl- or methyl (however, R
R is fluoro-iodo, fluoromethyl, chloromethyl-bromomethyl, 1 to 4 carbons atomic alkoxy or alkylthio of 1 or 4 carbon atoms]g
) -3i(CH3)3 and -51(CH3)2t
-C4H9; h) -3nR16R1-tR1s except for R161R17 and H engineering.

are each alkyl of 1 to 5 carbon atoms, phenylene or benzyl.

Particularly preferred within this group are compounds in which R1 is tributyltin and R is chloro, R1 is trimethylsilyl and R is chloro-, and R3 is 4-methoxybenzyl and R is iodo.

A fourth group of preferred compounds are those in which R13 is an ester-forming residue that is easily hydrolysable in vivo; 1-(alkanoyloxy)ethyl, 1-methyl-1 of 5 to 8 carbon atoms
-(alkanoyloxy)ethyl, alkoxycarbonyloxymethyl of 6 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl of 4 to 7 carbon atoms-1-methyl-1 of 5 to 8 carbon atoms -(alkoxycarbonyloxy)ethyl, 6-phthalidyl-4-crotonolactonyl and γ-butyllacton-4-yl. Among this group, R15 is particularly prioritized.
is chloro, R13 is pivaloyloxymethyl and dan is 00 compound and R13 is pivaloyloxymethyl, R
15 is iodine and dan is 00 compound.

The product of the process of the invention is also a pharmaceutical compound (including a pharmaceutically suitable carrier) useful in the treatment of bacterial infections in mammals.
and a compound represented by a β-lactam antibiotic or a pharmaceutically suitable basic salt thereof (wherein R15 is fluoro, chloro, iodofluoromethyl-chloromethyl-bromomethyl, 1 to 4 carbon atoms) atomic alkoxy or alkylthio of 1 to 4 carbon atoms; where ゛ is an integer from O to 2; and R13 is hydrogen or an ester-forming residue that is easily soluble in vivo - provided that when R is alkylthio, is an integer from 0 to 1) increases the efficacy of the β-lactam antibiotic when administered simultaneously.

Preferred compounds in this group are selected from the following compounds where R13 is hydrogen or an ester-forming residue that is easily hydrolyzed in vivo. namely alkanoyloxymethyl of 3 to 6 carbon atoms, -1-(alkanoyloxy)ethyl of 4 to 7 carbon atoms, -1-methyl-1-(alkanoyloxy)-ethyl of 5 to 8 carbon atoms, Alkoxycarbonyloxymethyl of 6 to 6 carbon atoms to 1-(alkoxycarbonyloxy)ethyl of 4 to 7 carbon atoms-1-methyl-1-(alkoxycarbonyloxy)ethyl of 5 to 8 carbon atoms-6 -7 Tarijiro
4-crotonolactonyl, and γ-antyrolacton-4-yl and half-o- and half-mirrolic β-lactam antibiotics are selected from penicillins and cephalosporins. Particularly preferred compounds are those in which R]5 is chloro or iodo and RJ3 is hydrogen and R1 is iodo or chloro and R13 is pivaloyloxymethyl.

The present invention relates to the general formula: (wherein R1, cafluoro, chloro, chromo, iodo-1
alkoxy of 4 carbon atoms or alkylthio of 1 to 4 carbon atoms; 2- and R13
is hydrogen or an ester-forming residue readily decomposable in vivo), which has the general formula: (wherein or chloro-chromo or io'-R19 is The one-bean paste method involves reacting an ester-forming residue that can be easily hydrolyzed in the body or a compound (the conventional method is a nidiline carboxy protecting group) with an organotin monohydride at about 0-110°C. (with the proviso that R19 is a conventional penicillin carboxy protecting group, with the proviso that the number is from O to 1).

A preferred percentage characteristic of the process of the present invention is to use an organotin hydride having the general formula: It is.

Another feature of this method is that R1 is a conventional 4-nidyline carboxy protecting group selected from the following: namely a) PR2R3 (wherein R2 and R3 are each alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or phenyl);

b) 3.5-di-1-butyl-4-hydroxybenzyl- c) -CH2Y (in the formula, Y is -c(o)n4, but R
4 is phenyl or alkyl-cyano of 1 to 6 carbon atoms or carbalkoxy of 2 to 4 carbon atoms) d) -N2CHR5 (wherein R5 is phenyl or alkyl of 1 to 6 carbon atoms) e) -CH(COCH3)G○2R6 (wherein R6 is alkyl of 1 to 4 carbon atoms) f) -0R7R8R9C where R7 and R8 are each hydrogen-phenyl or methyl- and R9 is phenyl-4-methoxy Phenyl or methyl.

However, when R7 and R8 are each methyl, R9 is methyl. ) g) -5i(c)13)3 and -5t(OH3)
2t-C;4H9;h), -8nR16R1□R18(
In the formula, R161R17 and R18 are each alkyl of 1 to 5 carbon atoms, phenyl or benzyl). A preferred method is that R19 is a commonly used nidyline carboxy protecting group -8nRi 6R17R1s (wherein R161R1
7 and R18 are each tan-methyl; R15 and Similarly, a particularly preferred step is that R19 is a conventional penicillin carboxy protecting group -8nR1
6R17R18 (in the formula, R16t R17 and R18 are each methyl, R15 is chloro, X is iodine and 0
When the organotin hydride is tri-notyltin hydride, the protecting group is removed by water hydrolysis. A particularly preferred method is that R19 is a conventional iniciline carboxy protecting group -81 (a''(3)3R15 and X are each promoter or R15 is chloro and X is iodo9,
The protecting group is removed by water hydrolysis in a manner in which O is O and the organotin monohydride is tri-notyltin hydride. Similarly, a particularly preferred method is to convert R19 to a conventional method with the nidiline carboxy protecting group -CR7R8R9 (in the formula R
7 and R8 are each hydrogen, R9 is 4-methoxyphenyl, R15 and Remove the car by disassembling it.

The method of the present invention uses a compound in which R1 is an ester-forming residue that can be easily hydrolyzed in vivo and is selected from the following groups: Namely, alkanoyloxymethyl having 6 to 6 carbon atoms, 1-(alkanoyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-( having 5 to 8 carbon atoms) alkanoyloxy)ethyl - from ro to alkoxycarbonyloxymethyl having 6 carbon atoms to 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms;
1-Methyl-1-(alkoxycarbonyloxy)ethyl-6-phthalidyl having 5 to 8 carbon atoms, 4
- crotonolactonil and gamma gatirolacton-4-yl. Particularly in the preferred step, when R is pivaloyloxymethyl, R5 and 9 are each chromo, dan is 0 and the organotin monohydride is triphenyltin hydride - R19 is pivaloxymethyl, R15 is chloro and X is iodo, danka0 and the organotin monohydride is tri-n-butyltin hydride, and R19 is pivaloyloxymethyl, R15 and X are each iodo, danka0 and the organotin monohydride is hydrogenated. This process is tri-di-phthyltin.

The method of the present invention takes into consideration a method for synthesizing a wide variety of 6-β-nidylanic acid and its derivatives without substantially containing 6-α-epimer, and contains only a small amount of β-epimer (at least 75%). It is unique in that it provides 6-substituted penicillanic acids.

The required β-epimer content in the case of poly() is as high as 995%. Since the α-epimer is essentially inactive as a β-lactum degrading enzyme inhibitor, the β-epimer content of one compound can be reduced. In order to take advantage of this, it is essential to obtain high concentrations of alpha-ebimer.Compounds containing large amounts of alpha-ebimer inhibit beta-lactam-degrading enzymes and require large doses to make beta-lactam antibiotics effective. It must be used in

Large doses of these substances η result in toxicity to the mammalian host.

The method of the invention is illustrated as follows.

■ (In the formula, X-R16, R79, R16, R17-R
(18 and R13 as previously defined) In general, the reduction can be carried out conveniently without the use of a solvent - or the solvent may remove more or less of the reactants under the reaction conditions without much reaction with the reactants or products. The reaction can be carried out in a solvent as long as it is a reaction-inert solvent that dissolves it. When a solvent is used, it is desirable that the solvent be an aprotic solvent, immiscible with water - and that the reaction temperature be carried out to match the boiling and freezing points. The solvent or mixture includes aromatic solvents such as benzene or toluene.

When the above reaction is carried out without solvent, the reactants are thoroughly mixed and heated to the stated reaction temperature.

The molar ratio of the starting penicillanic acid derivative to the organotin monohydride is not critical for the claims. The use of a small excess of the complex hydride, from an equivalent amount to a 10% excess, helps to complete the reaction and is of great help in isolating the desired product in pure form.

The reaction time is negatively dependent on the concentration-reaction temperature and reactivity of the starting reagents. The process of the invention is carried out without solvent at a reaction temperature of -60 to 100'C. Under these temperature conditions, the reaction is usually completed in 5 to 8 hours. When a solvent is used, the reaction is carried out at a temperature of 5o-iooC, and it takes 4 to 6 hours to complete one reaction.

The reaction time and reaction temperature can be significantly reduced by carrying out this step under radiant radiation. The reaction under these conditions is initiated with a free radical initiator such as azobisisonotyronitrile and carried out under cold conditions such that the temperature is maintained at about 15-25°C. The reaction time under these conditions is about 15 minutes to several hours.

The preferred reaction temperature is one that allows the reaction to proceed at a practical rate without causing thermal decomposition of the starting reagents or the products of the process. Therefore, it is operated at 0-100°C.

Since the type of reagent to be added is not critical, it is preferable to add a monoorganotin monohydride to the 6,6-disubstituted dilanic acid derivative. In this preferred method, two dehalogenation reactions are minimized when 6,6-dihalo is used as a nidilanic acid derivative.

In compounds of the above formula, the dashed bond of a substituent to a bicyclic penicillanic acid radical indicates that the substituent is below the plane of the nucleus and is said to be in the α-configuration. A solid line bond substituted with the nucleus indicates that the substituent is bonded on a plane, and is referred to as a β-configuration. The wavy line is intended to indicate two epimers or a mixture thereof.

The organotin monohydrides used as reagents in the process of the invention are prepared by methods known to those skilled in the art. Reagents that are difficult to obtain commercially are described by Hayashi et al. (J, Org.
a, nometal, Chem, 10.81 (196
7)).

The first of the carboxylic acid groups used in the process of the invention is a phosphine ester. West German patent application No. 2
, 218.209, a suitable 6β-hydride 80-oxymethyl or 6,6-disubstitution can be achieved by reacting nidillanic acid as a triethylamine salt with a monodialkyl or dialkoxy-chlorophosphine for the Ichiki process. Generate the desired starting reagents. By adding water during the reaction between the semi-loaded reagent and the halogenating reagent or organotin monohydride, the protecting group can be converted to a 6-β-substituted 2
Elimination from Nijiline results in this product where -R13 is hydrogen.

The second retaining group is 6,5-di-1-phthyl-4-i-proxybenzyl ester. This is the essential 6β-
It is easily synthesized from hydroxymethyl or 6,6-substituted penicillanic acid according to the procedure of German Patent Application No. 2,063,493. For this treatment, the aforementioned penicillanic acid is reacted as a triethylamine salt with ethyl chloroformate, and the resulting mixed anhydride is reacted with 3,5-di-1-butyl-
A subsequent reaction with 4-no-idroxybenzyl alcohol is included. Following the reaction of the starting reagent with the halogenating reagent or organotin monohydride in this step, the protecting group is removed by water hydrolysis at -pHs, o.

A sixth type of protecting group suitable in the method of the invention is R
19 CH2Y, where Y is as previously defined. These 6β-no-iso-90oxymethyl and 6,6-disubstituted nidiranic acid esters can be prepared by converting the corresponding penicillanic acid triethylamine salt to the appropriate halide 90
[Act
a, Chem, 5cand, 21. 2210 (19
67)]. Following the subsequent reaction of the aforementioned reagents with halogenating reagents or organotin monohydrides, the protecting group is preferably eliminated together with potassium thiophene oxide.

The fourth type of protecting group in this series is R1, or -N-CHR5, where R5 is as previously defined.
) according to the literature 6β-hydroxymethyl or 6,
Incorporated into 6-disubstituted penicillanic acids. and reacting the requisite 6β-hydroxymethyl or 6,6-dihydrane, a mixed anhydride formed from ground nidiranic acid and ethyl chloroformate with the appropriate aldehyde oxime.

6-β-substitution by reacting a 6-hydroxymethyl compound with a reagent for rogenation or a 6β-hydroxymethyl compound with a tin hydride in accordance with the process of the invention followed by treatment with potassium thiophenoxide 9. The protecting group is removed from the benidylanic acid.

A fifth type of protecting group is an ester derived from acetoacetate. A method for introducing this type of protecting group into the carboxylic group of Nidyline is described by Shimaru et al. [Ch.
emistry Letters, 131 and 1
317 (1977)). and 6β-hydroxymethyl or 6,6-disubstitution is included by treating the sodium salt of nidilanic acid with the appropriate alkyl α-no-roacetoacetate.

After reacting this product with a rognating reagent or an organotin monohydride, the protecting group is removed from the 6-β-penicillanic acid derivative by treatment with an aqueous solution of sodium nitrite.

The sixth type of protecting group can be prepared in a number of ways with the group being R19 or -CR7R8R9. All their details are given in the chemical literature. 8-Compatible method is known 6-β
- Amino starting from nidilanic acid ester and then - for example by Cama et al. (J, Am.

etc. (J, Chem, Soc, (Perkin I
)-1772 (1976)) includes the substitution of the 6-amine moiety with a -6-diazo group. When a 6,6-disubstituted penicillanic acid having a 6-carboxy group bonded to a nidiline carboxy protecting group is reacted with an organotin monohydride, the mono-protecting group is eliminated. substituent R
7, R8 and R9 are phenyl or if R9 is 4-methoxyphenyl or R7,
When R8 and Ro are each methyl, the protecting group is removed by treatment with trifluoroacetic acid. This mode of elimination is consistent with all possible substituents in the first β-position. If R7 or R8 is methyl or R7 and R8 are hydrogen and R9 is phenyl - the protecting group is removed by treatment with trimethylsilyl iodide [Jung et al. J, Am Chem, Soc.
, 99.968 (1977)) These groups can in any case be eliminated by hydrogenation if they are not 6-β-substituents or halogen or alkylthio moieties.

The required 6β-hydroxymethyl penicillanate can be prepared by reacting the corresponding 6β-hydroxymethyl penicillanic acid as an active anhydride with a suitable alcohol or by alkylating a salt of the acid with R7R8R9G-halide. It can be implemented by 6β-
After treating the hydroxymethyl benicilinate with a suitable halogenating agent, the protecting group is removed as indicated above.

The seventh type of protecting group is trimethylsilyl or dimethyl-1-butylsilyl ester, which is 6,6-
Disubstitution is achieved by the reaction of triethylamine of nidilanic acid with the appropriate silyl chloride [Ref. Ann, 673. 166
(1964)) and generate it there.

After reacting the 6, 6-:) substituted nidiranic acid with a protective shield group attached thereto with an organotin monohydride, the protecting group is removed by water hydrolysis.

The eighth type of protecting group envisaged by the present invention and already discussed is R19-18nR16R17R18- and R1
6ff R17 and R18 are as previously defined. The tin ester protecting group is prepared by adding 1 mole of bis-tin-oxy)-'' to 2 moles of free 6,6-disubstituted 4-nidylanic acid [Cb-em, Ind, 1025 (j
976)) Generated by ko. At the completion of the step, one protecting group is removed by water hydrolysis.

A penicillin carboxy protecting group that is particularly useful in the synthesis of compounds of formula (1) where R15 is the argylthio, n is 0 or 1 and R13 is hydrogen is trichloroethyl. This group is introduced onto the carboxy group of the appropriate 6,6-disubstituted penicillanic acid using a procedure as described in German Patent Application No. 1.937,962. Conversion of the disubstituted penicillanic acid trichloroethyl ester to a 6-halo 6-alkyl penidilanic acid trichloroethyl ester al or sulfoxide is carried out according to the procedure described below - followed by treatment with organotin monohydride -6 -β-Alkylthiopenicillanic acid trichloroethyl ester or sulfoxide is produced. Elimination of the protecting group trichloroethyl moiety to obtain a compound of formula (1) (wherein R23 is hydrogen) is achieved by treatment with zinc dust in a buffer solution.

As recognized by experts in the field, there are numerous other unmentioned nidiline carboxy protecting groups that can be applied to the synthesis of compound 411 of the above formula, where 13 or hydrogen. The concept of the use of such protecting groups for the process of the present invention, although not exhaustively exemplified, is considered in the broad scope of the present invention. 6-β-substituted penicillanic acids are effective intermediates leading to the corresponding free acids.

R23 is an ester-forming residue that can be easily hydrolyzed in vivo in compounds of formula II, -R such that in such compounds of formula 11 the C00R13 moiety represents an ester group;
is a group conceptually derived from an alcohol of formula R,3-OH. Furthermore -R13 is GO○R□3
is easily decomposed in vivo to form a free carboxy group (000
8) has the tendency to release. That is, when a compound of the formula it (wherein R13 is an ester-forming residue that is easily thawed in vivo) is exposed to the blood or tissue of a mammal, R is a compound of the formula (wherein R13 is hydrogen).
This is a type of group that is easily produced. This R
13 - known in the mini cylinder industry. In addition, R13 has been shown to improve the absorption properties of the compound R13 as a drug.In addition, R13 has been shown to confer properties suitable for use as a drug in the compound of formula H. It should have the characteristics of being suitable.

As mentioned above, the -R43 group is known, and the West German patent Nakazume 2
, No. 517, 316, it is easily identified by the technology of the Nishirin industry. Typical groups for R13 are -
Phthalidyl, 4-crotonlactonyl, γ-butyrolactone-4-yl-alkanoyloxyalkyl- and alkoxycarbonyloxyalkyl. Shigashi R
Preference groups for 13 are alkanoyloxymethyl with 3 to 6 carbon atoms, 1-(alkanoyloxy)ethyl with 4 to 7 carbon atoms, 1-methyl-1- with 5 to 8 carbon atoms, (alkanoyloxy)ethyl - alkoxycarbonyloxymethyl with 6 to 6 carbon atoms, 1-( with 4 to 7 carbon atoms)
alkoxycarbonyloxy)ethyl, 1-methyl-1-(alkoxycarbonyloxy)ethyl-6-phthalidyl having 5 to 8 carbon atoms, 4-crotonolactonyl and γ-butyrolactone-4-yl.

The compound of formula 11 (wherein R13 is an ester-forming residue that can be easily dissolved in vivo) can be directly produced from the compound of formula (1) (wherein R13 is hydrogen) by esterification. The particular method chosen will depend on the exact structure of the ester-forming group, but a suitable method will be readily selected by one skilled in the art. R13 is 6-7 talidyl, 4-
When selected from the group consisting of crotonolactonyl-γ-dtyrolactone-4-yl-alkanoyloxyalkyl and alkoxycarbonyloxyalkyl, these compounds are substituted with 6-phthalidyl halide-4- It can be produced by alkylation with crotonolactonyl halide, γ-phthyrolactone-4-yl halide-alkanoyloxyalkyl halide 9 or alkoxycarbonyloxyalkyl halide. The term "halide 9" refers to chlorine-bromine and iodine derivatives. This reaction involves dissolving the salt of the compound of formula I (wherein R13 is hydrogen) in a suitable polar, organic solvent such as N,N-dimethylformamide, and then adding about 1 molar equivalent of the halide. easily carried out by When the reaction has proceeded to essentially completion, the product is isolated by standard procedures. It is often sufficient to dilute the reaction solvent with excess water. The product is then extracted with an organic solvent that is immiscible with water, and then the solvent is distilled off and recovered. Commonly used starting material salts include alkali metal salts such as sodium and potassium salts, triethylamine, N-ethylpiperidine, N,N
- Sixth amine salts such as dimethylaniline and N-methylmorpholine salts. The reaction is carried out at a temperature ranging from about 0 to 100°C, usually about 25°C. The length of time required to complete the reaction will vary according to various factors such as the concentration of the reactants and the reactivity of the reagents. Thus, considering halo compounds, iodide reacts faster than bromide, and bromide reacts faster than chloride. In fact, when using chloride, it is often advantageous to add up to 1 molar equivalent of ~alkali metal iodide. This has the effect of speeding up the reaction. Reaction times of 1 to about 24 hours are commonly used, taking into account the aforementioned factors.

In any case, the compound of the present invention of formula II (wherein R13 is an ester-forming residue that can be easily hydrolyzed in vivo) is of the formula
(wherein R□9 consists of the ester-forming group) according to the process of the present invention.

Formula ■ (wherein R1 is an ester-forming residue that can be easily hydrolyzed in vivo, selected from ro-phthalidyl-4-crotonolactonyl, γ-notyrolactone-4-yl, alkanoyloxyalkyl, and alkoxycarbonyloxyalkyl) The starting reagent of formula (1) is a compound of formula (where R1,
It can be produced by alkylation with γ-notyrolactone-4-yl halide 9, alkanoyloxyalkyl halide, or alkoxycarbonyloxyalkyl halide. The reaction is carried out by dissolving the salt of the compound of formula I (wherein R19 is hydrogen) in a suitable white, polar, organic solvent such as N,N-dimethylformamide and adding -1 molar equivalent of the halide. be exposed. When the reaction has proceeded to essentially completion - the product is isolated using standard techniques. It is often sufficient to dilute the solvent with excess water. The product is then extracted into a water-immiscible organic solvent and recovered by distilling off one solvent. The salts of the starting materials commonly used are alkali metal salts such as sodium and potassium salts, and 6th class amine salts such as triethylamine, N-ethylpi-lysine, N,N-dimethylaniline and N-methylmorpholine salts. The reaction is approximately 0-100℃
The process is carried out at a temperature in the range of - usually about 25°C. The time required for the reaction to complete will vary according to various factors such as the concentration of the reactants and the reactivity of the reagents. Thus, when considering halide compounds, iodide reacts faster than bromide, and monobromide reacts faster than chloride. In practice - when using chlorine compounds, adding up to 1 molar equivalent of alkali metal iodide often gives good results. This has the effect of promoting the reaction. If the above factors are taken into account, the reaction time will be approximately 1~
Usually used for about 24 hours.

An alternative method for preparing the starting reagent for this step of formula 1 (wherein R19 is the ester-forming residue) is to diazotize a suitable 6-β-aminopenicillanic ester and react the resulting diazopenicillanic ester. , one purpose 6,6-disubstituted penicillanic acid ester is synthesized as described below.

Compounds of formula (1) (wherein R19,
- Dihalo is very conveniently synthesized as a nidylanic ester, preferably 6,6-siglomo as a nidylanic ester. The 6,6-dino-nidylanic acid ester is 6
, 6-dino-mouth compound and a solution of approximately equal amount of t-butylmagnesium chloride in anhydrous tetrahydrofuran at -75°C.
It is converted into a 6-noromo6 Grignard derivative by reacting with The intermediate Grignard reagent is not isolated;
Subsequently, it was reacted with methyl alkylthiosulfonate, monohydrolyzed, and made into a viscosity to form formula I (wherein X and dan are as defined -
R15 is alkylthio and R19 is an ester-forming residue or protective group that can be easily decomposed in vivo.
- Obtain a halo 6-alkylthiopenicillanic acid ester.

The group of compounds of the invention of formula II (wherein R1 is as defined, with the exception of alkylthio, and R13 is as defined, and is an integer of 1 or 2) comprises formula II (wherein R1, with the exception of alkylthio) As defined except that R13 can be synthesized by direct oxidation of the compound of - and 0).

When a compound of formula 1 (wherein n is 0) is oxidized with a metal permanganate to the corresponding compound of formula 2 (wherein n is 2) as defined above, the reaction is usually carried out by formula This is carried out by treating the compound of H with a suitable solvent system of from 1.0 to about 5 molar equivalents of permanganate, particularly about 2 molar equivalents of permanganate.

A suitable solvent system is a solvent system that has no corresponding interaction with either the starting material or the product, and water is usually used. If necessary, a co-solvent, such as tetrahydrofuran, which is miscible with water but has no interaction with permanganate, can be added. The reaction will normally be carried out at a temperature in the range of -20 to about 50°C at a time of about 0°C. At about 0°C, the reaction is usually substantially complete within a short time, ie, within one hour. The reaction may be carried out under neutral-basic or acidic conditions, and is preferably carried out under substantially neutral conditions to avoid decomposition of the beta-lactam ring system of the compound of formula II. In fact, it is often effective to VC buffer the pH of the reaction solvent to near neutrality. The product is recovered in a conventional manner. Excess permanganate is usually decomposed using sodium bisulfite, and the product is isolated by conventional solvent extraction after previously acidifying the aqueous layer.

When a compound of formula 1 (where 0 is 0 as previously defined) is oxidized to the corresponding compound of formula 11 (where 2 is 2) using an organic peracid, i.e., 1ξ-oxycarboxylic acid - the reaction is This is usually carried out by treating a compound of formula (1) with a solution of about 2 to about 4 molar equivalents, particularly about 2.2 equivalents, of an oxidizing agent in a reactive inert organic solvent. Typical solvents are chlorinated hydrocarbons such as dichloromethane-chloroform and 1,2-dichloroethane; and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is normally carried out at a temperature of -20°C to about 50°C, preferably about 0°C. The reaction time is approximately 25℃ at approximately 25℃.
It is usually used for about 16 hours. The product is isolated by evaporation, usually by vacuum distillation.

Purification of the product may be carried out by conventional methods well known in the art.

Compounds of formula 11 (where f315 is, as defined, with the exception of said alkylthio, R13 is hydrogen- and then 1) also include transfer of the penicillin carboxy protecting group as defined for R19 in these compounds of formula I. It can be manufactured by The protecting group is required to have the following properties: 1) The compound of formula I (wherein R19 is the protecting group and R45 and X are as defined) is oxidatively stable.

11) β-lactams can be removed from compounds of Formula H using substantially intact conditions.

l11) Derivation of scales from the compound of formula (1) using conditions that substantially avoid evimerization of the β-substituent.

Compounds of formula 11 (wherein R15 is as defined with the exception of alkylthio and R13 is hydrogen once 2) have R1
9 can actually be produced by elimination of the inisilane carboxycarboxylic group as defined by No. 9.

Except where the compound is R15 or alkylthio-
It is best prepared by direct oxidation of homologues in which R13 is hydrogen.

Similarly, the above-discussed compound 00 is oxidized, and the synthesis of the corresponding compound (in formula 0-1) is carried out exactly as described above, except that the amount of oxidizing agent is 7. The sulfoxides described in this invention are α- and β-
It is meant to include epimers and mixtures thereof.

These compounds of formula 1 (wherein R□3 is partly an integer of 1 or 2 as defined and R15 is alkylthio) are represented by formula 1
1 (wherein R13, as defined, is 0 and R1, is alkylthio) cannot be practically prepared by direct oxidation of the compound. Oxidation of these compounds often results in a mixture of products in which the alkylthio moieties are oxidized. It is then necessary to carefully separate and purify the target product.

For the production of the product, 6-cyhalobenicilanic acid and its derivatives are subjected to a first oxidation under the conditions described above, and then a 6, 6-) halogen acid sulfone or sulfoxide is added. Desirable are methods for producing these and their ester derivatives. Conversion of the resulting sulfones and sulfoxides to the corresponding 6-halo-6-Grignard reagents is carried out in the manner described above, and the Grignard reagents are similarly converted to the appropriate 6-halo-6-alkylthiobenisilanic acid sulfones or sulfoxides and Convert it into its derivative. These products are then reacted with organotin monohydrides according to the steps previously described to provide the useful target products of the process of the invention.

The compound of formula 11 (wherein R13 is an ester-forming residue that can be easily hydrolyzed in vivo) is converted in vivo to the compound 2 in which R13 is hydrogen as follows.

The compounds of formulas 11 and 2 form salts with acidic and basic reagents. Such salts are considered within the scope of this invention. These salts may be prepared by standard techniques such as fusing the acidic and basic components, usually in a 1 molar ratio, in aqueous, non-aqueous or suitably partially aqueous solvents. The reactant is recovered by filtration, forming a precipitate with a non-aqueous solvent and distilling off the solvent, or in the case of an aqueous solution, suitably freeze-drying or the like. Suitable basic reagents used in the formation of salts belong to both organic and inorganic types.

Ammonia - organic amines - alkali metal hydroxides, carbonates to bicarbonates - halides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Typical examples of such bases are primary amines such as propylamine, diphthylamine, aniline, cyclohexylamino, benzylamine and octylamine, secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine. Amines, triethylamine, N-ethyl bilysine, N-
Methylmorpholine and 1,5-diazabicyclo[4
,3,0]non-5-ene - hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide - such as sodium ethoxide and potassium ethoxide alkoxides - hydrides such as calcium hydride and sodium hydride, carbonates such as potassium carbonate and sodium carbonate - bicarbonates such as sodium bicarbonate salt and potassium bicarbonate salt - and 2-ethylhexane. There are alkali metal salts of long chain fatty acids such as sodium chloride.

Preferred salts of compounds of formulas (1) and (2) are the sodium, potassium and triethylamine salts.

As has been mentioned, compounds of formulas II and ■ are potent inhibitors of microbial β-lactamases, and are effective inhibitors of many microorganisms, especially β-lactamase-producing microorganisms 1 (vs. Enhances the antibacterial effect of antibiotics (R-nigilins and cephalosporins).The way the compounds of formulas ① and ② enhance the effect of β-lactam antibiotics is based on the minimum inhibitory concentration (MI) of a given antibiotic alone.
○) and compounds of formula II or ▪ alone can be evaluated for experiments in which MTC values were measured. These minimum inhibitory concentrations are compared to the minimum inhibitory concentrations obtained by combining the antibiotic with a compound of formula (1) or (2).

If the antibacterial activity of the combination is sufficiently greater than that expected from the antibacterial activity of the individual compounds - this is considered to consist of enhanced activity. The MIC value of the combination is Barry and 5abath bi Manual of C11n-i
cal MicrobioLogy"Lenetle,
, edited by Spaulding and Truant - 2nd edition, 1974 - American 5ociet
y for Microbiology).

Compounds of formulas II and 1 enhance the antibacterial effects of β-lactam antibiotics in vivo. That is, these compounds have a certain β-
It has the effect of lowering the amount of antibiotics required to protect 20-day mice against a lethal inoculum of lactamase-producing bacteria.

The ability of compounds of Formula 11 or ■ to enhance the effectiveness of β-lactam antibiotics against -β-lactam, mu-degrading enzyme probiotic bacteria makes it possible to simultaneously administer -β-lactam antibiotics in the treatment of fungal infections in mammals, especially humans. These compounds are effective against. For the treatment of fungal infections, the compounds of Formula I or ■ may be combined with a β-lactam antibiotic, so that both reagents are administered simultaneously. Alternatively, the compound of formula (1) or (2) may be administered as a separate agent during treatment with a β-lactam antibiotic. In one example -
It may be advantageous to pre-medicate the subject with one of the compounds in series 1 or 2 prior to initiating initial ββ-lactam antibiotic therapy.

When a compound of formula (1) or (2) is used to enhance the efficacy of a β-lactam antibiotic, it is preferably administered in a dosage form with a standard pharmaceutical carrier or diluent. Pharmaceutically suitable carrier - β-lactam antibiotic and formula ■ or ■
Pharmaceutical compositions containing the compound will normally contain from about 5 to about 80% by weight of a pharmaceutically suitable carrier.

When the compound of formula 11 or 2 is used in combination with other β-lactam antibiotics, the compound can be administered orally, parenterally, intramuscularly, subcutaneously-intraperitoneally. Although the prescribing physician ultimately determines the dosage to be used for a subject, the daily dosage ratio of compound 2 or 2 and beta-lactam antibiotics is usually approximately 1:6. 6=1. To add, the expression j
When compounds of 1 or V are used in combination with other beta-lactam antibiotics - the daily oral dosage of each component is usually about 10 to about 200 my/ky body weight. and the daily parenteral dosage of each component is usually about 10 to about 400 w
i/xy weight. However, these numbers are only examples - in some cases it may be necessary to use dosages outside these limits.

Typical β-lactam antibiotics that can be co-administered with compounds of formula 1 or V and their esters that are readily deiceable in vivo are: 6
-(2-phenylacetamide)-<nidylanic acid,
6-(2-phenylpropionamido) nidylanic acid, 6-(D-2-amino-2-phenylacetamido)penicillanic acid, tonopenicillane oxymethyl, yloxymethyl-acetamido)penicillanic acid pivaloyloxymethyl ,
7-(2-cyanoacetamido)cephalosporanic acid-
7-[dan-(-)-alpha(4-ethyl-2,6-
Appropriate salt for shioki.

As appreciated by experts in the field, some of the above-mentioned beta-lactam compounds are effective when administered orally or parenterally, while others are effective when administered by the parenteral route. Effective only in time.

When Formulas (1) or (2) are used simultaneously (ie, mixed together) with a β-lactam antibiotic that is effective only for parenteral administration - a combination dosage form suitable for parenteral use is required. Expression ■
Or V orally or parenterally effective β-
When used together with lactam antibiotics, the combination is suitable for either oral or parenteral administration. It is also possible to orally administer a preparation of a compound of Formula 11 or ■ and simultaneously administer β-lactum antibiotic a parenterally. β-lactam antibiotics can also be co-administered orally.

The following examples are provided for further illustrative purposes only. The nuclear magnetic resonance spectrum (NMR) is 60 MHz (MH2
), 1 chloroform (CDC13) - heavy dimethyl sulfoxide (DMSO-d6) + or heavy water (D20)
Alternatively, other solvents described were used. And the peak position is tetramethylsilane or 2,2-dimethyl-2
- Sila Dung - 5-Sulfonic Acid Sodium Salt to Downfield Expressed in parts per million (ppm). The following abbreviations are used for peak types: S-singlet (singlet); d, goblet (2N line); t, triplet (sextet); q, quartet (quartet). ;m-multiplet (multiplet).

6-chloro-6-iodosonidylanic acid sodium salt 2
95 g were converted to the free acid and then dissolved in 125 ml of benzene under a stream of nitrogen. To this solution was added 13 ml of hetodiethylamine and the mixture was cooled to 0-5°C. Then 0.977 ml of hetrimethylsilyl chlorite was added to the cold mixture and the reaction mixture was stirred for 5 minutes at 0-5°C, 60 minutes at 25°C and 60 minutes at 50°C. Cooled to °C - triethylamine hydrochloride was removed. The P solution was heated to reflux - 151 ng of asobisisonotyronitrile and 2.027 d of tri-n-butyltin hydride were added. The reflux mixture was exposed to UV light for 5 d. The solvent was removed in vacuo and the residue was dissolved in a 1:1 mixture of tetrahydrofuran and water.

The pH was adjusted to zO and -tetrahydrofuran was distilled off under reduced pressure. The aqueous layer was washed with ether, and then an equal volume of ethyl acetate was added. The pH was adjusted to 1.8 and the ethyl monoacetate layer was transferred. The aqueous layer was further extracted with ethyl acetate, and the combined ethyl acetate solutions were dried and evaporated under reduced pressure. From this one 6-β-
980 mg of chloropenicillanic acid was obtained.

The above product was dissolved in 80 francs of tetrahydrochloride and an equal volume of water was added. The pH was adjusted to 6.8 and tetrahydrofuran was distilled off in vacuo. When the remaining aqueous layer is freeze-dried, 6-β
- 850 mg of sodium chloropenicillanic acid salt are obtained. Nuclear magnetic resonance spectrum (D20) shows the following absorption. That is -5,7'0(d-I H-J =4Hz)-5
,50((L IIt J =4Hz)−4,36(s
, IH), 1.60 (s, 3H) and Wang 53 (s-
38) ppm.

The title compound converts 6,6-diiodobenicilanic acid into 1-
! Use J-n-butyltin hydride at °C and mf! It is produced by reduction according to the process of No. 11.

, r' +-, 1: 6-β-Fluoropenicillanic acid-Flomo-Fluoronidyrane'benzyl ester fluorohydrogen-pyridine 77 and N-bromoconophosphoric acid imide 1.11.9 diethyl ether 10 The solution was cooled to -20 DEG C. and a solution of 1.8 g of benzyl nidylanic acid ester in 6-diazo in 13 mA of tetrahydrofuran and 50 mA of diethyl ether was added thereto. The reaction mixture was stirred at -10°C for 15 minutes and then poured into ice water. The organic layer was separated and the aqueous layer was further extracted with diethyl ether (3X2ON). Collect the organic layer and washing liquid and wash successively with sodium bicarbonate solution and water, then dilute with monosulfuric acid)
It was dried with IJum. When the solvent was distilled off in vacuo, crude 6-bromo-6-fluoropenicilanic acid benzyl ester 1.
6g was obtained.

The intermediate was purified by chromatography using 100 g of silica gel and chloroform as an eluent. 10w each
The required product is fraction 30-4.
It was collected because it was included in 5. Removal of chloroform gives 0.51 g of pure intermediate product.

---Fluorocarbon 1 benzyl ester 6-fluoro 6-fluoro nidylanic acid henzyl ester 610
Place a 15 mA solution of 7 nI10 dry benzene in a stream of nitrogen - then add 5 mA of hairzobisine buteronitrile)! J-n-butyltin hydride was added. Mixture approx. 2
The outside was cooled to maintain the temperature at 5°C and ultraviolet rays were irradiated for 40 minutes. Removal of the solvent yielded 500 nm of crude product. This was dissolved in ethyl acetate 2511Li, then 25 ml of water was added and the pH was adjusted to 8. After separation of the organic layer, drying over sodium monohydric acid, removal of one solvent in vacuo and chromatography on silica gel, the desired intermediate was obtained.

6--Fluoro R Nidylanic Acid Into a dry flask protected from air and moisture, add a 4 Q ml solution of 6-β to Fluoro-nidylanic acid benzyl ester 3.1.9 in dry carbon tetrachloride. Iodide (l-limethyl)
) Add 2.2.9 and stir the reaction at room temperature for 15 hours. A saturated solution of sodium bicarbonate (100 d) is added to the reaction mixture and the aqueous layer is separated. Diethyl ether and the same amount of ethyl acetate are added to the separated aqueous layer. pH
Adjust to 1.8 and separate the organic layer. The aqueous layer is further extracted with ethyl acetate (2×5 Qml), and the ethyl acetate extracts are combined and dried over sodium sulfate. The solvent is distilled off in vacuo to obtain the desired 6-β-fluoropenicillanic acid.

-6-Noromo-6-methoxybenicilanic acid benzyl ester + (J, Am, ○hem, soc, , under anhydrous conditions)
941408 (1972)) 660m? A mixture of 2.5 ml of 0.46811 liters of butyltin hydride and 5 ml of azobisisoduthyronitrile was heated under reflux in a nitrogen stream for 2 hours. Additional amounts of metal hydride (o, o) (5 ml) were added, and heating was continued for one additional hour. The reaction mixture was concentrated to dryness in vacuo to give the crude product i,
05 Get y.

The crude product was chromatographed using Silicage A/759-hexane 21. Then, the bathed armpit was changed to chloroform and chromatography was continued. Fractions 68 to 102 (10 m, lt each) are collected and concentrated in vacuo to yield ~500 of the product. Nuclear magnetic resonance spectrum (CD(J3) showed the following absorption: 1.45C8
, 3H), 1.68 (s, 3H), 658 (s= 3H)
)-4,5(s-1H le4.82(d-IH-J=4I
→z)-5,2(s-2H)-5,45(a-IH-J
= 4Hz) and 7.4 (s-5H) ppm 6-β-methoxy is nidilanic acid 6-betamethoxy and nidilanic acid benzyl ester 2
35ml7 methanol 15mA solution pre-hydrogenated palladium-calcium carbonate catalyst 265η water 15ml
1 solution - The resulting mixture was heated to an initial pressure of 5 in a hydrogen stream.
Shake at 5 psi. After 4 hours, the spent catalyst was filtered off and the liquid was concentrated. The mass was washed with methanol and water. Methanol was removed by vacuum distillation, and the combined aqueous layers were washed with ethyl acetate.

Freeze-drying the aqueous layer yields the desired product, a calcium salt of 94.
I got it. The same nuclear spectrum (D20) showed the following absorption. 1.5 (s-3H)-1,6(s~
3H), 3.45 (s-3H), 4.18 (s-1H
), 4.94 (d-IH-J=4H2) and 5.4
5 (d, IH-J=4Hz) pp, m The processing method of Example 4 is applied. Starting from a suitable 6-noromo-6-alkoxybenicillanic ester, the following 6-β-alkoxypenicillanic ester is synthesized.

6-β-Ethoxy is nidilanic acid benzyl ester; 6-
β-Methoxypenicillanic acid 4-nitroindyl ester; 6-β-1-propoxynidylanoic acid henchhydryl ester; 6-β-21proboxylic acid benzhydryl ester; 6-β-7') nidylanic acid trityl ester: 6-β-methoxynidylanic acid trityl ester; 6-β-ethoxypenicillanic acid trityl ester; and 6-β-butoxy (nitroindyl ester of nidylanic acid).

Starting with the 6-β-alkoxypenicillanic acid ester described above and using the hydrogenation treatment of Example 4; the following 6-β-alkoxypenicillanic acid calcium salt is synthesized: 6-β-methoxypenicillanic acid ; 6-β-ethoxypenicillanic acid; 6-β-impropoxypenicillane Fl;
6-β-2-furboxy to nidilanic acid; 6-β-2-
Phthoxybenicillanic acid; 6-β-n-7' toxybenicillanic acid; and 6-β-notoxybenicillanic acid.

A solution of 4.9 g of 6,6-7' lomobenicillanic acid chloroethyl ester in 10 ml of dry tetrahydrofuran was cooled to -75°C, and 1.95 ki of t-butylmagnesium chloride was added to the solution. The solution was added over 6-4 minutes. Heat the reaction mixture to -75°
The mixture was stirred for 20 minutes and then 26 g of methyl methylthioisosulfonate was added.

Stirring was continued for about 1 hour or more in a cooled state, and 11 nl of acetic acid was added. The cooled mixture was allowed to warm back to room temperature over 60 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water-ethyl acetate (5
0 ml/5 Qml).

The aqueous layer was further extracted with ethyl acetate (5[]mA), and the organic layers were combined and washed once with water and then with saturated brine.

The ethyl acetate layer was dried over sodium sulfate and concentrated to give a yellow oil.

This oily residue was chromatographed using 500 g of silica gel and chloroform as the eluent. Fractions 94 to 1 (each 14 mA) were collected (4% condensation) to obtain 3.0 g of the desired product as a pale yellow oil (which solidified on standing). Melting point 103.5-105°C;
Nuclear magnetic resonance spectrum (○DC13) showed the following absorption. 1.55(s, roH)-1,7(s-3H)-2
,4(s-3H)-4,6(s-1H)-4,8(s-
2 tol) and 5.82 (s-IH) ppm 6--methylthiopenicillanic acid trichloroethyl ester 6-promo 6-methylthiopenicillanic acid trichloroethyl ester 500 #l of benzene 5011 Ll solution was purified under anhydrous conditions and passed through a nitrogen stream. To this was added a solution of 0.29 tri-butyltin hydride. The resulting reaction mixture was heated under reflux for 6 hours. Added tin hydride 0.
1 ml was added and heating continued overnight. The solvent was removed in vacuo to give a crude product.

Residue a was cross-polluted using silica gel 1009 - chloroform - ethyl acetate (9515-
It was eluted with a mixture of volume/volume).

Fractions containing 12yn,l were collected every 0.5 minutes.

Fraction 33-'42 is collected and concentrated to produce the product'
I got v00m9. This was rechromatographed using 60 g of silica gel at -7 rnl for each 0° C.
Fractionation was performed every 5 minutes, fractions 25 to 34 were collected, and one solvent was concentrated under reduced pressure to obtain the target product of 1φO~ as an oil. Nuclear magnetic resonance spectra showed sublunary absorption (
CD CIj 3)-i, 53 (s, RoH), 16
9(S-roH)-2,28(S-3H)-4,roro and 4.42(d-',H)-4,54(s,IH)~4
, 73 (s-2H) and 548 and 5.56 (6
= 1H) pp" 6-β-Methylnanyl acid A round bottom flask with a stirrer and a stopcock was equipped with -6-β-
Methylthiopenicillanic acid trichloroethyl ester 1.
38.9 of a 28 ml solution of tetrahydrofuran, 5.6 g of zinc powder, and 5.6 g of potassium hydrogen phosphate.
A total of 6 ml was added. The reaction mixture was allowed to stir for 15 minutes, the mixture was passed through a supercell and the mass was washed with tetrahydrofuran-water (50150 vol/vol) (2
X20md)l,,ta. The washing liquid and filtrate were collected and the tetrahydrofuran was distilled off in vacuo. The residual oil and water were extracted with ethyl acetate (2×3 []mA). The ethyl acetate was transferred, the pH of the aqueous layer was adjusted to 2.5, and another ethyl acetate was added.

The ethyl acetate was combined, washed with monosaturated brine, and dried over sodium sulfate. Evaporation of the solvent gave 620 m9 of the product as a clear oil. Dissolve the residue in 5Qml of ethyl acetate and add 4907n of thorium 2-ethylhexanoate.
9 and 15 ml of ethyl acetate. The formed precipitate was filtered, washed with ether, and dried to obtain 628 m9 of the target product as its sodium salt. Nuclear magnetic resonance thrower (
DMS○-D6) indicates the following o) 7 danals. 1.43(
s-3H)-1,52(s-3H)=2.17(s-
3H)-3,86(s-IH), 448 and 4.55
(cl 11() and 5.67 and 5.44 Cd
-IH)99m Example 7 The treatment of Example A is repeated using 6,6-dibromo-nidylanic acid trichloroethyl ester and an appropriate alkyl methylthiosulfonate as starting materials to obtain the following penicillanic acid as its sodium salt: 6-β-ethylthio-? Nidylanic acid-6-β-Furovirthio is Nidylanic acid, 6-β-↓-propylthio is Nidylanic acid, 6-β-Nibutylthiopenicillanic acid- and 6-β-8-ButylthioR Nidylanic acid under anhydrous conditions and under nitrogen atmosphere. Under flow conduction conditions, 6,6-dibromotakunidylanic acid pivaloyloxymethyl ester 4,73.9
100 rul solution of dry tetrahydrofuran
The mixture was cooled to 0.degree. C. and treated with an ether solution of -1,95M t-butylmagnesium chlorite 9 for 3 to 4 minutes. The resulting reaction mixture was stirred for an additional 20 minutes at -75°C.
1.26 g of methyl methylthiosulfonate was added. After stirring for 15 minutes in the cold, the reaction mixture was treated with 11 nl of acetic acid and allowed to warm to room temperature. The solvent was evaporated in vacuo and the remaining crude product was mixed with 507 rLl of ethyl acetate and 5 liters of water.
Distribution between 0TLl was made. The aqueous layer was further extracted with ethyl acetate, and the organic layer portions were collected, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off to obtain 4.6 g of crude product.
It was worshiped.

The product was purified by chromatography using 500 g of silica gel and chloroform as an eluent. 14 each
Fractions containing punishment were collected every 0.6 minutes. Fractions 126-242 were collected and concentrated in vacuo to yield 2.2 g of the purified reaction product as a pale yellow oil - which was packed and crystallized after standing.

Melting point: 79-81°C - Nuclear magnetic resonance spectrum (■J3) showed the following signals. That is, 1.24 (S, 9H), 1
．． 45 (S, 3H), 1.68 (s-3)i)-2,
40 (s, 3H), 4.5 (s=IH), 5.8 (s,
IH) and 5.88 (S, 2H) 99 m 6-/' lomo 6-y'f ruthiopenicillanic acid hivaloyloxymethyl ester 2.2 I and tri-butyltin hydride 2.64 mjj in benzene 75yu solution The reaction mixture was heated under reflux in a nitrogen stream and under anhydrous conditions overnight.

The solvent was distilled off in vacuo, and the residue was mixed with 400 g or more of silica gel.
Chromatography was performed using chloroform-ethyl acetate (9515; vol/vol) as the eluent, and fractions of 14 ml were collected every 0.6 min. Fraction Nos. 18-21 were combined and concentrated to yield one product 1.
．． 6g was obtained. The product was further purified using 650 g or more of silica gel using Romatodarafy, and the pure product 1 was obtained.
．． 2g was obtained in the form of an oil. NMR spectrum (CDC1
3) showed the following signal. 1.2(s-9H)-1
,5(s-3H), 1.66(S,3H)-2,26C
s-3H)-4,3 and 44(d,IH), 4.4
(s, IH), 5.42 and 5.5 (cL IH) and 5.61-57L 5.7 and 5,8 (q-
2H) ppm Example 9 The procedure of Example 8 is repeated with the appropriate 6,6-dipromoinisilane and alkyl methylthiosulfonate starting materials to give the first-order analogue.

6-β-Methylthiopenicillanic acid 3-thucridyl ester-6-β-methylthiopenicillanic acid 1-(acetoxy)-ethyl ester; 6-β-ethylthiopenicillanic acid pivaloyloxymethyl ester; 6-β -Etherthiopenicillanic acid 4-crotonolactonyl ester: 6-β
-Methylthiopenicillanic acid gamma-butyrolactone-4
-yl ester: 6-β once-propylthioinisilane acid acetoxymethyl ester; 6-β once-propylthiobenicilanic acid pinogloyloxymethyl ester;
6-
β-2-phthylthiopenicillanic acid 1-methyl-1-(acetoxy)ethyl ester; 6-β-phthylthiopenicillanic acid 1-methyl-1-(hexanoyloxy)-
Ethyl ester; 6-β-phthylthiobenicilanic acid methoxycarbonyloxymethyl ester; 6-β-s
-,7' Tylpenicillanic acid fluoroxycarbonyloxymethyl ester: 6-β-methylthiopenicillanic acid 1
-(ethoxycarbonyloxy)ethyl ester; 6-
β-ethylthiopenicillanic acid 1-methyl-1-(methoxycarbonyloxy)ethyl ester; and 6-β-
1-Methyl-1-(impropoxycarbonyl)ethyl nitrite dinidylanate (methylthio) A solution of 594 g of IJium in 260 ml of water and 2.63. ! ;'methylene chloride 260
The mixture of m1 solutions was stirred with cooling in a water bath. p-
Divide toluenesulfonic acid (1.2 g) into 3 portions and add 160 g.
was added over a period of minutes - and the mixture continued to stir at room temperature for 1 hour. The organic solvent layer was separated and dried over sodium sulfate.

Iodine (1,3,1 L) was added to the organic solvent layer and the resulting solution was kept stirring at room temperature for 4 hours. The solution was washed with aqueous sodium thiosulfate, separated, and concentrated to a low volume by vacuum distillation. The residue silica gel and petroleum ether (bp, 60-80°
Chromatography was performed using an eluent containing increasing amounts of ethyl acetate. The product-containing fractions were collected, dried over sodium sulfate, and evaporated to dryness in one vacuum to yield 41. Melting point 1ro6-138°C-NMR
The spectrum showed the following signals: 5.79 (bp-
2H)-5,71(s-IH)-4,52(s=IH
)-1,65(s-3H)-1,44(s-3H) and 1.21(S,9H) ppm --iodopenicillanic acid hivaloyloxymethyl ester 6, s''-short 8 penicillanic acid pi A solution of 8 ml of benzene containing 29 g of baloyloxymethyl ester was placed in a nitrogen stream, and 500 ml of triphenyltin hydride was added thereto.
9 and a few crystals of azobisisobutyronitrile (~10 m
9) was added, and the resulting reaction mixture was heated at 50°C for 1 hour. Gold layer hydride 500711 & nitrile 10m9
was added, and heating was continued with stirring for an additional 6 hours. Chromatography on silica gel with petroleum ether (boiling point 60
Using an eluate with increasing proportions of methylene chloride (gradient elution method), 140 m9 of the desired product (melting point 7 - 77°C) was obtained. NMR, ;<Baek)
(ODCJ3) showed the following signals. 5.9
(d-AB, J=5.8Hz)-5,82(d-AB
-J=5.8Hz)-5,66(d-IH-AB-
J=4.1Hz)-5,42(d-IH18BJ=
41Hz) = 4.59(s-IH), 1.71(s
, filtration H)-1,30 (s, 3H) and 1.24 (s
-9H) ', 6-β in the same manner as ppm disaster example 10
-Conversion of aminopenicillanic acid benzyl ester to 6.6-short dinidylanic acid benzyl ester.

NMR spectrum (CDGIJ 3) showed the following signals:

That is, 7.40 (m-5H), 5.77 (s-IH), 5
．． 21 (S, 2H)-4,59(s-IH)-1,6
7 (s-38) and 67 (S-3H) ppm isolated 6,6-short R dilanic acid benzyl ester-6-
It was converted to β-iodopenicillanic acid benzyl ester. Nuclear magnetic resonance spectrum (CDCA3) showed the following signals. That is, 7.42 (m, 5H), 5.64
Cd, IH-A, J=4.0Hz), 5.42(d-
IH-AB=J=4.0Hz)-4,59(s
, IH), 1.69 (s-3H) and 1.40 (
s=3H) ])I)m Example 12 Appropriate 7. =6-β-amino, nopenicillanic acid ester was used as the starting material and the treatment method of Example 10 was carried out to prepare the following 6-
β-iodopenicillanic acid esters were synthesized.

6-β-iodopenicillanic acid 6-phthalidyl ester-
6-β-iodopenicillanic acid 1-(acetoxy)ethyl ester; 6-β-iodopenicillanic acid 4-crotonolactonyl ester: 6-β-iodopenicillanic acid γ~
Notyrolactone-4-yl ester; 6-β-iodo9
Penicillanic acid acetoxymethyl ester; O-β-iodo'' x hexanoyloxymethyl penicillanic acid ester:
6-β-iodopenicillanic acid 1-(isobutyryloxy)ethyl ester; 6-β-iodo2R nidylanic acid methoxycarbonyloxymethyl ester; 6-β-iodo9penicillanic acid phloboxyloxycarbonyloxymethyl ester; 6-β- Iodo 9-nidylanic acid 1-(ethoxycarbonyloxy) ether ester; 6-β-iodo 9-nidylanic acid 1-(butoxycarbonyl)ethyl ester; 6-β-iodopenicillanic acid 1-methyl-1-(methoxycarbonyloxy) ethyl ester; and 6-β
-Iodopenicillanic acid 1-methyl-1-(impropoxycarbonyl)ethyl ester 6-chloro-6-iodobenicillanic acid acetoxymethyl ester 6-chloro-6-iodopenicillanic acid 5.0.1 solution in 50 Tnl of acetone and acetonitrile G to 50a
Add 900 μl of isopropylethylamine, and then add 0.77 d of acetoxymethylpropylene. The resulting solution is kept stirring at room temperature for 48 hours.

Add 0.7 ml of bromide and 900 mg of amine and continue stirring for a further 48 hours. The solution is concentrated to dryness by vacuum distillation and the residue is suspended in ethyl acetate. Insoluble materials are filtered and the filtrate is washed successively with water, 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic solvent layer is dried and one solvent is removed by vacuum distillation. The remaining product is chromatographed using silica gel and methylene chloride as eluent. Fractions containing the target substance are collected and one solvent is removed by vacuum distillation.

For 6-β-chloro, a solution of 866 η of nidylanic acid acetoxymethyl ester, 5-chloro-6-iodoinisilanic acid acetoxymethyl ester, and 70 Q of dienylmethyltin aqueous complex in 20 ml of toluene was added under nitrogen purge (in the stream). 4
．． 5 o'clock n1j 80'C, add 7-ru. A series of Molten Bay 1
The residue was distilled off using air evaporation and chromatographed using silica gel and methylene talola chloride as the distillate.
, layer line rhIδj1-roto-6-β-chloropenicillane ace)-oxymethyl ester was obtained.

Missing Example 14 Using the procedure of Example 16, the following 6-β-talolobenicilanic acid ester is prepared from a thick core starting material (2): 6-β-chloropenisilane Acid 6-Fuku IJ) ester: 6-β-talolobenicilane 1-methyl=1-(
Impropoxy) ethyl ester; 6-β-chlorodilanic acid pinochloyloxymethyl ester; 6-β-
Chloropenicilane (11,4-crotonolactonyl ester; 6-β-chloropenicillane 1-methyl-1-
(methoxycarbonyloxy)ethyl ester: 6-β
-Chloropenicillanic acid γ-butyrolactonyl-4-yl ester; 6-β-chloromenisilane hexanoyloxy 2° methyl ester; 6-β-chloroinidylanic acid 1
(ri: sulfonyloxy)ethyl ester; 6-β
- Chlorovanidylanic acid 1-(isobutyryloxy)ethyl ester; 6-β-chloropenicilane dispersion metho4 dicarbonyloxymethyl ester; ] stool 6-β-chloroRnidylanic acid propoxycarbonyloxymethyl ester.

A solution of 6-diazoRnidyranic acid 1-(ethoxycarbonyloxy)ethyl ester (3,7&) in 2 Qrnl of tetrahydrofuran and 13 mA of diethyl ether was added to 15.4 ml of pyridine and 2.2' of N-bromosuccinimide). 2 g diethyl ether 20 mA
Add the solution to a medium that has been cooled to -20°C. The reaction mixture was stirred at -10°C for 20 minutes, and then placed in ice water to stop the reaction. The organic layer was separated and the aqueous layer was further extracted with diethyl ether (6 x 40 ml, ). The organic layer and extract were combined, washed successively with aqueous sodium bicarbonate and water, and dried over aliquots of sulfuric acid. The solvent was distilled off under reduced pressure to obtain 1-(ethoxycarbonyloxy)ethyl 6-7'romo-6-fluoroinisilanic acid ester.

The intermediate was chromatographed using 200 g of silica gel and chloroform as the eluent. The fraction containing the target compound is filtered and the solvent is removed by vacuum distillation.

6-bromo-6-fluoropenicilanic acid 1-(ethoxycarbonyloxy)ethyl ester 614m? 7 m9 of azobisisobutyronitrile and then 500 m/m of di-n-butylphenyltin hydride are added to a solution of 15 m6 of dry toluene under a nitrogen stream. The reaction mixture is irradiated with UV light for 70 minutes without external cooling to maintain the temperature at about 25°C. The solvent is removed by vacuum distillation,
Pour the residue into water 5Qa/! Process with. Adjust the pH of the mixture to pH1
, 8 fC, separate one organic layer, dry with sulfuric acid (IJ), and concentrate to dryness to obtain the desired product. This product is further purified by chromatography to obtain f'l-.

J Fluid 16 Starting from the required 6-diacypenisilanic acid ester, the primary esters are prepared according to the procedure of Example 15: 6-β-fluoropenicillanic acid methoxycarbonyloxymethyl ester: 6-β-fluoro R Nidylanic acid hivaloyloxymethyl ester; 6-β-fluoro-nidylanic acid 3-phthalidyl ester: 6-β-fluoropenicillanic acid 1-methyl-1-(impropoxy)ethyl ester: 6-β-fluoro-nidylanic acid Acid 4-crotonolactonyl ester: 6-β-fluoropenicilane m1-7
! Thyl-1-(methoxycarbonyloxy)ethyl ester; 6-β-fluoropenicilanic acid γ-dtyrolactonyl-4-yl ester; 6-β-fluoropenicilanic acid hexanoyloxymethyl ester; Nidylanic acid 1-(innotyryloxy)ethyl ester; 6-β-fluoro-nidylanic acid 1-(innotyryloxy)ethyl ester; 6-β-fluoropenicillanic acid soloboxycarponyloxymethyl ester; -β-fluoropenicillanic acid acetoxymenal ester.

A solution of 11.88 g of IJ in 500 d of water and 6-β-amino acid pivaloyloxymethyl ester 5.26. ! 7 methylene chloride 500
The mixture of m1 solutions was stirred without cooling in a water bath to obtain i=(
-P-) luenesulfonic acid (2,4,9) into 6
Add in equal portions over 0 minutes and continue stirring the mixture at room temperature for 1 hour.

Separate the organic layer and dry with sodium sulfate. A solution of 2.21 g of N-promoacemide in 100 g of anhydrous methanol was cooled to -10 DEG C. and added to the organic layer over 10 minutes. The resulting reaction solution was then continued to be stirred at 0°C for 2 hours. This solution was washed with saturated brine, and the organic layer was separated, dried over sodium monosulfate, and concentrated under reduced pressure. The residue is subjected to chromatography as a silica gel eluent using a solution containing increasing amounts of ethyl acetate and benzene. The fractions containing the desired intermediate are concentrated to dryness by vacuum distillation.

2- Toxic acid was poured into a solution of 1.93.9 ml of pivaloyloxymethyl ester 6-promol 6-methoxyR dilanic acid pivaloyloxymethyl ester in dry toluene through which a stream of nitrogen had been passed. 11 dibenzylethyltin hydride and a few crystals of azobisisobutyronitrile are added - and the resulting reaction mixture is heated to 50°C.
Warm for an hour.

Further add 750 m9 of hydride and 10 μm of nitrile,
Continue stirring at 0°C for an additional 6 hours. A desired product was purified by column chromatography on silica gel using an increasing eluate method using cyclohexane and ethyl acetate. The fractions containing the product are collected and concentrated to dryness by vacuum distillation.

Example 18 Following the procedure of Example 17 and starting from the appropriate 6-β-aminopenidylanic acid ester and the required alcohol, the following compound is prepared: 6-β-methoxypenicillanic acid 6 -phthalidyl ester; 6-β-ethoxy is nidilanic acid 1-(acetoxyethyl ester); 6-β-methoxypenicillanic acid acetoxymethyl ester; 6-β-infropoxybenicillanic acid 4-crotonolactonyl ester ; 6-β once-phthoxy nidilanic acid γ-butyrolactone-4-yl ester: 6-β once once propoxy is nidilanic acid hexanoyloxymethyl ester-6-β-methoxypenicillanic acid hexanoyloxymethyl ester; 6- β-5-butoxy 4-nidylanic acid methoxycarbonyloxymethyl ester; 6-β-ethoxy is nidylanic acid ethoxycarbonyloxymethyl ester; 6-β-phthoxybenicilanic acid 1-(ethoxycarbonyloxy)ethyl ester; 6- 6-β-methoxybenicillanic acid 1-(butoxycarbonyl)ethyl ester; Acid 1-methyl-1-(impropoxycarbonyloxy)ethyl ester.

A solution containing 100 μl of 6-β-chloronidylanic acid sodium salt and 831 μl of sodium periodate in 5 d of water was stirred at room temperature for 90 minutes, and ethyl acetate was added to bring the pH of the aqueous layer to 8 to 6. Adjust with NH (J). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 10 mA). The organic layer and washings were collected, backwashed with water and a saturated saline solution, and dried over sodium monohydric acid. The solvent was removed by vacuum distillation and the remaining free acid was dissolved in tetrahydrofuran.An equal volume of water was added to adjust the pH of the resulting volume.
dilute hydroxide to 6.8%) and prepared with an IJ solution. Tetrahydrofuran was removed by vacuum distillation, and the remaining aqueous solution was freeze-dried to obtain 45 m of the desired sodium salt. Nuclear magnetic resonance analysis of the free acid showed the following absorption. That is, 56 and 5.7 (two sets of doublets ~ l H (3
: 1)-J=4Hz)-4,92 and 5.3(2
Double line of pair = IH1 (3:1), J = 4Hz le 4.56
(S,3H)-1,7(s,3H) and 1.6 and 1.36 (2,1 doublet, (3:1)3H)I)9m
A water 5a solution of 150 m9 of sodium 6-β-chloropenicillanic acid salt was kept at 0 to 5°C, and 185 mg of potassium permanganate, 85% phosphorus, and 663 m of water were added dropwise thereto. Dilute water. The pa+ was maintained between 6° and 6.5 by careful addition of sodium oxide solution. When the permanganate color became persistent - the addition was stopped. A small amount of sodium bisulfite was added. The color of permanganate was removed.The reaction mixture was passed through Supercel, and 25 ml of ethyl acetate was added to solution F.The pH was adjusted to 1.8 with 6N hydrochloric acid, and the organic layer was separated.The aqueous layer was further separated. Extracted with ethyl acetate (3 x 10 mJ). The organic layer and washings were combined and backwashed with water and saturated brine at °C.
-Dried with sodium sulfate. The solvent was removed by vacuum distillation to obtain 118 ml of the desired acid.

This acid was dissolved in 90 francs of tetrahydrochloride and an equal volume of water was added to the solution. The pH was RM'd to 6.8 with dilute sodium hydroxide solution. Tetrahydrofuran was removed by vacuum distillation, and the residue was freeze-dried to obtain 90~ of the target sodium salt. Nuclear magnetic resonance spectroscopy of free acids (acetone-D6
) showed the following signal: That is, 5.82(d-
1H-J=4Hz)-4,54(s-18)-1,65
(s-3H) and 1.5 (s, 3H) ppm Example 21 --Chlorobenicine Sulfone 6 to Nororo 6-Yo)' to Nidylanic acid 6,09 6N to a suspension in a mixture of 25ml of methylene chloride and 15mA' of water.
A sufficient amount of sodium hydroxide was added to adjust the pH to ZO. The aqueous layer was separated and the organic layer was extracted several times with water. The aqueous layer and washings were combined, cooled to 5°C, and poured over 64E of potassium permanganate.
A solution containing /, 08d of phosphoric acid, and 25ml of water was added dropwise over 20 minutes. Maintain temperature at 5-8℃ and pH at 3N
The temperature was adjusted to 5.5-6o by addition of sodium hydroxide solution.

Ethyl acetate (30 mA) was added to this reaction solution, and the pH was adjusted to 1.5 with 16N hydrochloric acid. While keeping the pH below 16 with 61'4 hydrochloric acid, add 10% sodium bimyelite solution (
20 mJ) was added dropwise. The lower layer was separated and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate layer and the washings are combined, dried over sodium sulfate, and concentrated by vacuum distillation to obtain the desired intermediate (melting point 167-169°G) 2.0.

6--Chloropenicillanic acid sulfone 6-chloro-6-yo)'10 Nidylanic acid sulfone 60
2 g of toluene group 125 solution is placed at 0-5° C. in a nitrogen stream, and 0.8 ml of triethylamine and then 0.977 ml of trimethylsilyl chloride are added thereto. 0-5
After stirring for 5 minutes at 25°C, 60 minutes at 50°C, the reaction is cooled to 25°C and the triethylamine hydrochloride is removed by filtration. To the obtained solution F, 151 ng of azobisisobutyronitrile and then 2.02 ml of tribenzyltin hydride are added. The mixture is externally cooled and maintained at about 20-25°C and then irradiated with UV light for 15 minutes.

The solvent was removed by vacuum distillation, and the residue was dissolved in tetrahydrofuran.
Dissolve in a 1=1 mixture of water. The pH was adjusted to ZO and tetrahydrofuran was distilled off under reduced pressure.

The remaining aqueous solution is diluted with diethyl ether and then an equal volume of ethyl acetate is added. The pH was adjusted to 1.8 with 6N hydrochloric acid, and one organic layer was separated. The aqueous layer was further extracted with ethyl acetate, and the organic layer and the washings were combined and vacuum distilled to obtain the desired product, which is the same as the material obtained from Example 20.

Example 22 The following compounds are synthesized using the appropriate penicillanic acid as a starting material and according to the treatments shown in the examples: RN Treatment Method 1 Example 19 ■
2 Implementation 91121F 1
Example 19F 2 Implementation (11'
! 120F 2 Example 21 H0 31 Example 19 CHO2 Example 21 C2H501 Example 19 C2H502 Real Mfu20 n-C3H701 Example 19 1 1-c3H7o2 Example 20
RN Treatment method 1-C3H702 Example 21 n-C4H901 Example 19 n-C4H902 Example 21 S-C4H001 Example 19 6-β-buD Mo<= N, N of 280 mg of sila7 acid
260Tn9 of diisopropylmethylamine (260Tn9) followed by 155% of chloromethyl pivalate and 16% of sodium iodide. The reaction mixture is stirred at room temperature for 24 hours. It is then diluted with ethyl acetate and water. The pH was adjusted to Z5, then the ethyl acetate layer was separated and diluted 6 times with water and 1 time with saturated co-brine.
Wash twice. The ethyl acetate solution is dried over anhydrous sodium sulfate and evaporated by vacuum distillation to yield the title compound.

-'Se 1 24 Suitable 6-halo is nidylanic acid, 6-phthalidyl chloride, 4-crotonolactonyl chloride, 9-gamma-
Butyrolactone-4-yl chlorideゝ or the necessary alkanoyloxymethyl chloride, 1-(alkanoyloxy)ethylflora 1F-1-methyl-1-(alkanoyloxy)ethyl chlorideゝ, alkoxycarbonyloxymethyl chloride 8.1-(alkoxycarbonyl When reacted according to the procedure of Example 23 with oxy)ethyl chloride or 1-methyl-1-go(alkoxycarbonyloxy)ethyl chloride, the following compound is obtained: 6-β-chloronidylanic acid 6 -lid+) /l/ ; 6-β-fluoropenicillanic acid 6-phthalicyl; 6-β-methoxy (nidilanic acid filtrate; 6-β-bromo to
6-β-iodine is 4-crotonolactonyl dilanate; 6-β-ethylthio is 4-crotonolactonyl dilanate; 4-yl; 6-β-fluoroRnidylanic acid γ-butyrolactone-4-yl-6-
γ-butyrolactone-4-yl β-ethoxypenicillanate; acetogysimethyl 6-β-promomenicillanate; 6
-β-methylthio pivaloyloxymethyl dilanate; 6-β-methylthiopenicillanate hexanoyloxymethyl; 6-β-n-flopoxypenicillanate 1-(acetoxy)ethyl: 6-β-chloropenisilane Silanic acid 1-(
imbutyryloxy)ethyl; 6-β-methylthio; 1-methyl-1-(hexanoyloxy)ethyl nidilanate; 6-β-bromo; methoxycarbonyloxymethyl nidilanic acid; 6-β-methoxypenicillanic acid; -Fropoxycarponyloxymethyl: 6-β-iodo-1-(ethoxycarbonyloxy)ethyl nidylanoate: 6-
β-1-Propoxynidylanic acid 1-(butoxycarbonyloxy)ethyl; 6-β-bromonidylanic acid 1-
Methyl-1-(ethoxycarbonyloxy)ethyl and 1-methyl-1-(methoxycarbonyloxy)ethyl 6-β-fluorinidylanate.

Example 25 6-Bromo Nidylanic acid pivaloyloxymethyl ester sulfone 6.6-Bromo Nidylanic acid pivaloyloxymethyl ester sulfone 6,6-Zinromopenicillanic acid pivaloyloxymethyl ester 1.8 g 1.63 g of 30% m-chloroperbenzoic acid was added to a solution of 12 in 5Qm of chloroform.
The resulting reaction mixture was then kept stirring at room temperature overnight. Water (0W1) was added to the reaction - and sodium bisulfite was added in sufficient amount to give a negative starch-iodine paper test. The pH was adjusted to Z5 with a liquium solution and one organic solvent layer was separated.

The aqueous layer was extracted with chloroform, and the organic layer and washings were combined, dried over sodium sulfate, and evaporated to dryness. The residue was subjected to chromatography using 250 g of silica gel and chloroform as the solution. Fractions containing the product were collected and condensed to obtain the target compound 1.2.9.

6.6-Cypromobenicillanic acid pivaloyloxymethyl ester sulfone 1.15.9 To a solution of 10 ml of toluene in a stream of nitrogen A1*Norized triphenyltin 500I719
and a few crystals of azobisisobutyronitrile. Warm the regulated reaction mixture to 40'C for 60 minutes. Add hydride 2501n9 and some nitrile and continue heating for 60 minutes. The solvent was removed by vacuum distillation, and the residue was dissolved in chloroform (151] mJ!). Process with. The mixture is filtered and the r solution is chromatographed on silica gel using an eluent of increasing proportions of ethyl acetate in chloroform J-. The fractions containing the product are collected and concentrated by one vacuum distillation to obtain the desired compound.

Sulfoxide 6-chloro-6-iodo-nidylanic acid acetoxymethyate A
To a solution of 2.1 g of Noester in 55 m of chloroform, 8
06 g of 0% sodium chloroperbenzoate is added and the resulting reaction mixture is kept stirring at room temperature overnight. Water (35ml)
and excess peracid is decomposed by carefully adding sodium bisulfite using starch-iodine paper as an indicator. Adjust the pH of the aqueous layer to 75 and separate the aqueous layer. The aqueous layer was extracted with chloroform (2x10ml). and remove the water layer. The original chloroform layer and washing solution were combined, washed with monosaturated brine, and dried over sodium monosulfate. After removing the solvent by vacuum distillation, the residue was dissolved in 60 ml of chloroform and 250 g of silica gel was subjected to chromatography using chloroform as the eluent. The fractions containing the product were combined and the solvent was distilled off under reduced pressure.

6-chloroRnidylanic acid acetoxymethyl ester sulfoxytide 2.63 ml of -tri-n-butyltin hydride was added to 6-chloro-6F under anhydrous conditions and in a nitrogen stream.
), = henisilanic acid acetoxymethyl ester sulfone 4.35 & added to a solution of 15 [] mA' in dry toluene. The resulting reaction mixture was stirred at 80'C for 20 minutes. Water (53 ml) is added to the reaction mixture and one organic layer is separated. The organic layer is concentrated by vacuum distillation and the residue is dissolved in 75% chloroform. The obtained solution is subjected to chromatography using silica gel 200.9 and chloroform as an eluent. The fractions containing the desired product are concentrated to dryness by vacuum distillation.

Example 27 Starting with the appropriate 6,6-disubstituted penicillanic acid ester and using the indicated procedure, the following compounds are synthesized.

□2□-R1 01-2 Example 25-CH20□CCH3Br-1 Example 26-CH202CC(CH3)3C1-1 Example 2
6 -CH(OH3)02CCH301-2 Example 2
5 -CH202CC(CH3)3'C1-1 Example 26-CH202CCH(CH3)2C1-2 Example 2
5-CH2C2C(CH2)4CH3F-1 Example 26
-CH2O. cCH3F-1 Example 26 -CH20
2CC(CH3)3F-2 Example 25-cH(OH3)
02CCH3F-1 Example 26 Ken; (CH3) 20
□CCH3F-2 Example 25 -CH(CH3)02
C(CH2)4CH3F-2 Example 25 -CH20
□CCH3Br-1 Example 26-OH20゜CCH3B
r-1 Example 26 -CH(CH3)02CCH3B
r-2 Example 25 -C(CH2)202CCH3B
r-2 Example 25-CH202G(OH2)40H3B
r-2 real heu25-aH(CH3)o2c(OH2)
4cI (gCH30-1 Example 26 -CH20°C
CH3CH30-1 Example 26-CH202CC(CH
3) 3''-2 Processing method I C 30-2 %4kN 25 -C)i(
CH3)020a-I (CH3)2C2H50-1 Example 26 -C; H2O. (X; H3C2H50-1 implementation uv 26 -c=H<0H3)02ccH302
H50-2 Example 25 -OH2O2CCH (C
)2nc3H702 Example 25 -OH2o2c(O
H2)4CH3℃3H70-1 Example 26 ~CH2
02CG(CH3)3 and -C3H70-1 Example 26
-C((g)3)20゜CCH31℃3H701 Example 26 -C(CH3)202CCH3i℃3H70
-2 Example 25 -C,<(g)3)202CCH3
i-C3H7o-1 Example 26-CH2O□CCH(C
H3) 2n-C4H90-1 Example 26 -CH20
2CCH3dan704H901 Example 26 -CH20
20C(CH3)3s-C4H9o-1 Example 26-C
I-1202CCH3S-C4H90-2 Example 25-
CH202CCH3jC4H9 Country 1 Example 26
-CH20°mark H2CH3S-C4H90-1 Example 26 -CH(CH3)02CCH3 Engineering 1
Example 26 -CH202■H3 engineering 2
Example 25-CH202GO (CH3) 3 engineering 1
Example 26-CH(CH3)02CCH3 engineering
2 Example 25 -C(CH3)20□CCH3
■2 Example 25-CH(CH3)020CH(a(3)
2 Example 28 6. Put a solution of 6-dibromopenicillanic acid hyvaloyl oxymethyl ester sulfone 12.37.9 in tetrahydrofuran 175d into a flask equipped with a stirrer, a cold source, an anatomical tube, and a nitrogen inlet. Into the inside that has been cooled to 75℃~
Add 9.4 rni of a solution of 2,6M t-butylmagnesium chloride in tetrahydrofuran over 5 minutes. The reaction mixture was stirred for 20 minutes at 75° C. and then treated with 3.09 g of methyl methylthiosulfonate. −
Continue stirring at 75°C for 6 hours - -1 hour at 50°C and 2 hours at 0°C. Acetic acid (3,5d) is added to the reaction mixture and the resulting solution is kept stirring for 15 minutes. The reaction mixture was then concentrated by vacuum distillation and the residue was dissolved in water-ethyl acetate (50 TLl).
/ 5 Q ml). The aqueous layer was further extracted with ethyl acetate (507d), and the combined organic solvent extracts were mixed with water,
Next, wash with saturated saline. Separate the ethyl acetate layer;
Dry with sodium sulfate and reduce to 80% to give a crude product.

The residual oil is chromatographed using silica gel 5009 and chloroform as the eluent. The product-containing fractions are collected and concentrated to obtain the desired product.

-6-promo-6-methylthiopenicillanic acid pivaloyloxymethyl ester sulfone 1 under anhydrous conditions in a nitrogen stream
．． 45.9 and tri-butyltin hydride 0.81 ml
No. 5 Heat the Qml solution at 500G for 3 hours. The toluene is distilled off in vacuo and the residue is treated with 25 TLl of ethyl acetate. The target product crystallizes when kept in the refrigerator overnight.

Example 29 By treatment of real fluid 28, using an appropriate amount of penicillanate sulfone or sulfoxide 9 and the required alkyl methylthiosulfonate as starting materials,
The following compound is synthesized: 6-β-methylthioinisilane acid 3-ntallydyl ester sulfoxide: 6-β-methylthiopenisilanic acid 1
-(acetoxy)-methyl ester sulfone; 6-β-
Ethylthio-nidylanic acid hivaloyloxymethyl ester sulfone; 6-β-ethylthiopenicillanic acid 4-crotonolactonyl ester sulfoxide: 6-β-methylthio-nidylanic acid γ-butyrolactone-4-yl ester sulfone: 6 -β-Furovirthiopenicillanic acid acetoxymethyl ester sulfoxide; 6-β-
1-propylthiopenicillanic acid hexanoyloxymethyl ester sulfone; 6-β-1-propylthiopenicillanic acid 1-(inbutyryloxy)ethyl ester sulfoxide; 6-β-zmethythiobenicillanic acid 1-
Methyl-1-(acetoxy)ethyl ester sulfoxide; 6-β-butylthio is 1-methyl-1-(hexanoyloxymethyl)ethyl ester sulfone; 6-β-s-methylthio is methoxycarbonyl nidilanate. Oxymethyl ester sulfone; 6-β-phthylthio propoxycarbonyloxymethyl ester sulfoxide; 1-Methyl-1-(methoxycarbonyloxy) thiopenicillanate
Ethyl ester sulfone; 1-methyl-1-(impropoxycarbonyloxy) ethyl ester sulfoxide; Acid sulfone 3.91,,! The resulting solution was kept stirring at room temperature for 2 hours. Then -tetrabutylammonium chloride '810, N-methylmorpholine CJ, 56ml and α-chlorodiethylcarbo Ney)
Add 3.64 g into the reaction mixture in the order shown. The reaction mixture is kept stirring at room temperature overnight.

The reaction mixture was reduced to 0. Pour into IN hydrochloric acid and wash with dienal ether. After distilling off the ether, 2.98 g of crude product was obtained as a brown oil. Sample 500rn! ! Chromatography was performed using silica gel and ethyl acetate hexane (1:2; vol/vol) as eluent to give a 210 mg sample of pure product.

A solution of 2.53 g of dry toluene solution of 6,6-siglomonidyranic acid 1-(ethoxycarbonyloxy)ethyl ester sulfone was cooled to -5°C. Add Lonitrile 101n9.

The resulting solution was kept outside at 25°C and irradiated with ultraviolet light for 20 minutes.
Do minutes. The solvent is removed by vacuum distillation, and the residue is dissolved in an ethyl acetate-water (1:1) mixture and the pH is adjusted to 6.8. The ethyl acetate layer is separated, and the aqueous layer is further extracted with fresh ethyl acetate. The organic layers are combined with the washings, washed with water and saturated brine, and dried over sodium sulfate. The desired product is obtained by distilling off the solvent under reduced pressure.

Example 61! Example 3 Using the corresponding 6.6-di[converted henisilane ester sulfone or sulfoxide 9 as a starting material]
0, the following compounds are synthesized: 6-β-fluoropenicilanic acid 6-phthalidyl ester sulfoxide: 6-β-fluoropenicilanic acid 4-crotonolactonyl ester sulfoxide Kisite 9;6-β-
Fluoro is i-v thyl-1-(methoxycarbonyloxy)ethyl ester sulfone of 6-β-fluoropenicillanic acid; 1-(butoxycarbonyloxy)ethyl sulfone of 6-β-fluoropenicillanic acid; γ-butyrolactone-6-β-fluoropenicillanic acid 4-yl ester sulfoxide; 6-β
-Chloropenicillanic acid 3-phthalidyl ester sulfoxide; 6-β-chloropenicillanic acid methoxycarbonyloxymethyl ester sulfoxide; 6-β-chloropenicillanic acid 1-(7'roboxycarbonyloxy)ethyl Ester sulfoxide; 6-β-chloropenicillanic acid 1 y'thyl-1-(1soproboxycarbonyloxy)ethyl ester sulfoxide 8; 6-β
-chlorohenisilanic acid ethoxycarbonyloxymethyl ester sulfone; 6-β-bromopenicillanic acid 1-methyl-1-(propoxycarbonyloxy)ethyl ester sulfone; 6-β-furomoRnidylanic acid methoxycarbonyloxymethyl ester sulfoxide; 6- β
-Zulomobenicillanic acid 1-())oxycarbonyloxy)ethyl ester sulfoxide; 6-β-bromo 4
Nidylanic acid 3-7 cridyl ester sulfoxide;
6-β-Gromopenicillanic acid γ-butyrolactone-4-
6-β-iodopenicillanic acid 6-phthalidyl ester sulfoxide; 6-β-iodopenicillanic acid 4-crotonolactonyl ester sulfone; 6-β-iodopenicillanic acid methoxycarbonyloxymethyl ester sulfoxide 9; 6-β-iodopenicillanic acid propoxycarbonyloxymethyl ester sulfoxide; 6-β-iodo8 penicillanic acid 1-
(butoxycarbonyloxy)ethyl ester sulfone; 6-β-iodo9 penicillanic acid 1-methyl-1-(impropoxycarbonyloxy)ethyl ester sulfoxide; 6-β-methoxycarbonyloxymethyl ester sulfoxide Side: 6-β-
Methoxypenicillanic acid 1-(ethoxycarbonyloxy)ethyl ester sulfoxide: 6-β-Methoxypenicillanic acid 1-methyl-1-(impropoxycarbonyloxy)ethyl ester sulfoxide 6-β-
Ethoxy is nidilanic acid γ-butyrolactone-4-yl ester sulfone; 6-β-ethoxy is nidilanic acid 6-7
ri) Dyl ester sulfoxide 9; 6-β-n-7
"Ropoxypenicillanic acid 1-<'yroboxycarbonyloxy)ethyl ester sulfoxide 9; 6-β-1
-propoxypenicillanic acid 1-methyl-1-(methoxycarbonyl)ethyl ester sulfone; 6-β-2-butoxybenicillanic acid 6-phthalidyl ester sulfone;
6-β-5-7” ethoxycarbonyloxymethyl ester sulfone: 6-β-n-ph)
6-β-phthoxypenicilane 1-methyl-1
-(-1 toxycarbonyloxy)ethyl ester sulfoxide; and 6-β once-ptoxypenicillanate 1-methyl-1-(i~propoxycarbonyloxy)
Ethyl ester sulfoxide.

A mixture of 5.09 ml of 6.6-dipromopenicillanic acid, 1.54 mz of triethylamine and 100 ml of benzene was stirred in a nitrogen stream until a solution was obtained. solution from 0 to 5
Cool for 2-6 minutes to -trimethylsilyl chloride 7°C
8mA was added. The reaction mixture was stirred at 0-5°C for 2-6 minutes - then at 50°C for 65 minutes. The cooled reaction mixture was filtered and the filtrate was cooled to 0-5°C. Add a small amount of azobisisobutyronitrile and hydrogenate the tri-butyltin filter 68
Added power. The reaction flask was irradiated with ultraviolet light for 13 minutes.

The reaction mixture was then stirred for 1.75 hours at about 25°C.

The reaction mixture was again irradiated with UV light for 15 minutes and continued stirring for 2.5 hours. At this point a further small amount of azobisisobutyronitrile is added and then hydrogenated tri-butyltin 0
．． 6 solutions were added and the mixture was irradiated again for 60 minutes. The solvent was then removed by vacuum distillation and 5% sodium bicarbonate solution and diethyl ether were added to the residue. The bilayer system was shaken vigorously for 10 minutes. Then pH 2
．． Adjusted to 0. The ether layer was transferred, dried, and vacuum distilled to obtain 2.33 g of oil. The oil was converted to the sodium salt with sodium bicarbonate and the solution was lyophilized. This product is 6-β-bromo nidylanic acid sodium salt and contains a small amount of the α-isomer. The sodium salt is purified by chromatography on Sephatex LH-20.

The nuclear magnetic resonance spectrum of this product showed the following signals: 5.56 (s, 2) 1), 4.25 (s, IH)
, 1.60 (s=3H) and 1.50 (s-filaH) ppm dry toluene 4003 to 6,6-dibromo to nidilanic acid 1000. ! ? and 39QmJ of triethylamine were added, and the resulting slurry was heated at 20-25°C.
Cool slowly until Trimethylchlorosilane (35
5711ffl) was added dropwise over 10 minutes and the reaction mixture was allowed to warm to 25°C. Triethylamine hydrochloride was filtered off and the solid was washed with toluene 1751. Combine the furnace liquid and washing liquid and put them in a flask in a nitrogen stream)
! jn-notyltin hydride 766 toluene 100
0m solution was added at a rate of 18-20 ml/min. When the addition was complete - the reaction mixture was allowed to stir for 1 hour and then placed in saturated bicarbonate solution (77) to stop the reaction.

Separate each layer and add saturated sodium bicarbonate to the organic layer.
Extracted with 1. The aqueous layer and extract were combined, treated with 5 portions of ethyl acetate, and adjusted to pH 1.5 using sufficient amount of -12N hydrochloric acid.
Adjusted to 5. The ethyl acetate layer was separated and the aqueous layer was further extracted with 2.51 g of ethyl acetate.

The original ethyl acetate layer and the extract were combined, dried over sodium sulfate, and treated with 2.2611 ml of an ethyl acetate solution containing an equal volume of -2-ethylhexanoic acid sodium salt. The precipitate of the sodium salt is allowed to stand overnight at 8-10°C, filtered and dried to give a crystalline mass of 391.59.

Dissolve the above sodium salt (380,!i') in 1 part of deionized water.
．． 91 at 8°C and add sufficient amount of 6N hydrochloric acid to adjust the pH.
was set to 1.5. After 1 hour of stirring in the cold (6-5 DEG C.), the free acid precipitate was filtered off and washed with 500 TL of cold water. Add 21 parts of the free acid in ethyl acetate wet with water to 10 parts of water at -8°C.
The pH was adjusted to 1.5 with 16N hydrochloric acid. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The organic layer and extract were treated with activated carbon and dried over magnesium monocarbonate. The ethyl acetate layer is stirred and a solution of about 1 equivalent of sodium salt of -2-ethylhexanoate in 811 ml of ethyl acetate is added. After stirring for 1.25 hours, the precipitated solid was filtered and dried to give 6-β-bromopenicillanic acid sodium salt 2.
62g was obtained.

To further purify this compound, the above sodium salt was dissolved in deionized water 13007d and the pH was adjusted to 1.6 at 6-8<0>C. The precipitated solid was stirred at 6-8°C for 1.5 hours. Then, it was filtered and washed with 300 ml of water.

The free acid was treated with 21 d of ethyl acetate and 200 d of water, and the pH was adjusted to 1.65-1.40 with 6N hydrochloric acid. The organic layer was separated and dried over magnesium sulfate. To filtrate 2
- 802 ml of ethyl acetate containing the equivalent of sodium ethylhexanoate salt were added. The precipitated sodium salt was stirred at room temperature for 1 hour, filtered, and dried to obtain 227 g of the desired crystalline sodium salt.

A sample of 40.0% of the above sodium salt was added to 200ml of water and the resulting solution was adjusted to pH using 6N hydrochloric acid at water bath temperature.
'+, adjusted to 6. The precipitated free acid was filtered off and re-kneaded twice in water. After vacuum drying at room temperature overnight, the desired crystalline compound was obtained with 34.0! I got l.

Melting point 190-195°C (decomposition point).

Theoretical value C3H1oNo3SBr: Q, 34.3
;H53,6;N,5.0 Experimental value:
C-34,4; H13,7; N-5,0[α]ゎ2+2
92゜6-β-zlomo Sodium Nidylanate 255 μm water 5
182 m9 of sodium periodate was added to 11 Ll of the solution, and the resulting solution was kept stirring at room temperature for 6 hours.

60 Biao of ethyl acetate was added to the reaction solution, and 6N hydrochloric acid was added to adjust the pI (1.3). The ethyl acetate layer was separated, backwashed with monosaturated brine, and dried over magnesium monosulfate. The solvent was removed by vacuum distillation. The product remaining after evaporation was then dissolved in water containing 1 equivalent of the sodium bicarbonate salt.This aqueous solution was freeze-dried to obtain 255 mg of the desired product as the sodium salt.

5 6--Bromopenicillanic acid sulfone sodium salt 6-β
- 2557 ng of bromopenicillanic acid sodium salt in water 5
ml solution of potassium permanganate 1401ψ and phosphoric acid 0
．． 11 ml of a six-part solution of water was added, keeping the pH at 6.0-6.4 by careful addition of sodium hydroxide. The reaction mixture was stirred at 0-5°C for 15-20 minutes and 5Qm/? of ethyl monoacetate was added. Processed with.

The pH was adjusted to 1.5 with 6N hydrochloric acid, and sodium bicarbonate Roro 0Tn9 was added little by little. The pH was adjusted to 1.7, and the ethyl monoacetate layer was separated and backwashed with saturated brine. When the solvent was removed by vacuum distillation, the product was obtained in the form of an oil.

Suspend the free acid in 10 ml of ethyl acetate and add monohydrogen carbonate)
It was added to a solution of 10 TLl of water containing 57 m9 of IJum.

The aqueous layer was separated and lyophilized to obtain the target compound 1401n9 as a sodium salt.

2,5 Ni acid I Q! IJ Iodine Bromide 6.21.9
E, [) [A solution of 2.76 g of thorium nitrate in 75 ml of methylene chloride is cooled to -5°C and -6-β
- To the amine, 4.32 g of dilanic acid was added over 15 minutes. After stirring for 20 minutes at -5°C, 100 ml of 10% sodium bicarbonate salt was added, while taking care to maintain the temperature of the reaction mixture at 10°C. The layers were separated and the aqueous layer was extracted with methylene chloride (3X501d). The organic layer and extract were combined, washed with saturated brine, dried over magnesium sulfate, and concentrated by vacuum distillation to yield 5.71i of the desired intermediate (melting point 145-147°G).
'was gotten.

6-Bromo-6-iodo" 6-bromo-6-iodopenicillanic acid sulfone 6-bromo-6-iodopenicillanic acid (4.05 g of methylene chloride)" 307d solution and water 60+d were layered on top, and 16N sodium hydroxide was added to pH 7. I set it to 0.

Separate the aqueous layer, cool it to -5°C, and add 1 tsp of a solution of 93 g of potassium monopermanganate and 85% phosphorus TLl through a water filter.
It was added dropwise over 5 minutes. pH 5.8-6.2 6N
Adjust with sodium hydroxide and maintain the temperature at about 5°C, when the addition is complete - 100% ethyl acetate. d - the pH was lowered to 1.5 with 6N hydrochloric acid and diluted with 10% sodium bisulfite solution (3 [
1 ml) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (4X50mA). The organic layer and extract were combined, washed with monosaturated brine, dried over magnesium nitrate, and concentrated under reduced pressure to obtain 6.6 g of a substance. Melting point 151-153
°C 6-β-bromopenicillanic acid sulfone sodium salt 6-
-i lomo 6-coat 9 penicillanic acid sulfone 3.36
A solution of 160 ml of toluene of & was kept at 5°C, and 1.09 me of triethylamine and 6 g of dimethyl-t-butylsilyl chloride were respectively added in a nitrogen stream. 5 min at 5°C, 60 min at 25°C and 6 min at -45°C.
Continue stirring for 0 minutes. The reaction mixture is then cooled to 25°C. Triethylamine hydrochloride is removed and 15 mg of azobisisobutyronitrile and 2.04 mA of dibenzylphenyltin hydride are added to the p solution. The mixture is maintained at an external temperature of about 20-25°C and irradiated with ultraviolet light for 15 minutes. The solvent was distilled off in vacuo and the residue was diluted with 90% tetrahydrofuran-water 1:1.
Dissolve in a mixture of The pH is adjusted to ZO and tetrahydrofuran is distilled off under reduced pressure. Aqueous ethyl acetate 100ml
- and the pH is adjusted to 1.8 with 6N hydrochloric acid.

The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The organic layer and extract were combined, backwashed with monosaturated saline, and dried over sodium sulfate. The organic solution is then treated with a solution of 2.2 g of 2-ethylhexanoic acid sodium salt in ethyl acetate and stirring is continued for 1 hour. The resulting precipitated salt is collected in a furnace and dried.

6. A solution of 6-dibromopenicillanic acid 5I and di-isopropylethylamine 900Tn9 in 50 ml of acetone and acetonitrile 5-0-0.7 ml of hair acetoxymethyl bromide was added. The resulting solution was stirred at room temperature for 48 hours. An additional 0.71 mg of bromide and 900 mg of amine were added, and stirring was continued for an additional 48 hours. The solvent was removed in vacuo and the residue was treated with ethyl acetate and filtered. P solution with water,
The mixture was washed with 1N hydrochloric acid and saturated hydrogen carbonate water, and dried over sodium sulfate. The solvent was distilled off in vacuo, and the remaining residue was subjected to chromatography on silica gel using methylene chloride as an eluent. Fractions containing the desired product are collected and concentrated to yield a colorless oil, which solidifies on standing. A portion was recrystallized to prepare an analytical sample. Melting point 79-82°C. Nuclear magnetic resonance spectrum (CI
XJ 3) showed the following signal. 5.78 (s
-3) 1) -4,51 (s-IH), 2.10 (5-
3H), 1.61 (s-38) and 1.48 (s,
3B) Nidylanic acid acetoxymethyl ester 6,6-dibromopenicillanic acid acetoxymethyl ester 430179 and triphenyltin hydride 650 ppm-1 flo.
The mixture in (1) was heated to 90°C in a nitrogen stream for 5 hours.

The residue was subjected to chromatography on 120 g of silica gel using methylene chloride as an eluent. Fractions containing the product were collected and concentration in vacuo showed the following signal: 5.81 (s, 2H) - 5,63 (s - 2H)
, 4.51 (s, IH), 2.05 (s-3H), 1
．． 65 (s-3H) and 1.48 (s-3H) p
pm ester 6-low dibromobenicilane pivaloloxylester pivaloyloxymethyl chloride 1.8 and 6.6-
5 g dibromopenicillanic acid dimethylformamide 15
1.9 mL of triethylamine was added to the 1rLl solution at 0°C. The resulting reaction mixture was then continued to be stirred at room temperature for 16 hours. The reaction mixture was mixed with 150% water and 150% ethyl acetate/
ll! injected into. The pH was then adjusted to 2.0 with 6N hydrochloric acid. The organic layer was washed with water-sodium hydrogen carbonate solution and saturated brine, then dried over magnesium sulfate. Removal of the solvent in vacuo gave a red solid 4.7I which was purified by column chromatography - melting point 9.
8 showed the following signal. 5.80 (s, 2H),
5.75(S,IH)-4,5(S,1H)-1,61
(s, 3H), 1.47 (s=38) and 1.2
1 (s, 9H) ppm 6-β-bromopenicillanic acid pivaloyloxymethyl ester When the reduction treatment used in Example 37 was applied to 6,6-dibromopenicillanic acid pivaloyloxymethyl ester, the desired product was obtained. Nuclear magnetic resonance spectroscopy of the product showed the following signals: 5.85 (d, 1H-J-5Hz), 5
．． 76 (d, IH-J=5Hz) - 5,56 (d, 11
(, J = 4 Hz), 5.31 (d, IH-J
=4Hz), 453(s, IH), 1.67(S, 3
H), 1.49 (S, 3H) and 1.22 (S, 9H
) ppm Example Fluid 6. Applying the procedure of Example 67 using 6-dibromopenicillanic acid and the appropriate halide as starting materials, the following compounds are prepared.

"14□ -CH(CH3)020CH3 -cH202CCH(CH3)2 -CH2o2C(CH2)4CH3 -CH(CH3)02CCH3 -C,H(OH3)O□C(CH2)4CH3-c(C
H3) 20□CCH3 -C(CH3)20゜CC(CH3)3-CHo," 32 -C4H5021108H502' -cH20□COCH3 -CHOC0GH(CH3)2 2 -cCH(CH3)0□C0(CH2) 3CH3-cH(
CH3)02COC2H5 -JS(CH3)202C○(CH2)2CH3 Yellow 4-
Crotonolactonil 1 gamma-butyrolactone-4-yl-6-phthalicylone fluid 40 3.58 g of methylene chloride of the ester 6,6-dibromo-4-nidylanic acid '4 Qml solution of hetriethylamine 1,
08 Add &. The solution is then treated with 1.289 g of dimethoxychloro7-osphine and left to stir for 30 minutes. The solvent was removed in vacuo and the residue was treated with dry diethyl ether 125. Insoluble triethylamine hydrochloride is passed through and the ether is distilled off under reduced pressure to obtain the desired intermediate.

B, 6--bromopenicillanic acid 6.6-dibromopenicillanic acid dimethoxyphosphine ester 4.5. Once a dry toluene solution of F is added, 6.4 g of butylphenyltin hydride is added, and the resulting reaction mixture is stirred at room temperature for 20 minutes.

Add 150 mA of saturated aqueous sodium bicarbonate solution to the reaction mixture and separate one organic layer and discard. The aqueous layer was further extracted with ethyl acetate (2x25mA), and the pH was adjusted to 15 with 6N hydrochloric acid.
Adjust carefully. Extract the acidified aqueous layer with ethyl acetate (3×507d), collect the extracts, dry over magnesium sulfate, and concentrate to obtain the desired product.

Using the procedure of Example 41A, Example 40A, and reacting the appropriate 6,6-disubstituted penicillanic acid and the required phosphine chloride as starting materials, the following compounds are prepared: rlo-6-iotohenisilanic acid diphenylphosphine ester; 6,6-770 mo-nidylanic acid dipropoxyphosphine ester; 6,6-cislomo-nidylanic acid diethylphosphine ester; short-nidylanic acid dimethoxyphosphine ester; 6
--10mo6-yo1''knidylanic acid diphenylphosphine ester;
7'Romo6~°Metho*C=nidylanic acid dimethylphosphine ester; 6-Tulomo6-n-7' toxybenicilanic acid dimethoxyphosphine ester; 6
-Bromo-6-nitoxybenisilanic acid phenylethylphosphine ester; 6 ;"bromo-6-methylthiohenisilanic acid diphenylphosphine ester; 6-bromo-6-1-propylthiopenicilanic acid methylmethoxyphosphine ester; 6-ri p-ro 6-iodine''
6-E-penicillanic acid di-1-propoxyphosphine ester sulfoxai)'; Silanic acid ethoxyphenylphosphine ester sulfoxide and 6-bromo-6-methylthiopenicillanic acid dimethoxyphosphine ester sulfoxide.

B. Using the above compound as a starting material and applying the treatment of Example 40B, the following homologous compound is obtained.

6-β-Chlorozunidylanic acid diphenylphosphine ester; 6,6-)-jlomoRnidylanic acid Shi-n-fluoroxyphosphine ester; 6,6-difuromozunidylanic acid diethylphosphine ester; short penicillane Acid dimethoxyphosphine ester; 6--10
6-bromo-6-iodopenicillanic acid cinenylphosphine ester; 6-bromo-6-iodo9penicillanic acid
n-furovirphosphine ester; (Is-furomo-6-methoxybenicilanic acid dimethylphosphine ester; 6-bromo-6-n-7' toxybenicilanic acid dimethoxyphosphine ester; 6-bromo-6-nitoxybenicilanic acid Phenylethylphosphine ester; 6-bromo-6-methylthiopenicillanic acid diphenylphosphine ester; (5-7').

6-i-furopylthionidylanic acid methylmethoxyphosphine ester; 6-chloro-6-iodo''
Nidylanic acid jetoxyphosphine ester sulfoxide; 6-]]'Romo-6-iodobenicilanic acid di-propoxyphosphine ester sulfoxide 9;
6-Bromo-6-methoxynidylanic acid ethoxyphenylphosphine ester sulfoxide and 6-bromo-6-methylthiobenicilanic acid dimethoxyphosphine ester sulfoxide.

B. When the above compound is reacted using the procedure of Example 40B as a starting material, the following homologous compound is obtained.

6-β-chloropenicillanic acid; 6-β-so' CI mopenicillanic acid; 6-β-iodonic acid; 6-β-
Methoxypenicillanic acid; 6-β-neebutoxybenicillanic acid; 6-β-ethoxybenidillanic acid; 6-β-methylthiopenicillanic acid; 6-β-1-propylthiopenicillanic acid; 6-β-chloro e.g.; silane acid sulfoxide;
6-β-solomopenicillanic acid sulfoxide; 6-β
-6~Methoxypenicillanic acid sulfoxide 9 and 6
-β-methylthiopenicillanic acid sulfoxide.

A solution of 3.62 g of 6-chloro-6-iodopenicillanic acid in 200 ml of dry methylene chloride. 1. Triethylamine. DI was added and the resulting solution was cooled to 0-5°C. Add ethyl chloroformate (1,1,!?) to the reaction mixture over a period of 15 minutes.

The reaction was held at 0°C for 6 hours - then 6,5-di-t
- Treat with 2.36 g of butylbenzyl alcohol. After further stirring in the cold for 2 hours, the reaction mixture was allowed to warm to room temperature. Add water (757d) to the reaction mixture and separate the organic layer, dry over IJ and concentrate in vacuo to give the desired compound.

B, /)-β-chloroRnidylanic acid 6-chloro-6
-yo)'' is nidilanic acid 6,5-di-t-/'thyl-4
-To a solution of 2.9 g of hydroxybenzyl ester in 125 parts of dry toluene, in a nitrogen stream, 10 m9 of azobisisobutyronitrile and 1.5 m of tri-methyltin hydride.
Add 11 Ll. After stirring the mixture for 20 minutes, the solvent was distilled off under reduced pressure and the residue was diluted with tetrahydrofuran-water (1:1
) Dissolve in the mixture - then add a solution of sodium 2-ethylhexanoate 1,08 & in 20 ml of methanol.

After stirring at room temperature for 6 hours, ethyl acetate was added to adjust the pH to ZO. Separate the ethyl acetate layer, add fresh ethyl acetate to the aqueous layer - and adjust the pH to 5 with 6N hydrochloric acid.

The organic layer is separated, dried over sodium monohydric acid, and concentrated to obtain the desired product.

Example 46 A Applying the process of Examples 42A and B using the required 6,6-disubstituted penicillanic acid as a starting material, the following compounds are prepared: 6-β-bromopenicillanic acid; 6-β-iodopenicillanic acid; 6-β-methylthiopenicillanic acid; 6-β-dutylthiopenicillanic acid; 6-β-chloropenicillanic acid sulfoxide; 6-β-bromonidylanic acid sulfoxide: and 6-β-metallic acid sulfoxide.

A solution of 2.98 g of 6-bromo-6-fluoropenicillanic acid and 40 ml of a 1:1 mixture of dry dimethyl-formamide 9-tetrahydrofuran and 1.99 g of 6-bromo-6-fluoropenicillanic acid and 1.99 g of 6-bromo-6-fluoropenicillanic acid and 90 furan was cooled to 0°C. - 14 m/7 of triethylamine is added dropwise to it over 15 minutes.

The cooled reaction mixture was stirred for 6 hours and then treated with 100 liters of ethyl acetate and 100 TL of saturated aqueous sodium bicarbonate. Separate and remove the aqueous layer and add fresh water to the organic layer. The pH was adjusted to 5.0 with 6N hydrochloric acid, and one organic layer was separated, washed with brine, dried over sodium monohydric acid, and concentrated by vacuum distillation to obtain the desired product.

B, 6-β-Fluoro-nidylanic acid 6-bromo-6-fluoropenicillanic acid phenacyl ester 2.01' dissolved in 6 oy of dry toluene was cooled to 0°C in a nitrogen stream - dibenzylmethyltin Hydride 1.59.9 and azobisisodutyroni) IJle 10■
and warm the resulting reaction mixture to 50° C. for 5 hours. The solvent is distilled off in vacuo, and the residue is chromatographed on silica gel using methylene chloride as a solvent. The fractions containing the product are collected and concentrated to dryness.

The residue was dissolved in 25 ml of dry dimethylformamide and treated with a 4 ml solution of potassium thiophenoxylate 3751n9 in dimethylformamide. After stirring at room temperature for 2 hours, the reaction mixture was added to 60 ml of saturated aqueous sodium bicarbonate. Ethyl acetate (60 m) , separate the organic layer, and add new ethyl acetate.Adjust the pH of the aqueous layer to 1.5 with 6N hydrochloric acid, separate one organic layer, wash with monosaturated brine, and dry with sodium monohydrate. The desired product is obtained by removing the solvent by vacuum distillation.

Example 45 A, the appropriate 6,6-disubstituted 4-nidylanic acid and the required α
- By using the halomethylcarbonyl reagent as a starting material and applying the treatment method of Example 44A, the following compound is obtained.

6-Bromo-6-fluoropenicillanic acid acetonyl ester; 6-bromo-6-fluoro is propionyl methyl nidylanic acid; 6,6-cyglomobenicillanic acid cyanomethyl ester; 6,6-cyclomopenicillanic acid methoxy Carbomethyl ester; 6,6-siglomonidylanic acid phenacyl ester; 6-chloro-6-iodo-nidylanic acid phenacyl ester: 6-chloro-6-iodobenylic acid phenacyl ester; 1'rollo 6-iodopenicillanic acid propionyl methyl ester; 6-chloro-6-iodopenicillanic acid propoxycarbomethyl ester: 6,6-short 9 penicillanic acid cyan methyl ester; 6,6-short 9 penicillanic acid e -i -, 7'tyryl methyl ester; 6.6-short''R nidilanic acid phenacyl ester; 6-normo-6-iothopenicillanic acid acetonyl ester;
- Noromo 6-iodopenicillanic acid cyan methyl ester; 6-7' Romo 6-moxypenicillanic acid phenacyl ester; 6-Noromo 6-methoxybenicillanic acid propionyl methyl ester; 6-;f Spider-6-methoxy Rnidylan Acid ethoxycarbomethyl ester; 6-/
'Romo 6-methylthiopenicillanic acid cyanomethyl ester; t5-/'Romo 6-methylthiobenicillanic acid phenacyl ester: 6-chloro-6-iodobenicillanic acid 2-notyryl methyl ester sulfoxide;6.
6-Dibromopenicillanic acid phenacyl ester sulfoxide; 6,6-diiodopenicillanic acid acetonyl ester sulfoxide; -Promo 6-methoxybenicilanic acid methoxycarbomethyl ester sulfoxide.

B. Using the esters obtained from Example 45A as starting materials and applying the treatment of Example 44B, the following homologues are prepared: 6-β-fluoropenicilanic acid; 6-β-nobrobenicilanic acid ; 6-β-chloropenicillanic acid; 6-β-iodo9penicillanic acid: 6-β-methoxyinisilanic acid; 6-
β-Methoxythio is nidilanic acid; 6-β-bromopenicillanic acid sulfoxide 9;
6-Iodo is a solution of 6.9 g of diranic acid sulfoxide in 200 ml of methylene chloride. 1.0 g of hetriethylamine is added, and the resulting reaction mixture is cooled to 0°C. Ethyl chloroformate (1.1 g) is added dropwise over 15 minutes. The reaction is then maintained at 0°C for 30 minutes. Penzaldehyde 8 oxime (1.2 g) in dry acetone 10
Dissolve and add to the mixture and continue stirring for 2 hours. The reaction mixture is then warmed to room temperature and stirring is continued for a further 2 hours. The reaction mixture is filtered, the filtrate is concentrated to dryness, and the residue is partitioned between ethyl acetate (100m) and water (501d). Separate the aqueous layer and wash the organic layer with saturated aqueous sodium bicarbonate solution and dry over magnesium sulfate. The desired product is obtained by distilling off the solvent in vacuo.

8.6-β-chloropenicillanic acid sulfoxide 9O-
A solution of 2.48 g of (6-10 rho-6-iodopenicilanoyl) benzaldehyde oxime sulfoxite in dry toluene was placed under a nitrogen stream, and 1.62.9 g of dibenzyl-nimethyltin hydride and azobis 15 μl of isodutyronitrile are added. The resulting reaction mixture is stirred and warmed to -50° C. and maintained at this temperature for 5 hours. The solvent is distilled off in vacuo and the residue is dissolved in 10,011 liters of ethyl acetate and 75 d of water. The organic layer is separated, dried over sodium sulfate and concentrated to dryness under reduced pressure. 1.8 g of the residue is dissolved in 25 ml of dimethylformamide, and then 660 ml of potassium thiophenoxide is added to the solution. Add 101 nl of solvent solution. After stirring for 2 hours at room temperature - the reaction mixture is added to monosaturated sodium bicarbonate solution.

The aqueous layer is extracted with 75 hours of ethyl acetate and the organic layer is separated.

The pH of the aqueous layer was adjusted to 1.5 with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer is separated, dried over sodium monosulfate, and concentrated to dryness in vacuo to obtain the desired product.

Example 47A, by applying the treatment of Example 46A and reacting appropriate 6,6-disubstituted penicillanic acid and oxime as starting materials, the following compound is synthesized:
5-''2 j5- BrF □ -CH5 BrF (3-CH5 BrF O-1-C3H7 Ac1- 0 -C2H5I-01-
' O-n-C3H7B r B r
O-Cs HsB r B r
O-C2Hs■=I (3-
C; H3I -I -0-02H5 I-BrO-CHa I-Br-0-06H5 Br-' CIOo -C6H5Br-
CH8□ '-c6u5Br-CH3SO-C
2H5 X RN R155□ Br-Br-i -CH5 Br-CHO1-C6H5 B r F1 -CH
3B r C11-CH3 Br-C1-1-C1; H5 Br-01-1-J6H5 Br-G knee 1-r4-C, H7B, Example 4
Using the esters in 7A as starting materials, Example 46
The following similar compounds are synthesized using the treatment method of B: 6-β-fluoropenicillanic acid-6-β-chloropenicillanic acid-6-β-bromomethylnidylanic acid, 6-β- Yo)
SS Nidylanic acid; 6-β-methoxypenicillanic acid: 6-
β-methylthiopenicillanic acid; 6-β-nobrobenicillanic acid sulfoxide; 6-β-methoxypenicillanic acid sulfoxide 9; 6-β-fluoropenicillanic acid sulfoxide; and 6-β-chloropenicillanic acid sulfoxide.

Example 48 -6-β-Aminopenicillanic acid (2.9 g of methyl ester todilate salt) in a solution of 5.9 C9 sodium nitrite in 250+1 L of water at 5°C.
A 25M solution was added with stirring. P-Toluenesulfonic acid (1,2,1 l in 6 portions!) was added over 60 minutes and the mixture was kept stirring at room temperature for 1 hour. The organic layer was separated, dried over sodium sulfate, and iodine 1
．． 69. The resulting solution was stirred at room temperature for 4 hours - then washed with aqueous sodium thiosulfate and concentrated to a small volume. The residue was subjected to silica chromatography using increasing mixing ratios of ethyl acetate to petroleum ether as the eluent. Fractions containing the product were collected and concentrated in vacuo to obtain the desired product.

8.6--Iodopenicillanic acid benzhydryl ester 6,6- Short 9 contains 1.92 g of benzene 8d solution with triphenyltin hydride 500Tn9 and azobisisonotyronitrile 1
0 m9 was added, and the resulting reaction mixture was heated in a nitrogen stream for 50 min.
C. and stirred for 1 hour. Hyrochloride (500 Iny) and nitrile (10 m9) were added, and heating was continued at -50°C for 6 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel using petroleum ether as an eluent with increasing ethyl acetate content. Fractions containing the product were collected and concentrated to dryness. This nuclear magnetic resonance spectrum (CDC13) shows the following signals. 7.50 (bs, 10H), 6.97
(S, IH), 5.66 (d, IH-AB-J=4.0
Hz)-5,44 (a-IH-AB-J=4,0Hz)
, 4.67 (s-IH) - 1,70 (s-3H) and 1.40 (s = 3H) ppm trifluoroacetic acid (0,5 ml) to 6-β-iodoRnidylanic acid benzhuman 9yl ester 80 μ of methylene chloride) and the reaction mixture was stirred for 60 minutes at room temperature. The mixture was distilled to dryness to give 76 cm of crude product.
I got it. Purification is carried out by silica chromatography.

EXAMPLE 49 A, Using the procedure of Example 48A starting from the appropriate nidilanic acid ester, the following compounds are prepared: B. Following the procedure of Examples 48B and C, the following compounds are prepared:
When synthesized using the esters in 9A as starting materials,
The following penicillanic acids are obtained.

6-β-fluorobenicif 7e; 6-β-chloropenicillanic acid; 6-β-bromo-nidylanic acid, 6-β-
Methoxypenicillane: 6-β-ethoxypenicillanic acid;
6-β-methylthiopenicillanic acid; 6-β-bromonidilanic acid sulfoxide; 6-β-fluoropenicillanic acid sulfoxide 9; and 6-β-chloronidilanic acid sulfoxide;
Acid sulfoxide.

Example 50 Ester The title compound was synthesized from 6-β-aminopenicillanic acid 4-aminopenicillanic acid 4-methoxybenzyl ester according to the procedure of Example 48A.

Ester The title compound was synthesized from 6,6-diiodobenicilla/acid 4-methoxybenzyl ester using the procedure of Example 48B. The magnetic resonance spectrum (CDC13
) showed the following jigsal. 7.36(d, 2H, A
A', XX', J=91(z), 6-9
5 (d, 2H+Lμ, XX', J=9.0Hz),
5.65 (d, IH, MUJ-4, 2Hz), 5.4
2(a, 1H,AB J=4.2)1z), 4.
58 (s, 18), 5.89 (s, 5H), 1.71 (
s, roH), 1.70 (s, 3H) and 1.
39 (s, filtration H) D'pHl.

C66-β-iodo” Nidylanic acid 6-β-iodopenicillanic acid 4-methoxybenzyl ester (90~) was dissolved in 2 ml of methylene chloride,
To this was added 11 m of trifluoroic acid and 6 drops of anisole. The mixture was stirred at room temperature for 5 hours and evaporated to dryness. The residue was chromatographed on silica gel using petroleum ether and ethyl acetate as eluents. The product-containing fractions were combined and concentrated to obtain 40 ml of the desired product. Nuclear magnetic resonance spectrum showed the following signals: Approximately 9 (bs.
, 18), 5.65 (d, IH, AB, J = 4.0Hz
).

5.39 (d, 1H, AB, J=4.0Hz), 4
．． 57 (s, 2H).

1.74 (s, 3H) and 1.57 (s, 3H)
.

Example 51 A. Using the process of Example 49A starting from the required tx penicillanate ester, the following compounds are prepared: B. Working Example 51 Using the compound as starting material, Example 48
According to the treatment method of B-F,; and C, the following 5 homologues “
The compound is synthesized: To a slurry of 700 g of toluene was added 29.5 g of bis(tri-butyltin)oxy)' and the reaction mixture was heated to reflux. The water distilled from the reaction mixture over about 45 minutes was azeotropically distilled off during this time. The remaining solvent was distilled off under vacuum at room temperature to obtain 78.7 g of the desired intermediate.

6-β-Bromopenicillanic acid sodium salt 6.6-)i
lomobeniciran ell-71L-butyltin ester soil O
0.4-tri-butyltin hydride was added dropwise to a 5 ml toluene solution of g at 55°C.

Heating continued for 6.5 hours. Thereafter, the solvent was distilled off, and the residue was dissolved in 25 TIL of chloroform. The chloroform layer was diluted with saturated sodium bicarbonate bath solution (2X 5Q ml
) to (le?m). The water washings were collected, pl-1 was adjusted to 1.5 with 6N hydrochloric acid, and the product was extracted with ethyl acetate.

The ethyl acetate extracts were combined and 1.24 ml of pxtyl acetate (24 mmol/CC) containing sodium 2-ethylhexane/acid was added (dried over 1Ut magnesium).

After stirring for 1 hour in the cold, the product was filtered and dried.

114■.

Example 56A Starting with the appropriate 6,6-disubstituted penicillanic acid and tin oxide, the procedure of Example 52A yields:
The following tin esters are produced; 6,6-ditulomopenicillanic acid triethyltin ester; 6,6-ditulomopenicillanic acid triethyltin ester;
“Fromopenicillanic acid diphenylbenzyltin ester;
6-bromo-6-chloro4-nidylanic acid triphenyltin ester; 6-z-bromo-6-10-brobenicilanic acid tri-propyltin ester; :
6-ioto9-b-chloronidylanic acid cyhendylphenyltin ester;6. s-Short 9 Venicilla 7mA-
'J phenyltin ester; 6-iodo'-b-bromopenicillane triethyltin ester; 6-promo b-methylthio is tri-n-butyltin dilanate ester; 6
-/'Romo b-chloropenicillane phototribe/dyltin ester sulfoxide'; 6,6-dipromohenicilla/
b) IJ -n-methyltin ester sulfoxide; 6,6-short dilanic acid tri-n-propyltin ester sulfoxide; and 6-promo b-chlorotanidyrane [1-IJ phenyltin ester sulfoxide side.

B. Using the reagents of Example 53A and the process of Example 52B, the following 6-β-substituted unisilane acids are prepared.

6-β-bromopenicillanic acid; 6-β-benicillanic acid; 6-β-iodonic acid, 6-β-chloropeninelanic acid sulfoxide; 6-β-bromopenicillanic acid sulfoxide 9; and 6 - β-Iodine with acid/acid sulfoxide.

Example 54 1-6 ml of methyl 2-chloroacetoacetate was added to a solution of 5.0 g of 6.6-siglomobenicillanic acid sodium salt in dimethylformamide) 100y, ffl, and the resulting reaction mixture was stirred at room temperature overnight. The mixture was soaked in 40M ice water.
and extracted with ethyl acetate. The organic layer was separated and washed successively with water, saturated sodium bicarbonate solution and brine. The organic layer was then dried with m&magnesium,
A dark oil (5,0,9) was obtained which was chromatographed on silica gel filter OO9.

The product-containing fractions of the eluate consisting of toluene/ethyl acetate (2:1 vol:vol) are collected and concentrated in vacuo to yield the desired product 4. Obtained OI.

B, 6-β-Glomovenicilla/6.6-β-Glomobenicilla under acid anhydrous conditions and nitrogen flow is a dry 17% solution of Nidylanic acid acetoacetic acid methyl ester 2.0.9)')-n-Butyltin hydride 1
．． The resulting reaction mixture was kept stirring at room temperature overnight. The benzene solvent was distilled off in vacuo, the residue was made into a slurry in hexane, and the insoluble matter was removed using silica gel 250.
Chromatography was performed using an eluent of F and toluene/ethyl acetate (5:1 vol:vol). Fractions containing the desired product were collected and evaporated to dryness under reduced pressure.

Aceto750 of 6-β-glomobenicillanic acid acetoacetic acid methyl ester 3.9i (synthesized by the above treatment method)
To Tnj4#ft, 2.1 g of sodium nitrite 10
Add m1 bath solution with stirring. After stirring at room temperature for 6 hours, the solvent was distilled off in vacuo, and the aqueous residue was extracted once with ether. Then the aqueous layer was acidified to pH 1.5 with 6N* acid,
Extract with ethyl acetate.

The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to obtain the desired product.

Example 55 Following the procedure of Example 54A and using the requisite 6,6-disubstituted penicillanic acid sodium salt as the starting material,
The following esters are prepared: 202R6 B Starting from the esters in Example 55A, the following compounds are synthesized using the procedure of the example in Example 54B: cl-.

I-□ Br-(3 CH8-0 C2H5S-□ Cl-1 1-1 Br-1 CH3S-1 Example 56 600 mJ of dry tetrahydrofuran The solution was cooled to -78°C and t-butylmagnesium chloride 56
．． 4'gLl was added dropwise under inert gas with vigorous stirring while maintaining the temperature at -60'C. After stirring for 60 minutes at 778°C, the solution was treated with formaldehyde vapor in a nitrogen stream,
Added up to 5 molar equivalents. The reaction was carried out at -78°C with 5.7 mL of acetic acid.
- was terminated by dripping over 25 minutes. The reaction solution was warmed to room temperature and concentrated in vacuo. 200a of water and 200ml of ethyl acetate were added to the residue. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined, washed successively with water (200 mA, 5% sodium carbonate water 20 omi) and brine (2007 u/+), and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. A-6 of the target compound has 3 epimers
8.2g was obtained.

B+6-fluoromethyl-6-turomo R nidylanic acid benzyldiethylaminosulfur trifluoride 6.2g
A solution of 80ml of dry methylene chloride was cooled to -78°C and placed in a nitrogen stream, and 8.0ml of bevezyl 6-promo-6-bidroxyzunisilane was added. 920 ml of methylene chloride of M' and 6.2 ml of pyridine solution were added. The resulting reaction mixture was stirred for another 45 minutes while cooling.
It was then warmed to room temperature.

The reaction solution was mixed with water (2 x 100 TLl) and saline solution (2
X100 mA) and dried over magnesium sulfate. The organic layer was concentrated to dryness in vacuo. The residue (64 g) was dissolved in toluene-ethyl acetate (4:1) for 20 minutes and subjected to column chromatography on silica gel, using toluene-ethyl acetate (4:1) as the eluent. Collect 68 from fraction/12 and concentrate to dryness to produce *3.5
4.9 was obtained.

6-Fluoromethyl-6-tulomo was added to a solution of 6.5 g of benzyl nidylanoate in dry benzene 3QmA in a nitrogen stream.
)! 2.28 Tnl of J-n-butyltin hydride were added and the resulting reaction mixture was heated to reflux.

After 1.5 hours the reaction mixture was cooled to room temperature and concentrated to give 2.1 g of an oil. The residual oil was dissolved in toluene-ethyl acetate (4:1) and subjected to silica gel column chromatography using toluene-ethyl acetate as the eluent. Fractions 46 from 6 filters were collected and concentrated to yield 1.8 g of product as an oil.

D. For 6β-fluoromethyl, 485 my of benzyl 6β-fluoromethylpenicillanate was added to 20 ml of pencil sulfonidilanate/methylene chloride, and the resulting solution was cooled to 0°C. m-chlorobenzoic acid (85%) (8
53m9) was added in portions and the reaction was stirred cold for 2 hours and then continued stirring at room temperature overnight. The solvent was distilled off in vacuo, and the residue was partitioned between ethyl acetate and water (1:1). The pH of the mixture was adjusted to Z2 with a sodium bicarbonate bath solution, and enough hydrogen sulfite (IJ) was added until the starch iodine test was negative. The organic layer was separated, washed successively with saturated sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate. When the solvent is distilled off under reduced pressure, the product 400z
We obtained η.

E, 6β-fluoromethylpenicillanic acid sulfone 5% palladium-calcila carbonate a3651n9 in advance 5Q
psi (pound per 5 square 1 inch
Pressure units - Lb/in) After reducing with hydrogen for 20 minutes, add to a 20 m suspension of methanol-water (1:1).
6β-fluoromethyl 4benzyl sulfone nidylanate 3
56 mA was applied and the mixture was brought to an initial pressure of 48 p in a hydrogen stream.
The mixture was shaken with si for 1 hour. The catalyst was filtered off and the filtrate was lyophilized to give the final product 2207'19 as a calcium salt. Nuclear magnetic resonance spectrum (D20) showed the following signals. 1.45 (S, 3H), 1.57 (s
, 3H), 4.2(s, IH), 4.4 and 4.9(
a, m, IH), 5.1 (d, IH, J=4Hz),
4.6 and 5,4 (d*m, 2H) 99
m0 Example 57 10 g of benzyl rhomelomo-6-hydroxymethylbenicillanate (Example 56A), 6.9a of tri-n-7'-thyltin hydride and traces of azobisinnotyronitrile of benzene 20 Qm/! 5 in a nitrogen stream
Refluxed for an hour. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with hexane and chromatographed on silica gel, eluting with toluene/ethyl acetate (2:1) to give the desired product 7.5F.

B, benzyl 6β-chloromethylpenicillanate 1,28 g of benzyl 6β-hydroxymethylbenylanate and 88 g of triphenylphosphine, 5 m of carbon tetrachloride
, 1 solution was stirred in room giA for 2 hours. The reaction mixture was treated with diethyl ether, and the solid precipitated from the resulting slurry was collected and chromatographed using 75 g of silica gel and toluene-ethyl acetate as eluents.

Fractions 20 to 24 were collected and concentrated to yield 658 liters of the desired product. The nuclear magnetic resonance spectrum is shown below. 1.42 (s, 3H), 1.6 (a, 6H),
3.86 (m, 3H), 4.4 (s, iH), 5.18
(s, 2H), 5.4 (d, IH, J=4Hz)
and 7.37 (s, 5H) pm a 6β-chloromethylbenicilla/acid Hensyl 200 da methylene chloride l-"3Qd solution was heated at 85% m
-600 ml of chloroperbenzoic acid were added in portions. The resulting reaction mixture was stirred overnight and concentrated to dryness. Water the residue
Partition of ethyl acetate (1:1) and adjust pH to hydrogen carbonate)
7-2 at IJum. Adjusted to. Sufficient sodium bisulfite was added to destroy excess peracid, and the organic layer was separated, washed with saturated sodium charcoal solution and saturated brine, and dried over magnesium sulfate. The solvent was removed by vacuum distillation to obtain 189 ml of product in the form of an oil. The nuclear magnetic resonance quill (CDCA'3) is shown below. 1
．． 6 (s, 3H), 1.52 (s, 3H), 3.6 (m
, IH), 3.9 (m, 2H), 4.5 (s, IH),
4.59 (C4゜1H, J=4Hz), 5.22 (
ABq, 2H, JAB=12Hz) and 7.55
(s +5H)Dpm.

D-6β-Chloromethylpenicillanic acid sulfo 15% palladium-calcium carbonate 200 μm was mixed with 5% palladium-calcium carbonate, hydrogen was introduced in advance at 50 psi for 20 minutes, and methanol-water (1:1) 20 mA Mf was added.
9 m of benzyl sulfone 6β-chloromethylbenicillanate was added to the fia, and the resulting suspension was shaken in a stream of hydrogen for 40 minutes at an initial pressure of 50 psi. The catalyst was filtered, and liquid E was distilled off under reduced pressure to dryness, yielding a final product of 125η as a calcium salt.

The nuclear magnetic resonance spectrum (D20) was shown below.

1.41 (s, 3H), 1.57 (s, 3H),
4.0 (m, 3H), 4.22 (S, IF () and 5
．． 05 (a, IH, J=4Hz) ppm.

Example 58 Benzyl 6β-hydroxymethylbenisidate 830
yy and carbon tetrabromide 2.2 g methylene chloride) 5
ml solution was cooled to 0-5° C. and a 5M solution of triphenylphosphine t 47.9 in methylene/chloride was added to this solution in a nitrogen stream. After stirring for 1 hour when cold,
The reaction mixture was chromatographed using silica gel and methylene chloride as an eluent. fraction 4
11 were combined and concentrated to give 580 ml of oily product.

Nuclear magnetic resonance (CDC73) was shown as follows.

1.42 (s, 3H), 1.6[] (s, 3H), 3.
6 (m, 2H), 3.9 (m, 1H), 440 (
S, IH), 5.18 (S, 2H), 5.4 (d, iH
, J = 4 Hz) and 7.37 (s, 5H) ppm.

13.6β-bromomethylpenicillanate benzyl sulfone 6β-bromomethylpenicillate benzyl 250〃1
The methylene chloride (g)'30d solution was cooled to 0-5°C, placed in a nitrogen stream, and 85% m-chlorobenzoic acid 330In9 was added. After stirring for 2 hours at 0-5°C, the reaction mixture was kept stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was partitioned between water and ethyl acetate (1:1). The pH was adjusted to 72 with a saturated aqueous solution of sodium hydrogen carbonate, and the remaining peracid was decomposed by adding IJium. The organic layer was washed with a saturated sodium hydrogen carbonate solution and saturated brine, and then dried over magnesium sulfate. did. The solvent was distilled off in vacuo to obtain 220 y of product as an oil.

The nuclear gas resonance system (○DC73) is shown below.

1.29 (s, 3H), 1.55 (s, 3H), 6.5
(m, 2H), 5.9 (m, IH), 4.5 (S, IH
), 4.59 (d, IH, J=4Hz), 5.22 (A
B, 2H.

JAB = 12Hz) and 7.65 (s +
5H) ppm.

C16β-bromomethyl is sulfone nidilanate 6β-bromomethyl to benzyl sulfone nidilanate 1290mg
and 300 Da of 5% palladium-calcium carbonate was previously reduced with hydrogen at 50 psi for 20 minutes, and methanol-water (
1:1) 20ml of suspension in a hydrogen stream at an initial pressure of 50ps
Shake for 35 minutes. The catalyst was filtered, the methanol was removed in vacuo from Part F, and the remaining aqueous solution was extracted with ethyl acetate, yielding 200 m9 of product as a calcium salt which was lyophilized.

Nuclear magnetic resonance (D20) is shown below. 1.4 (s.

3H), 1.60(s, 3F(), 3.8(m, 2H)
, 4.0 (m, IH), 4. ．． 2. (s, IH)
and 5. j), (d, lH.

J-4Hz) ppm.

Example 59 6β-chloromethylpenicillanic acid 5% palladium-calcium carbonate 503 m9 in advance
psi, and reduced with a hydrogen stream for 20 minutes.
= benzyl silanate 300 n+9 (Example M 57B) was added and the resulting suspension was heated to an initial pressure of 50 psi in a hydrogen stream.
Shake for 45 minutes. A further 600 m9 of catalyst was added and hydrogenation continued for 65 minutes. The catalyst was filtered and methanol was removed from the slurry in vacuo. The remaining water was extracted with ethyl acetate and then lyophilized to give the product as a calcium salt.
I got 011'9.

The nuclear magnetic resonance spectrum (D20) is as follows, 1.5
2 (s, 3H), 1.62 (s, 3H), 3. '? 5(
m.

3H), 4.2 (s, IH) and 5.4 (a, I
H, J -4Hz) ppmO In a similar manner, 6β-fluoromethylpenicillane d and 6β-bromomethylpenicillanic acid were prepared using benzyl 6β-fluoromethylpenicillanate and 6β-bromomethylbenicilla/benzyl as starting materials, respectively. Manufactured.

Example 60 85% m of benzyl oxide 6β-fluoromethylpenicillanate 623 to a solution of dry methylene chloride 257d at 0°C
- Add 240 mg of chloroperbenzoic acid in portions. After 2 hours, the cold bath is removed and the reaction mixture is left stirring at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with acetic acid and water (1:1).
) at pH 7.5. The organic layer is separated, washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The desired product is obtained by distilling off the solvent.

B. 6β-fluoromethylpenicillanic acid sulfoxide 5%/ξradium-calcium carbonate 400η was preliminarily charged with hydrogen for 20 minutes, and 6β-fluoromethylpenicillanic acid benzyl 400μ and methanol-water (
1:1) 20d suspension in a hydrogen stream at an initial pressure of 50 psi
Shake for 1 hour. The catalyst is passed through and methanol is distilled off from the filtrate. The remaining water bath solution was extracted with ethyl acetate and 6N
Acidify pl (PL) to 1.5 with hydrochloric acid. Ethyl acetate is added to separate the organic and stratified layers, washed with several baths of saturated saline, dried with magnesium sulfate, and the solvent is distilled off in vacuo to remove the desired compound. Obtained as free acid.

When benzyl 6-chloromethylpenicillanate or benzyl 6-tulomomethylbenicillanate is used as a starting material and the above-mentioned treatment is carried out, 6-chloromethylpenicillanic acid sulfoxide and 6-bromomethyl nidylanic acid sulfoxide are obtained, respectively.

Example 61! / m-chloroperbenzoic acid (11.8 g) and 6β-hydroxymethyl benzyl dilanate (Example 57A)7.
5 g of Mef-L/7 Chlorite" (600 ml) was added to the solution which had been cooled to 0-5°C. The solution was then warmed to room temperature and stirred for 5 hours. The solvent was removed in vacuo and the residue was partitioned between 200 ml of water and 20 Qm of ethyl acetate.

The pH of the mixture was adjusted to 7 by adding saturated thorium bicarbonate solution. and hydrogen sulfite) IJ
A sufficient amount of aluminum was added to make the peroxide test (starch-iodine) negative. The layers were separated, the aqueous layer was washed with ethyl acetate, the organic layer and washings were combined, washed successively with water, 5% sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a foam, which was chromatographed on silica gel (chloroform-ethyl acetate 20:filtration) to yield the desired intermediate 6.5y.

Sulfone water - 1 /- / l / (1: 1) (7) 3 Qm
5% z'' radium/calcium carbonate 3.5.!i' was added to the catalyst, the catalyst was previously reduced at 47 tDsi in a hydrogenation apparatus, and 6β-hydroxymethyl R benzyl sulfone dilanate was added to the resulting catalyst. .5g methanol 1
Add 3m13 and 20d of tetrahydrofuran,
The mixture was shaken under a stream of hydrogen at 48 psi for 30 minutes. The catalyst was filtered through a filter and the filtrate was concentrated in vacuo.

The remaining water bath solution was extracted with ethyl acetate (2X1007111) and lyophilized to yield 6.0 g of the desired product as a calcium salt.

Nuclear magnetic resonance spectroscopy (CDC13-free acid) was shown below. 1.49 (s, 3H), 1.6 (S,
3H) 4.1 (m, 3H), 4.32 (s, IH) and 4.9 (d.

1H, J=4Hz) ppm.

Example 62 6β-Hydroxymethyl R Nidylanic Acid Sulfoxide A, 6β-Hydroxymethyl Benzyl Nidylanate (
Example 57 A) A solution of 7.5 g of dry methylene chloride in 500 TLl was cooled to O-5°C and added to m
- Add 5.9 g of chloroperbenzoic acid in portions.

The solution was then warmed to room temperature and stirred overnight (.

The solvent is removed in vacuo and the residue is treated with water-ethyl acetate (1:1). Adjust the pH of the mixture to Z2.

Then, sodium bisulfite is added to decompose the remaining peracid. The organic layer is separated, washed successively with water, 5% sodium carbonate solution and saturated sodium chloride solution, and dried over hTJi 2 magnesium. The solvent is distilled off under reduced pressure to obtain the desired product.

Example 66 A 10 d solution of 1.0 g of pivaloylox 6β-hydroxymethylpenicillanic acid sulfone sodium salt in dimethylformamide was added to 6β-hydroxymethyl.
Cool to -5°C and add 0.5 chloromethyl pivalate to it.
2 rnl was added. After stirring at room temperature for two nights, the reaction mixture was poured into a water-ethyl acetate mixture. Separate the ethyl acetate layer and add water (3x100m, A) and brine (3x5Qm
A) and dried over magnesium sulfate. When the solvent is distilled off in vacuo, the product becomes an oil with a concentration of 1.1, ? Obtained.

Nuclear magnetic resonance (CDC13) shows the following signals.

1.27 (S, 9H), 1.42 (s, 3H), 1.6
．． (s.

31(), 2.9(bs, IH), 4,4. (m, 3H
), 4.58 (S, IH), 4.75 (m, IH) and 5.82 (AB.

2H, 8A-8B = 16H2) ppm.

Example 64 When the treatment of Example 63 is carried out using the appropriate 6β-hydroxymethyl acid, sulfoxide or sulfone, and the necessary halide as starting material, the following intermediate compound is prepared: Q- CHOCCH O-CH202CCH(CH3)2 0-CH(CH3)020CH3 0-CH202C(CH2)4CH3 0-C4H302* 0 -C(CH3)202CO(CH2)2CH
31-CH20□CC(CH3)5 l-OH(CH3)02CoC2H5 1-C(CH3)202C○(CH2)2GH31-G
HQ+1-CH2O. CCH(CH3)2 l-CH(CH3)02CCH3 2-CH202CCH3 2-CH(C;H3)O□C(X;2H52-C(CH
3) 202CCH3 2-CH20□C0CH(CH3)2 2 -CH○* 2-CH202C(CH2)4CH3 2-C4H502+ 2-C3H502# *4-crotonolactonyl γ-butyrolactonyl/-4-yl# 6- Phthalidyl Example 65 Rusulfone diethylaminosulfur trifluorite''6.2
80g of dry methylene chloride solution at 78°C
C., placed in a room temperature air stream, and added 6β-hydride 80oxymethyl to pivaloyloxymethylsulfone dilanate (Example 63) 7.5.9 Pyridine 3.2
Methylene chloride containing ml) 20mA! Add the bath solution. The reaction mixture is stirred cold for 45 minutes and allowed to warm to room temperature. The reaction solution is washed with water (2×100 atl) and saturated saline bath (2×100 α) and dried over 'AH magnesium. Separate the organic layer and concentrate to dryness. The residue is subjected to silica gel chromatography, and the fractions containing the product are collected and sieved to obtain the desired substance.

Example 66 6β-chloromethyl is pivaloyloxymethytriphenylphosphine nidilanate 1.88,? A solution of 6β-hydroxymethyl and pivaloyloxymethyl nidylanate (Example 64) in carbon tetrachloride (6 ml) was stirred at room temperature for 6 hours. The reaction mixture is treated with diethyl ether and the solid obtained is filtered and chromatographed on silica gel. Fractions containing the target product are collected and concentrated in vacuo to obtain the target product.

Example 67 Acetoxymethyl 6β-bromomethylpenicillanate 6β
-acetoxymethyl hydroxymethylpenicillanate 7
A methylene chloride solution of 88rn9 and carbon tetrabromide 2,2I is cooled to 0°C and placed in a nitrogen stream, and a 5mnJ solution of triphenylphosphine 1,47.9 methylene chloride is added dropwise thereto. After 2.5 hours of stirring while cooling, the reaction mixture is treated with diimpropyl ether, the solid is filtered off and chromatographed on silica gel.

Fractions containing the target substance are collected and concentrated in vacuo to obtain the desired product.

Example 68 Starting from the appropriate 6β-hydroxymethylpenicillanic acid ester and using the method of the indicated examples, the following compounds are prepared: Rn Process R13*4-Crotonolactonyl* γ-Butyrolactone-4-yl # 6-Tuclidine Example 69 Ester 6β-hydroxymethyl to herring: /1172.31
A mixture of g and phenacyl bromide methylformamide-tetrahydrogen, 90 norane, and 40 g of a 1:1 mixture was cooled to 0'C, and 1,4 rnl of triethylamine was added dropwise thereto over 15 minutes. The cold solution was stirred for 6.5 hours and then added with 125+ lu of ethyl acetate and a saturated water bath solution of sodium bicarbonate.
Process with y. Separate and discard the aqueous layer, and pour fresh water into the organic layer. The pH is adjusted to 5.0 with 6N hydrochloric acid, the organic layer is separated, washed with brine, dried over chlorinated magnesium, and concentrated in vacuo to obtain the desired product.

In the same manner as in Example 56B, a solution of 62 g of diethylamine sulfur trifluoride in 80 ml of methylene chloride was placed in a nitrogen stream at -78 DEG C., and 6.beta.-hydroxymethyl was added to a solution of 6.98 g of phenacyl phenylanoic acid ester. Pour 25ml of methylene chloride containing 3, 2a into a gallon. Stir the resulting reaction mixture in the cold for 45 minutes, then warm it up to room temperature. Add the reaction bath solution to water (2X 100TLl) and Oyohi 9fO food Jm.
After washing with water (2×100 mg), dry over magnesium sulfate. Separate the organic layer and concentrate to dryness in vacuo.

The residue is subjected to silica gel chromatography to collect the fractions containing the desired product and concentrated to obtain an intermediate product.

The above condensate was dissolved in 25 ml of dry dimethylformamide and treated with a solution of potassium thiophenoxite "3751+lj7 in 41 liters of dimethylformamide. After stirring at room temperature for 2 hours, the reaction mixture was dissolved in saturated sodium bicarbonate. Aqueous solution 63ml
Add inside. Add ethyl acetate (601 nl), separate the organic layer and add more ethyl acetate. The pi of the aqueous layer was adjusted to 1.5 with 6N hydrochloric acid, and the 1st layer was separated, washed with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off in vacuo to obtain the desired product.

Example 70 A, Using the procedure of Example 69A starting with the appropriate 6β-hydride 90 oxymethyl R nisila/acid sulfoxide 9 or sulfone and the necessary α-halomethylcarbonyl reagent, the following compound 5 is prepared. Will be: n R,・ 1 -CH2COC6H5 2-CI-42CoC6H5 0-CH3COCH3 2-OHGOGH 〇 -〇H2C0CH2CH31-CH2GO
CH2CH3 Q -Gi(CN O-G1712G02CH3 1-OHCo CH □ -OH2co.CH2CH2CH30-
CH2COCH(,CH3)2 2 -CH2COCH(CH3)2i
-0H2C○2C2H50-OH2C○(CH2)
2CH3 1-OH2co(OH2)2CH3 2-OH2co(CH2)2GH3 B, using the esters obtained from Examples 69A and 70A as starting materials, the following intermediates are synthesized using the method indicated. : ClCH2-2-OH2co(CH2)2CH3 Using the esters of Example 66C8 and Example 70B as starting materials and using the treatment method of Example 1S9G, the following R nidylanic acids are synthesized: 6β-chloromethyl penicillanic acid, 6β-chloromethy,
v 'Nicilla/acid sulfone, 6β-fluoromethylpenicillanic acid sulfoxide, 6β-fluoromethylpenicillanic acid, 6β-bromomethylpenicillanic acid, 6β-
Zullomomethyl deepnidylanic acid sulfoxa 4” door, 6β-
Bromomethylbenicilla/acid sulfone, 6β-chloromethylbenicilla 7 (fit sulfoxite 16 and 6β-fluoromethylpenicillane [sulfone]).

Example 71 6β-Hydroxymethyl is prepared by adding 200 g of methylene chloride of 2.47.9 nidylanic acid sulfoxide and 1,0 g of hetrimethylamine, and the resulting reaction mixture is cooled at 0°C. Chloro@ethyl acid (1,1& ) 1
Add dropwise over 5 minutes and maintain reaction at 0°C for 60 minutes. A solution of penzaldehyde oxime ('i,2y) in 1Qml of dry acetone is added and stirring is continued for 2 hours. The reaction mixture is allowed to warm to room temperature and stirring is continued for an additional 2 hours. The reaction mixture is filtered and concentrated to dryness. The residue was dissolved in ethyl acetate (1
0°rnl) and water (5011Ll). The aqueous layer is separated and the organic layer is washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The desired product is obtained by distilling off the solvent in vacuo.

○-(6β-HydroxymethylRnisilanoyl)penzaldehyde 2.8 g of oxime sulfoxide and 4.19 g of triphenylphosphine 1Q
ml solution was stirred at room temperature for 2.5 hours.The reaction mixture was treated with diethyl ether and the solid was dissolved into F.
, chromatographed on 150 g of silica gel.

The fractions containing the product are collected and concentrated to dryness in vacuo.

For C16β-chloromethyl, dissolve the above concentrate 8I in dimethylformamide and add 107 d of a solution of potassium thiophenoxylate (660) in the same solvent. After stirring at room temperature for 2 hours, the reaction mixture is saturated. Add to sodium carbonate aqueous solution. Extract the aqueous layer with ethyl acetate 75.d and separate the organic layer. Adjust the DH of the aqueous layer with Soil 5 and 61i hydrochloric acid and extract with ethyl acetate. Separate the organic layer. , dried over sodium sulfate, and evaporated to dryness in vacuum to obtain the target compound.

Example 72 A: Using the procedure of Example 71A starting from 4-(6β-hydroxymethyl) sulfoxide or sulfone, the following compound is synthesized: 0-(6β-hydroxymethyl R nisilanoyl)penzaldehyde oxime and Q-(6β-hydroxymethyl is nisilanoyl)penzaldehyde oxime sulfone.

B. Using the esters obtained from Examples 71A and 72 as starting materials, the following compounds are synthesized using the indicated procedure: C1 Performed using the esters of Example 72B as starting materials. Using the procedure of Example 71G, the following compounds are synthesized.

6β-fluoromethylpenicillanic acid; 6β-fluoromethylbenicillane/acid sulfoxide; 6β-fluoromethyl Rnidylanic acid sulfone; 6β-chloromethylpenicillanic acid; 6β-chloromethylpenicillane sulfone;
- Bromomethylinisilane sulfoxide and 6
β-Bromomethyl nidylanic acid sulfone.

Example 73 Diphenyldiazomethane (19,4,1 ether 10
0a solution to 6β-hydroxymethyl, dilanic acid 2
3.1 Add to a 200M solution of & in tetrahydrofuran. After 2 hours, the solvent is removed in vacuo, the residue is dissolved in methylene chloride and washed with saturated sodium carbonate solution. The organic layer is dried over magnesium sulfate and evaporated. The crude product is triturated with a mixture of ether and petroleum ether (boiling point 40-60°C). Then, it is filtered to obtain the desired intermediate.

The bath solution of benzyl 6β-hydroxymethylbenicinate 1.03 &# and methylene chloride of carbon tetrabromide 2,2I was cooled to 0°C, placed in a nitrogen stream, and triphenylphosphine was added to it. 1.47. Drop 6 ml of methylene chloride solution of ? at 0°C.
After stirring for 5 hours, the reaction solvent is removed in vacuo and the residue is chromatographed on silica gel. The fractions containing the product were collected and concentrated to dryness.C16β-bromomethylnidylanate trifluoroacetic acid (0:5m) was added to a solution of 80ml of 6β-bromomethylnidylanate henchhydryl in methylene chloride, and the reaction mixture was filtered at room temperature. Stir for 0 minutes. The mixture is distilled to dryness to obtain the crude product. Is this thing silica gel evening +? Purify by mudgraphy.

Example 74A Starting with the appropriate 6β-hydroxymethylpenicillanic acid sulfoxide 9 or sulfone and diphenyldiazomethane and using the procedure of Example 76A, the following intermediate compounds are prepared: 6β- Herbal) "Roxymethyl Penicilla 7rl 11. Benzhydryl sulfoxide and 6β-hydroxymethyl is benzhydryl sulfone dilanate.

B. Using the appropriate benzhydryl 6β-hydroxymethylpenicillanate, the following compounds are synthesized by the indicated procedure: ClCH21 Example 66 Using the appropriate ester obtained from C8 Example 74B, the following compounds are synthesized: The following compounds are synthesized by the treatment of fluid 76G: 6β-fluoromethylpenicillanic acid; 6β-fluoromethylbeny7lanic acid sulfoxide; 6β-chloromethyl 4-acid sulfoxide; 6β-chloromethyl R
6β-bromomethylpenicillanic acid sulfoxide; and 6β-bromomethylbenicillanic acid sulfone.

Example 75 6β-hydroxymethyl is nidylanic acid sulfone 2.6
g and 4-methoxybenzyl bromide 2.01,9
Dry dimethoxyformamide tetrahydrofura/1
：1 Mixture 5Qmli liquid was cooled to 0°C, and triethylamine soil was added dropwise over 20 minutes. The solution is stirred in the cold for 4 hours and then treated with 150 ml of ethyl acetate and 125 ml of saturated aqueous sodium bicarbonate solution. Separate and discard the aqueous layer and add fresh water to the organic layer. p) Adjust 1 to 5.0 with 6N hydrochloric acid, separate the organic layer, wash with saline solution, dry over magnesium sulfate, and concentrate in vacuo to obtain the desired product.

A cold solution (-78°C) of 3.2 g of “diethylaminosulfur trifluorite” in 85 ml of dry methylene chloride.
was placed in a nitrogen stream, and 6β-hydroxymethylpenicillanic acid 4-methoxybensyla, 0,? +7) Add 25 ml of methylene chloride (containing 6.2 ml of pyridine) solution. The resulting reaction mixture was diluted with warm water (2X10
0d) and saturated brine (2 x 100 rule) and dried over magnesium sulfate. The organic layer is concentrated to dryness to obtain an intermediate product.

6β-7) L/olomethylbenicillanic acid 4-methoxybenzyl sulfone (90■) womethylene chloride 2rI
Dissolve in Ll and add thereto fi i ml of trifluoro vinegar and 6 drops of anisole. The mixture is stirred at room temperature for 5 hours and evaporated to dryness. The residue is chromatographed on silica gel. The product-containing fractions are combined and concentrated to filter out the desired product.

Example 76 A + The following intermediates are prepared by adapting the procedure of Example 75A using the appropriate 6β-no-idroxymethylbenicillanic acid sulfoxide or sulfone and the necessary halide: OCH-CH-G6kA, -OCR-CH-GH- 6565 0H-GH-4-CH30C6H4- D C) (3GH-4-CH30C6) (4-OH
-G H-4-CH30C6H4-1H-H-4-CH
30G6H4- i H-CH-4-CH30C6H4-1C6H5
-06H5-CH- I CH3-CH-4-CI QCH-i
CH-CH-CH-2Ck(-OH-4-CHQCE(-2C6H5-C6H5-C6H5-B) Starting from the esters in Example 76A, the following compounds were prepared using the indicated procedure. : FeI2- Q Cl3-06H5-C6H5-Example 6 FC) 1- Q G H-CH-CH-Example 6
c7cH2-01(f CH3-4-aH30C
6H4-Example product GiGH2-0GH3-Cf (3-4
-0H30C6H4 Example 668rGH2-D H-
C6H5-4-0H30C6H4-Example 67Br(J
-Q CH-G H-CH-Example 67F'CH2-
1H-H-4-CH30C6H4-Actual flow example 65FCH2
-1CH3-06H5-C6H5-Actual flow example 65czcu
2-I H-CH3-4-0H30C6H4-Example 66BrGH2-1C6H5-C6H5-C6H5-
Example 67FCH2-2C6H5-C6H5-C6H5
- Example 65FCH2-20H3-CH3-4-CH3
0C6H4 Example 65C7CH2-2CH3-0f (
3-4-0H30C6H4 Example 66BrCH2-2
0H3-CH3-4-CH30C6H4 - Example 67B
rCH2-2C6H5-C6H3-C6H5-'4 Example 67C1 Using the esters in Example 76B, the following compounds are synthesized by processing Example 75G: 6β-fluoromethylpenicillanic acid: 6β-chloro Methylpenicillanic acid; 6β-bromomethylpenicillanic acid; 6
β-fluoromethylpenicillanic acid sulfoxide; 6β
-Chloromethylpenicillanic acid sulfoxide 8;6β-
Bromomethyl is nidylanic acid sulfoxide; 6β-fluoromethyl is nidylanic acid sulfone: 6β-chloromethylpenicillanic acid sulfone; and 6β-bromomethyl o
= sulfone silane.

Example 77 6β-hydroxymethyl is sodium nidylanate j4
3.22,? dimethylformamide)'IC1[1m
6d of methyl 2-chloroacetoacetate was added to AmW, and the resulting reaction mixture was stirred overnight at room temperature. The mixture is poured into 4001 nl of ice water and extracted with ethyl acetate. The organic layer is separated and washed successively with water, saturated aqueous sodium carbonate solution, and brine.

The organic layer is dried over magnesium sulfate, concentrated and chromatographed on silica gel. Fractions of the eluate containing the desired product are collected and concentrated in vacuo to obtain the desired product.

B, 6β-Bromomethyl Nidylanic Acetoacetic Acid Methyl ester 6β-Hydroxymethylpenicillanic Acetoacetic Acid Methyl ester 897 μm and 2.2 g of carbon tetrabromide in a 5 mg methylene/chloride bath solution were cooled to 0°C and heated in a nitrogen stream. Then, a solution of methylene chloride 7TLe@ of triphenylphosphine 1.47.9 was added dropwise thereto. O℃ above 5
After stirring for an hour, the reaction is allowed to warm to room temperature and concentrated to dryness.

The residue is subjected to silica gel chromatography to combine the two columns (containing the reactants) and concentrated to obtain the desired intermediate.

c, 6β-bromo-nidylanic acid 6β-bromomethylpenicillanic acid acetoacetic acid methyl ester 411 (produced by the above treatment method) a-I=)one 5Q
A solution of 2.1 g of sodium nitrite in 10 me of water is added to the al solution with stirring. After stirring for 6 hours, the room temperature solvent is distilled off in vacuo, and the remaining aqueous layer is extracted once with ether. The aqueous layer is acidified to pH 1.5 with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated under reduced pressure to obtain the desired product.

Example 78 A + The following compounds were prepared using the procedure of Example 77A starting with the appropriate 6β-hydroquine methyl ester, lanic acid, sulfoxide or sulfo/ and the necessary 2-chloroacetoacetate. : n R6 T~-1 □ C2H5 [1n-C3H7- 0' n-C3H7- 1CH- C2H3- I n''' C3H72CH3 2, n-C3H7 21''' C3H7 B, using the esters of Example 77A , the following intermediates are synthesized by the treatment of the instructions: 02R6 Rn Rs Procedure C1 Starting from the esters in Example 78B and using the treatment of Example 77G, the following compounds are prepared: .

Nidyrane relative to 6β-fluoromethyl; 6β-chloromethylpenicillanic acid; 6β-bromomethyl Rnisila/acid; 6
β-Bromomethylpenicillanic acid sulfoxide; 6β-fluoromethylpenicillanic acid sulfoxide; 6β-chloromethylpenicillanic acid sulfoxide; and 6β-zlomomethylbenicillanic acid sulfone.

Example 79 6β-Hydroxymethyl was prepared by adding 1.08 g of triethylamine to a 40 ml solution of 2.51 g of dilanic acid in methylene chloride, and treating the bath liquid with 1.289 g of dimethoxychlorophosphine. The solvent was distilled off in vacuo and the residue was dissolved in dry diethyl ether for 12 minutes.
Process with 5d. Insoluble triethylamine salt V salt is filtered and ether is distilled off under reduced pressure to obtain the desired intermediate.

B, 6β-chloromethylpenicillanic acid dimethoxyphosphine ester 6β-hydroxymethylpenicillanic acid dimethoxyphosphine ester 1.29, ? Triphenylphosphine 1889 was added to 5 liters of carbon tetrachloride containing 1,889 liters of carbon tetrachloride, and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture is treated with diethyl ether (751 nA) and the resulting slurry is filtered and chromatographed on silica gel. The fractions containing the desired product are combined and concentrated in vacuo to yield the intermediate.

Dissolve the above concentrate in 10 Tnl of ethyl acetate-water and adjust the pH
Adjust to 5. Stir at room temperature for 20 minutes, separate the organic layer,
Dry with magnesium sulfate and concentrate to dryness to obtain the desired product.

Example 80 Example 7 using 6β-hydroxypenicillanic acid, sulfoxide or sulfo/ corresponding to A-38 as a starting material
Using the procedure of 9A, the following compounds are prepared.

0P(C6H5)2 0P(0-n-CyH7) 20P(
C2H5)20 p(n-C3H7)20
P(CH3)C6H5I
P(OCH3)21P(OC2H5)
C6H5 1P(OC2H5)2 1P(C6H5)2 2P(OCH3)2 2P(C2H5)C6H5 2P(OC2H5)CH3 B, using the esters synthesized in Example 80A and the indicated treatment method, the following intermediate compound is synthesized: BrCH2
-2P(C2H5)C6H5 Example 67G, Example 80
Taking care of the esters synthesized in B, the following compounds are synthesized by the procedure of Example 79C: 6β-chloromethyl with Nidyranllt, 6β-chloromethylbenicilla/acid sulfoxide; 6β-chloromethyl Penicillanic acid sulfo/: 6β-bromomethylbenicillanic acid: 6β-bromomethylhenicillanic acid sulfoxide; and 6β-bromomethylpenicillanic acid sulfone.

Example 81 A solution of 40 ml of dry methylene chloride containing g of diethylaminosulfur trifluoride was placed in a nitrogen stream at -78°C to prepare 6β-no-idroxymethylbenicilanic acid dimethoxyphosphine ester (Example 79A) 3.2
3 g and 16 ml of pyridine methylene chloride"i
Add oy solution to it. The reaction mixture was heated to -78°C for 4 hours.
Stir for 5 minutes and then allow to warm to room temperature. The reaction mixture was then treated with 100 g of water and the pH was adjusted to 6N to 540.
Adjust A with hydrochloric acid. The organic layer is separated, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The final product is purified by chromatography on silica gel.

Example 82 A, 6β-hydroxymethylbenicilla/acid 3.5
-C6β-hydroxymethylpenicillane ff2.3
．． Triethylamine 1. to the dry methylene chloride 200117 solution of 9. Add Og and mix the resulting solution with 0-5°
Cool to C. Ethyl chloroformate (1.1 g) is added portionwise to the reaction mixture over 15 minutes. This reaction was maintained at 0°C for 60 minutes, then 3.5-E>-t-
Treat with 7' chill/sil alcohol 2.361. After stirring for 2 hours in the cold, the reaction mixture was warmed to room temperature and diluted with water (75
7d) is added to the reaction mixture and the organic layer is separated, dried over sodium sulfate and concentrated in vacuo to yield the desired compound.

6β-hydroxymethylpenicillanic acid 3.5-di-t
-butyl-4-hydroxybenzyl 1.7I and triphenylphosphine: / 1.88 g carbon tetrachloride 5
The solution was stirred at room temperature for 2 hours. Treat the reaction mixture with diethyl ether and filter the resulting slurry.

C06β-chloromethyl-nidylanic acid The solid residue obtained above was mixed with tetrahydrofuran-water (1:1).
and carefully adjust the pH to 8°0. After stirring for 20 minutes, 100 d of ethyl acetate was added to adjust the pH to ZO. Separate the ethyl acetate, add new ethyl acetate to the aqueous layer, and adjust the pH to 1.5 with 6N hydrochloric acid. Separate the organic layer, dry with magnesium sulfate, and concentrate to obtain the desired product.

Example 86 A. Using the procedure of Example 82A starting with the requisite 6β-hydroxymethyl penicillanic acid sulfoxide 9 and the sulfone, 6β-hydroxymethyl penicillanic acid 6,5-di-t-phthyl 4 -Hydroxybenzyl sulfoxide and 6β-hydroxymethylpenicillane e 3.5-di-t-butyl-4-hydroxybenzyl sulfono is produced.

B, Using the appropriate esters synthesized from Example 82A, the following intermediates are synthesized by the indicated procedure: G, H Starting from the esters of Fluid 83B, the following intermediates are synthesized: The process produces the following end products: 6β-fluoromethylpenicillanic acid; 6β-zlomomethyl is nidilanic acid: 6β-fluoromethylpenicillanic acid sulfoxide; 6β=chloromethylpenicillanic acid sulfoxide? :6β-bromomethylbenicilla/acid sulfoxide;6β-fluoromethylbenicilla/acid sulfoxide:
6β-chloromethyl to nidilanic acid sulfone; and 6β
- Promomethylinisilane sulfone.

Patent applicant Pfizer Inc. Representative Patent attorney Kyo Yuasa 4 (2 others)

Claims (1)

[Claims] In the L formula, R15'! , fluorochloropromo
Iodo-C1-C4 alkoxy and C1-C4 alkylthio. n is an integer from 0 to 2; R13 is selected from a group consisting of hydrogen and an ester-forming residue that is easily hydrolyzed in vivo. ] The compound represented by the method for producing the compound (in the formula, carboxy protecting groups) with an organotin monohydride of about []-110
A method comprising reacting at °C and eliminating -R when R19 is a conventional penicillin carboxy protecting group. However, R1
In the case of a conventional penicillin carboxy protecting group, ゜9 is an integer from 0 to 1. (2) A patent claim in which the organotin monohydride is represented by the general formula: % formula % (wherein R16, R1□ and R18 are each selected from the group consisting of alkyl-phenyl and benzyl having 1 to 5 carbon atoms) The method described in item 1. (3+ R, 9 is a conventional penicillin carboxy protecting group selected from the following groups. a) -PH2R3 (wherein R2 and R3 each have 1 to 1 carbon atoms) ); b) 3,5-geniebutyl-4-human90xybenzyl; c) CH2-Y (wherein Y is a) -N=CH-
R5 (wherein R5 is selected from the group consisting of phenyl and alkyl having 1 to 4 carbon atoms); e) -CH(COCH3)Go2R6 (wherein R6 is an alkyl group having 1 to 4 carbon atoms) f) -CR7R8R9 (wherein R7 and R8 are each selected from hydrogen-phenyl and methyl, and R9 is selected from the group consisting of phenyl-4-methoxyphenyl and methyl, provided that R7 and R8 are each methyl When R9 is methyl);g) -81(CH3)
3 and -5i(CH3)2t-C4H9; -8nR1s R17R1s (R161 in the formula
R17 and R□8 are each selected from the group consisting of alkyl-phenyl having 1 to 5 nitrogen atoms and benzyl. ). (4) R19 is a conventional penicillin carboxy protecting group -i:) nR16h I 7R18 (R16J R
17 and R18 are each tan-methyl), -R15 and Method. (5) The method according to claim 4, wherein the conventional penicillin carboxy protecting group is removed by ice thawing. (6) R19 is a conventional 4-nidyline carboxy protecting group -8
nR16R1□R□8 (in the formula R161R17 and R1
8 is each tan-notyl), R15 is chloro-X or iodo, tan is 0, and the organotin monohydride is tri-n-butyltin hydride. (7) The method according to claim 6, wherein the penicillin carboxyl group of li- is removed by ice melting. (8) R, 9 is a conventional penicillin carboxy protecting group -3i(CH3)3, R15 and X are each 0-E-
1n is 0 and organotin monohydride is hydrogenated) IJ
-n-butyltin. (9) The method according to claim 8, wherein the conventional 4-nidyline carboxy protecting group is removed by ice thawing. α0) R19 method penicillin carboxy protecting group -C
R7R8R9 (wherein R7 and R8 are hydrogen and R
9 is 4-methoxyphenyl), -R1° and X are each iodo, n is 0 and the organotin is hydrogenated) so-11-notyltin. (]1)' R19 is a conventional penicillin carboxy protecting group -8i(CH3)3 and -R15 is chloro-
4. The method of claim 3, wherein X is 0 iodo and the organotin monohydride is tri-wotyltin hydride. 02. The method of claim 11, wherein the conventional penicillin carboxy protecting group is removed by ice thawing. U) The method according to claim 1O, wherein the conventional penicillin carboxy protecting group is removed by ice thawing. (14) R, is alkanoyloxymethyl having 6 to 7 carbon atoms, 1-(alkanoyloxy)ethyl having 4 to 7 carbon atoms, 1- having 5 to 8 carbon atoms;
Methyl-1-(alkanoyloxy)ethyl-C3-C6alkoxycarbonyloxymethyl-C4-C71-(alkoxycarbonyloxy)ethyl, C5-C81-methyl-1 −
Claims which are easily hydrolyzed ester-forming residues selected from the group consisting of (alkoxycarbonyloxy)ethyl, 6-phthalidyl, 4-crotonolactonyl, and gamma-butyrolactone-4-yl. Second
The method described in section. (15i R19 is pivaloyloxymethyl-R05
5. The method of claim 4, wherein and X are each 0 and the organotin monohydride is triphenyltin hydride. (1,6) R19 is pivaloyloxymethyl-R1
5. The method of claim 4, wherein 5 is oo to (11) F(,9 is pivaloyloxymethyl, R1
5. The method of claim 4, wherein 5 and X are each iodo, 0 and organotin monohydride or tributyltin hydride.