CN1015462B - Method for preparing 6-(substd.) methylenepenicillanic acids or 1,1-dioxide and derivatives thereof - Google Patents

Abstract

The present invention discloses a penicillinase inhibiting compound with structural formula (I') or medically applicable acid addition salts or carboxylic esters thereof, preparing intermediates therefore, preparing and using methods thereof and medicinal compositions thereof. In the structural formula (I'), n is equal to 0, 1 or 2; meanings of R1, R2 and R3 are defined as the specification.

Description

Method for preparing 6-(substd.) methylenepenicillanic acids or 1,1-dioxide and derivatives thereof

The invention relates to that novel 6-(replaces) methylene radical penam acids or its 1,1-dioxide, its ester class and the salt that pharmaceutically is suitable for, the medical composition that contains them, its preparation method and with them as penicillinase inhibitor and its intermediate.

In antiseptic-germicide, be most that people's know is this class material that is called penicillin antibiotic with a most popular class.The feature of these compounds is that they all have a nuclear that is made of 2-azetidinone (penicillin) ring, are fused to thiazolidine ring or dihydro-1, on the 3-thiazine ring.When this nuclear contained the thiazolidine ring, these compounds were called penicillin usually, and when containing dihydro thiazine ring in this nuclear, formed compound then is called cephalosporins.In clinical practice, in the penicillins of common employing, penicillin G (penicillin G), phenoxymethylpenicillin (penicillin v), penbritin and Pyocianil are arranged more typically; In the common cephalosporins, be representative with cephalothin, cephalexin and Kefzol.

Yet as valuable chemical therapeutic, though penicillin antibiotic uses extensively, widely acceptance again, they have a main drawback, and promptly some penicillin is inoperative to certain micro-organisms in penicillins.It is believed that, certain specified microorganisms develops immunity to drugs under many circumstances for certain specific penicillin antibiotic, its reason is the result of a kind of penicillinase of this microorganisms, and it destroys the mould prime ring of penicillins and the mould class of pioneer family antibiotic, generates no antibiotic active product.But, some material has the inhibition ability for penicillinase, and when the penicillinase inhibitor is used in combination with penicillin or cephalosporins, can improve or increase the effect of penicillin or the anti-certain micro-organisms of cephalosporins.It is believed that when the penicillinase inhibitory substance was used in combination with penicillin antibiotic, anti-microbial activity improves, and was more much bigger than single composition anti-microbial activity sum.

Therefore, the invention provides some new compounds, these compounds are that 6-(replaces) methylene radical penam acids, its 1-oxide compound, 1,1-dioxide and the ester class of hydrolysis easily in vivo thereof.The penicillanic acid that these are new and the easy ester class of hydrolysis in vivo thereof are effective inhibitor of bacterium penicillinase.And, also proposed to use this sour ester class of acid, its salt and some easy hydrolysis of these novelties, improve the method for penicillin antibiotic validity.

In addition, also provide have the carboxy protective group, 6-(replaces) methylene radical penam acids, its 1-is oxide-based and 1, the derivative of 1-dioxide class, said compound can be used as chemical intermediates.

Moreover, the present invention also provides 6-(to replace) methylol penam acids, its 1-be oxide-based, 1,1-dioxide class and its esters and ester class, these materials both can be used as chemical intermediates, can be used as the penicillinase inhibitor again and used.

European patent application No 50,805 discloses the compound that the penicillinase inhibitor uses that can be used as with following structural formula:

Wherein, n is 0,1 or 2, R ₁Be CN or some carbonyl moiety; R ₂Be hydrogen, low alkyl group or halogen, R ₃It is the group of hydrogen or easy hydrolysis.6-oxapenam esters of gallic acid, corresponding sulfoxide class and sulfone class are also disclosed in the identical text, and by make it with molecular formula be R ₁R ₂C=P(C ₆H ₅) ₃The method of compound (PhosPhoran) prepared in reaction structure formula III compound of phosphorane.

Particularly at UK Patent Application GB ₂, 053, some 6-methylene radical-1 is disclosed among the 220A, the ester class of 1-dioxy penam acids and said structure formula III, wherein n is 2, R ₁And R ₂Alkyl, aryl, any cycloalkyl, aralkyl or any amino of selecting replacement of selecting replacement of representing hydrogen, any selection to replace separately separately are perhaps by R ₁And R ₂With constitute 3 to 7 yuan of carbocyclic rings or heterocycles with the carbon atom that is attached thereto is common.

US Patent No 4,287 discloses the penicillanic acid 1 that some 6-replaces in 181,1-dioxide class and ester class thereof, and wherein the 6-substituting group is:

Inter alia, R ₃Be hydrogen or alkanoyl, R ₄Be hydrogen (C ₁-C ₄) alkyl, phenyl, benzyl or pyridyl, these materials all can be used as the penicillinase inhibitor.

The invention provides structural formula is:

New 6-(replace) methylene radical penam acid esters class, wherein, n is 0,1 or 2, R ¹Be R ^aPerhaps R ^b, and R ^aBe by THP trtrahydropyranyl, allyl group, benzyl, 4-nitrobenzyl, diphenyl-methyl, 2,2, the residue of the carboxy protective group that chooses in 2-three chloroethyls, tert-butyl and the phenacyl, R ^bBe hydrogen or by 3-(2-benzo (C) furanonyl), 4-butylene lactone group, r-butyrolactone-4-base,

In the easy residue of the ester group of hydrolysis in vivo that chooses; R ⁴And R ⁵All be hydrogen or methyl, R ⁶Be (C ₁-C ₅) alkyl, R ¹⁴Be

X wherein ₂Be the 3-substituting group of known cynnematin beta-Lactam antibiotics, R ¹⁵Be respectively the 6-substituting group of known penicillin or the 7-substituting group of cephalosporins penicillin antibiotic.Particularly preferred R ¹⁴Be above-mentioned penicillin residue, wherein R ¹⁵Be 2-phenylacetyl amido, 2-benzene acetamide oxide base, D-2-amino-2-phenylacetyl amido, D-2-amino-2-(4-hydroxyphenyl) acetamido, 2-carboxyl-2-phenyl-acetamides base, 2-carboxyl-2-(2-thienyl)-acetamido, 2-carboxyl-2-(3-thienyl)-acetamido, D-2-(4-ethyl-2, the 3-dioxy

The piperazine carbon acylamino)-and 2-phenyl-acetamides base, D-2-(4-ethyl-2, the 3-dioxy The piperazine carbon acylamino)-and the 2-(4-hydroxyphenyl) acetamido or 2,2-dimethyl-4-phenyl-5-imidazolone-1-base;

R ²And R ³In, one is hydrogen, another is Cl, CH ₂OH, vinyl, (C ₁-C ₄) alkylthio, (C ₁-C ₄) alkane alkylsulfonyl, furyl, thienyl, N-methylpyrrole base, N-acetyl-pyrrole base,

M is 2 or 3, and P is 0 or 1, and t is 0,1 or 2, X ₁Be S, O or NR ¹¹, R ⁷Be hydrogen, (C ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group, allyloxy, hydroxyl, carboxyl (C ₂-C ₅) alkoxy carbonyl, (C ₁-C ₅) alkyl-carbonyl, phenyl, benzyl, naphthyl, pyridyl, NR ⁸R ⁹, CONR ⁸R ⁹, NHCOR ¹⁰, NO ₂, Cl, Br, CF ₃Perhaps SR ⁸; R ⁸And R ⁹The two all is hydrogen, (C ₁-C ₄) alkyl, phenyl or benzyl; R ¹⁰Be (C ₁-C ₄) alkyl, CF ₃Perhaps phenyl; R ¹¹Be hydrogen, CH ₃, C ₂H ₅Perhaps CH ₃CO; R ¹⁶And R ¹⁷The two all is hydrogen, (C ₁-C ₄) alkyl, (C ₂-C ₄) hydroxyalkyl, perhaps R ¹⁶And R ¹⁷Form 5 to 7 yuan of heterocyclic groups together with the nitrogen-atoms that is attached thereto, these the most suitable heterocyclic groups be pyrrolidyl, Pyridine base, morpholinyl, thio-morpholinyl or 4-methyl

The piperazine base;

Perhaps said compound is the additive salt of the acid that pharmaceutically is suitable for, wherein R ²Perhaps R ³It is the group that contains basic nitrogen atom;

The perhaps cationic salts that pharmaceutically is suitable for of said compound, wherein R ¹Be hydrogen, perhaps R ²Perhaps R ³Contain carboxyl.

In the above-mentioned compound, R ¹Be R ^aCompound the preparation R ¹Be R ^bCompound the time use as intermediate.R ¹Be R ^bCompound be active penicillinase inhibitor of the present invention.

The present invention also provides 6-(R ¹²R ¹³-replace) methylol penam acids, 1-be oxide-based, 1,1-dioxide class and ester class thereof, its structural formula is:

Wherein, n and R ¹What illustrate during with top definition (I) formula compound is identical, X ₃Be H or Br, R ¹²And R ¹³In one be hydrogen, another is a vinyl, (C ₁-C ₄) alkane alkylsulfonyl, furyl, thienyl, N-methylpyrrole base, N-acetyl-pyrrole base,

If R ¹²Perhaps R ¹³Be , and P is 0, then R ⁷Not H or CH ₃; R ¹⁸Be H, (C ₂-C ₅) alkanoyl, (C ₂-C ₅) alkoxy carbonyl base, pyrazinyl carbonic acyl radical, benzoyl, CF ₃CO or CON-R ⁸R ⁹; And m, p, t, R ⁷R ⁸, R ⁹, R ¹¹, R ¹⁶, R ¹⁷And X ₁With the front defined identical;

Perhaps it pharmaceutically is suitable for the additive salt or the carboxylate salts of acid.

Compound shown in (II) formula all replaces in the 6-(of corresponding (I) formula of preparation) methylene radical-1, be used as chemical intermediate during 1-dioxy penicillanic acid ester compound.And, the compound shown in (II) formula, (R wherein ¹Be hydrogen or the easy residue of the ester group of hydrolysis in vivo stipulated above) because its penicillin enzyme inhibition activity and can use better effects if when especially being used in combination with penicillin antibiotic.

In the compound shown in (I) formula, the compound of selecting for use at first is that wherein n equals 0 or 2, R ²And R ³In have one to be hydrogen, another is furyl, thienyl, CH ₂OH, phenyl, methylsulfonyl, N-methylpyrrole base,

In (II) formula compound, the compound of selecting for use at first is the material that is limited by following substituting group, and promptly n equals zero or 2, R ₁₂And R ₁₃In have one to be hydrogen, another be vinyl, 2-furyl, 2-thienyl, N-methylpyrrole-2-base, N-acetyl pyrrole-2-base, 3-hydroxyl-2-pyridyl, 4-methoxyl group-2-pyridyl,

And R ¹⁸Be H or CH ₃CO.

The carboxy protective radicals R of specifically selecting for use ^a, be allyl group, phenmethyl, tert-butyl and 2,2,2-three chloroethyls, preferred especially allyl group because use allyl group to prepare and remove all easy.

Gui Ding those are in vivo easily in the residue of the ester group of hydrolysis in the above, i.e. R ^bIn, what specifically select for use is:

The residue R that selects for use at first ^b, R wherein ⁴And R ⁵All be hydrogen, R ⁶With the front defined identical.

The present invention is except that the manufacture method that the represented compound of (I) formula and (II) formula is provided, the method of infectation of bacteria in treatment Mammals (the comprising human body) body also is provided, this comprises, when Mammals needs this medical treatment, (I) formula compound of the antibiotic amount of coming into force of prescribe medicine, R in this compound ¹Be the R of above-mentioned definition ^b

In addition, the invention allows for and cure the Mammals medical composition that (comprising the people), infectation of bacteria was used, wherein contain (I) formula compound (R of the antibiotic amount of coming into force ¹Be R ^b).

With (I) formula and (II) represented compound (wherein, R ¹Be R defined above ^b) can be as the inhibitor of penicillinase.According to this mechanism, these compounds can improve the anti-microbial activity of penicillin antibiotic (penicillins and cephalosporins class), especially improve for occurring the antibiotic anti-microbial activity that have resistance or drug-fast those microorganisms of part of penicillin, otherwise the enzyme that is produced (penicillinase) will destroy or partial destruction penicillin antibiotic by producing enzyme (penicillinase).The various activity of penicillin antibiotic have been increased in this way.

The present invention has further proposed the method for treatment Mammals (comprising human body) infectation of bacteria, and this method comprises to certain penicillin of the antibiotic amount of coming into force of Mammals prescribe medicine of this treatment of needs or (I) formula or (II) formula compound of cephalosporin (cited specifically) and penicillinase amount of suppression.

Though these compounds that proposed generally can improve the activity of penicillin antibiotic, it is more satisfactory to find in these compounds and the clinical practice to determine that certain penicillin that adopts or cephalosporin combine prescribe medicine.The penicillin or the cephalosporin that can be used in combination have: amoxycillin, penbritin, apalcillin, azlocillin, azthreonam, Bacampicillin, Pyocianil, carindacillin, carfecillin, cefaclor, cefadroxil, cefaloram, cefadole, cefadole sodium methyl esters, cephalo

Sieve, rocephin, Kefzol, Cefbuperazone, cefonicid, cefmenoxime, Cefodi-zime, Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, cefoxitin, Cefpiramide, Cefpirome, Cefsulodin, Ceftazidime, Ceftizoxime, Ceftraxone, Cefuroxime, cefacetrile, cephalexin, cephaloglycine, cephaloridine, cephalothin, brisfirina, cefradine, cyclacillin, speciophylline, furazlocillin, hetaeillin, lenampi-cillin, left-handed propyl group penicillin (levopropylcillin), mecillinam, Mezlo, penicillin G, penicillin v, penicillin B, serge Penicillin, PC-33994, pivampicillin, Sarmoxicillin, Sarpicillin, suncillin, talampicillin and ticarcillin, with and the salt that pharmaceutically is suitable for.The title of these penicillins is generally the title usAN that the U.S. adopts.

The material that is used in combination with penicillinase inhibitor of the present invention also comprises: 7-(2-(2-amino-4-thiazolyl)-2-methoxyl group imido kharophen)-and 3-(5,6-dihydro-4-(4-azepine indenes) methyl-3-cephalo element (Cephem)-4-carboxylate salt (HR-810), 7-(2-(2-amino-4-thiazolyl)-2-methoxyl group imido kharophen)-and the 3-(N-crassitude) methyl-3-cephalo element-4-carboxylate salt (BMY-28,142) and 7-(D-(2-(4-carboxyl-5-imidazoles carboxylic amino))-2-phenyl kharophen)-3-(4-(2-sulfoethyl (Sulfonatoethyl))-pyridine)-3-cephalo element-4-carboxylic acid.

Though compound of the present invention can separate prescribe medicine with penicillin antibiotic, is advisable with the medicine of compound formulation.This medical composition, no matter be oral also be that non-enteron aisle is used, wherein contained by weight (I) formula or (II) formula penicillinase inhibitor are 1: 3 to 3: 1 with the ratio of penicillin antibiotic, it enough cures mammiferous infectation of bacteria in single agent or the total amount in the multi-agent of more frequent employing.

(I) formula of the present invention or (II) formula compound (R wherein ², R ³, R ¹²Perhaps R ¹³Having one in the group is to contain basic nitrogen atom) can form sour additive salt.These salt that generate with the acid that pharmaceutically is suitable for are also included among the present invention.This acid has: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, citric acid, oxysuccinic acid, tartrate, maleic acid, FUMARIC ACID TECH GRADE, glyconic acid, saccharic acid, Phenylsulfonic acid, right-toluenesulphonic acids, right-chlorobenzenesulfonic acid and 2-naphthene sulfonic acid class.

R ' is it (I) formula of the present invention or (II) formula compound of hydrogen, generates the positively charged ion salt and is also included within the scope of the present invention with cationic this salt that medicine is suitable for.This cationoid for example has: sodium, potassium, ammonium, calcium, magnesium, zinc, and by diethanolamine, choline, quadrol, thanomin, the formed substituted ammonium salts of amine such as N-methylglucosamine and PROCAINE HCL, PHARMA GRADE.

The invention relates to derivatives class by the represented penicillanic acid of following structural formula:

In the derivatives class of penicillanic acid, have broken line (

) the substituting group that is connected on the dicyclic ring represent that this substituting group is under the plane of this nuclear.This substituting group is called as α-configuration substituting group.Otherwise, be connected on this dicyclic ring and have heavy line (

) substituting group, show that this substituting group is in the plane top of this nuclear.A kind of configuration in back is called beta configuration.As employed in this article, the substituting group that is connected on the dicyclic ring by fine line (-) shows, this substituting group or α-configuration, or beta configuration.

The method for preparing The compounds of this invention for example is one or several following general methods.

Method A

Method B

Method C

The molecular formula of using among the top method A is:

R ²R ³CHP（C ₆H ₅） ₃Cl

Required Wei Tixi salt (Wittig Salts), be compound known, or, for example prepare with the method that the following describes with the compound that the precursor of having bought from the market easily adopts common synthetic method to be prepared.

The preparation of Wei Tixi salt

By general formula R ³CH ₃The typical method that the primary alconol that OH represents is transformed into corresponding chloromethyl compound is, in the presence of inert solvent (for example chloroform or methylene dichloride), in room temperature or near under the room temperature, make the thionyl chloride reaction of this alcohol and equimolar amount, for example isolate reaction product by neutralization reaction mixture and method of extraction.

Then, for example, make this chloromethyl compound (R with the reaction of equimolar amount triphenyl phosphine ³-CH ₂Cl) change into required Wei Tixi salt.Typical condition is that this step is preferably under the reflux temperature, in for example carrying out in this kind solvent of toluene under the temperature that improves.Required product generates precipitation, filters then and is collected.

6-Alpha-hydroxy penicillanic acid is a kind of compound known, for example sees Hauser etc., Helv.chim.Acta, 50,1327 pages (1967).This acid is transformed into the derivative that certain carboxyl shown in (IV) formula is protected.Identification carboxy protective group is unimportant; requirement to this carboxy protective group only is: (I) generating oxidizing condition that 6-oxapenam acid esters (V) adopted 6-oxapenam acid esters and Wittig reagent reaction generation 6-(replacement down and subsequently) and methylene radical penam acid esters (VI-, R wherein ¹Under=oxidizing condition Ra) time, it must be stable.(II) replaces penicillin and this 6-() under the condition that do not act on substantially of methylene radical both, must can be with it from (VI, R ¹=Ra) in the compound of formula institute formula, selectively remove; (III) is for this compound of oxidation (VI, R ¹=Ra) with under the condition that generates the sulfone class shown in (VII) formula, it must be stable.Satisfy in this carboxylic acid protectiveness group of above-mentioned requirements, THP trtrahydropyranyl, benzyl, diphenyl-methyl, 2,2 are more typically arranged, 2-three chloroethyls, allyl group, tert-butyl and phenacyl.See for details: United States Patent (USP) № 3632850 and 3197466; English Patent № 1041985; J.A.C.S.88 such as Woodwara, 852(1966); Chauvette, Organic Chem.36,1259(1971; " cephalosporins and penicillin, chemistry and biology " H.E.Flynn, academy of sciences publishes company limited, 1972.This group of preferentially selecting for use is allyl group, phenmethyl and 2,2,2-three chloroethyls, and what select for use at first is allyl group, because allyl group prepares easily and selectivity is removed.

The model experiment condition that the 6-Alpha-hydroxy penam acid esters (IV) that carboxyl is protected is oxidized to corresponding 6-oxapenam acid esters (X) is: in the presence of inert solvent (for example chloroform or methylene dichloride), use the trifluoroacetic anhydride and the excessive one mole dimethyl sulfoxide (DMSO) of about equimolar amount.The temperature of reaction of preferentially selecting for use is approximately-80 ° to-70 ℃.The method that for example use to add tertiary amines such as triethylamine this reaction mixture that neutralizes, then it is allocated in water with the immiscible solvent of water in so as to separating this mixture, the evaporation organic solvent layer.

Then make (V) formula represented 6-oxapenam acid esters and R ²R ³

(C ₆H ₅) ₃The Wittig reagent reaction that formula is represented.Under existing, the organic solvent that this reaction is preferably in certain reactionlessness carries out, the organic solvent of operable reactionlessness for example has: alkane such as pentane, hexane, benzene, toluene or dimethylbenzene, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, 1, halogenated alkanes such as 2-ethylene dibromide or chlorobenzene, tetrahydrofuran (THF), diox, diethyl ether, 1, ethers such as 2-glycol dimethyl ether or t-butyl methyl ether.Though this reaction can be good with-78 ° to 25 ℃ temperature ranges from approximately-100 ° carrying out to+50 ℃ of temperature ranges.

Utilize known method to separate required (VI, R ¹=R ^a) the formula product, for example add aqueous ammonium chloride solution and make this reaction terminating, use certain and the immiscible solvent extraction of water, evaporate this solvent then.In case of necessity, utilize the known traditional method of those of skill in the art in this technical field, as the product of purifying and being generated with the silicagel column chromatography.

Then, can make (VI, R ¹=R ^a) (the R wherein of the ester shown in the formula ^aBe carboxy protective group as defined above) be transformed into accordingly by (VI, R ¹=R ^b) acid or the ester (R wherein of expression ^bBe the hydrogen or the easy residue of the formation ester of hydrolysis in vivo).In typical case, from (VI, R ¹=Ra) remove this carboxy protective group in the intermediate compound shown in the formula, to make corresponding carboxylic acid.For removing the selected ad hoc approach of this carboxylic acid protectiveness group, different because of the characteristic of this ester residue Ra, those skilled in the art will find in this technical field but the method that is suitable for will be easily.

As top mentioned, the carboxy protective radicals R a that selects for use at first is an allyl group.Obtain satisfied result though utilize weak acid or alkali hydrolysis method can remove this group, but the method for selecting for use at first when removing allyl group is to use the complex compound of soluble palladium (O), i.e. four (triphenyl phosphine) palladium (O), as catalyzer, this method once was reported in " J.Org.Chem. " 47 by Jeffrey and McCOmbie, 587-590(1982) on.Typical working method is in nitrogen, make the allyl ester in the inert solvents such as being dissolved in ethylene dichloride, chloroform or ethyl acetate, triphenyl phosphine combination in addition with four (triphenyl phosphine) palladium (O) (by mole percentage ratio, its amount for example is the 1-5% of allyl ester) of catalytic amount and weight such as about.Add sodium salt or sylvite with the 2 ethyl hexanoic acid of initial allyl ester mole number equal quantities therein, at room temperature stir this mixture that obtains, until required salt, (the R wherein of the salt shown in (VI) formula for example ¹Being sodium or potassium) precipitation is fully.About 2 to 20 hours, should react complete substantially generally speaking in the time.Then, for example adopt filtration method to collect the salt that generates.

If wish to obtain sulfoxide class of the present invention or sulfone compound, for example the compound shown in (I) formula (wherein n=1 or 2) then uses the interior known oxidation sulfoxide class of this technical field to become the various oxygenants of sulfone to come the sulfocompound shown in oxidation (VI) formula.But the most frequently used reagent is the permanganate of metal (the permanganic acid salt and the organic peroxide acid of for example alkali-metal permanganic acid salt and alkaline-earth metal, for example organic peroxy carboxylic-acid).Reagent commonly used is sodium permanganate, potassium permanganate, 3-chlorine peroxybenzoic acid and peracetic acid.

The oxygenant group of selecting for use at first comprises the organic peroxide acid class, and the organic peroxide acid of preferentially selecting for use is a 3-chlorine peroxybenzoic acid.

When required oxidation products was sulfoxide shown in (I) formula, wherein n was 1, used the initial sulfide (n is zero) and the oxygenant of about equimolar amount; When required product is sulfone, the sulfone class shown in (I) formula for example, wherein n is 2, then makes this sulfide and two or three moles of oxidant reactions.Perhaps, certainly use the raw material of this sulfoxide compound, use the oxygenant that approximately waits mole number in this case at least as the corresponding sulphones of preparation.

For example, when using peroxycarboxylic acid and so on organic peroxide acid, (VI, R ¹=R ^a) (the R wherein of certain compound shown in the formula ^aDefined identical with the front) when being oxidized to the compound shown in corresponding (VII) formula, usually by in certain inert organic solvents, with oxidizer treatment (VI, the R of about 2 to 4 molar weights ¹=R ^a) compound shown in the formula, to carry out this reaction.Typical solvent is hydrochloric ether (for example methylene dichloride, chloroform and 1,2-ethylene dichloride) and ethers (for example ether, tetrahydrofuran (THF) and 1,2-glycol dimethyl ether).This reaction is preferably under about 25 ℃ and carries out usually approximately-20 ° carrying out to about 50 ℃ of temperature ranges.Under about 25 ℃, the reaction times of adopting is about 2 to about 16 hours usually.Usually utilize vacuum-evaporation to remove this separated from solvent product.This product can be purified with known traditional method in this technical field.

In the oxidation operation of mentioning in the above, preferably employing carboxyl wherein is by the top carboxy protective radicals R of carrying ^aProtective material is used as raw material.For from its product sulfoxide or sulfone, removing this carboxy protective group, be according to removing the used usual way of specific protectiveness group, for example in the above for compound (VI, R ¹=R ^a) described method operates.

Compound of the present invention, for example represented compound of (I) formula or (II) formula (R wherein ¹Be the easy residue of the generation ester of hydrolysis in vivo) can adopt traditional esterification process directly by R wherein ¹The corresponding compounds that is hydrogen directly prepares.Selected this ad hoc approach depends on the concrete structure of the residue that forms ester, and the method that is suitable for is easy to be come out by professional personnel selection in this technical field.Work as R ¹Be to be by 3-cumarone ketone group, 4-butylene lactone group, r-butyrolactone-4-base and by structural formula:

(R wherein ⁴, R ⁵And R ⁶With stipulate previously identical) when selecting in the represented group, these compounds can be R with molecular formula ^b" halogenide " of Q is with suitable compound 1(of the present invention R wherein ¹Be H) the in addition method preparation of alkaneization, molecular formula is R ^b" halogenide " of Q is 3-benzofuranone halogenide, 4-butylene lactone halogenide, r-butyrolactone-4-muriate or the compound with following structural formula:

Wherein Q is " halogen ", R ⁴, R ⁵And R ⁶With previously defined identical.Speech such as " halogenide " and " halogen " refers to the derivative of chlorine, bromine and iodine.The typical method that this reaction is carried out is: will be for example the compound (R wherein of (I) formula or (II) formula representative ¹Being hydrogen) salt is dissolved in the suitable polar organic solvent, for example is dissolved in N, in the dinethylformamide, adds about 1 mole suitable " halogenide " (R Q) then.After this reaction is carried out fully substantially, use the standard method separated product.Separation method is very simple, usually only needs to dilute with excessive water, then product is extracted to not miscible certain organic solvent of water in, evaporate organic solvent then and reclaim product.Normally used salt raw material is alkali-metal salt such as sodium, potassium and triethylamine, N-ethylpiperidine, N, tertiary ammonium salt and quaternary amines such as tetramethyl ammonium and 4-butyl ammonium such as accelerine and N-methylmorpholine salt.In about 0 to 100 ℃ of temperature range, under about 25 ℃ of temperature, react usually.Required time that reacts completely is different because of various factors, as the reactive behavior of concentration of reactants and all ingredients.In the halogen compound of research, the iodide reaction is faster than bromide, and bromide is faster than muriate again.When using chlorine compound, it is in fact favourable often to add the alkaline metal iodide that is not higher than 1 mole, and this has the effect of accelerated reaction.Taking into full account under the condition of above-mentioned factor, the reaction times of adopting is about 1 to about 24 hours usually.

The method B that outlines above adopting prepares (II) of the present invention formula compound, and (n is 2 in this compound, X ₃And R ¹⁸All be hydrogen) or during the compound of (VIII) formula, by with wait the low-molecular-weight Grignard reagent of mole number (for example methyl-magnesium-bromide, ethylmagnesium chloride or normal-butyl iodate magnesium) in certain ether solvents (being preferably tetrahydrofuran (THF) or ether), (typically temperature is-78 ℃) reaction under-80 ° to 25 ℃ temperature, make needed 6-alpha-brominated-1,1-dioxy penam acid esters raw material (IX) is converted into Grignard reagent.Stir after the several minutes, the adding molecular formula is R ¹²R ¹³The suitable aldehyde that waits mole number of C=O, and it is complete substantially to be continuously stirring to this reaction, needs about 10 minutes to about 4 hours usually under same temperature.Isolate needed ester with (II) formula structure with standard method then, wherein n equals 2.For example, this reaction is stopped, and use and the immiscible solvent extraction product of water with aqueous ammonium chloride solution.For example with the further purified product of silica gel chromatography (II).Then, can make secondary alcohol (n=2 wherein, the X of (II) formula ₃=H) dehydration is equivalent to make that the 6-(of (VIII) formula replaces) methylene radical-1,1-dioxy penicillanic acid ester cpds.Though in order successfully to carry out this dehydration operation, can adopt in this technical field known the whole bag of tricks to make the secondary alcohol dehydration generate alkene, but the method for preferentially selecting for use is to use diacetyl oxide and the pyridine that waits mole number at least, make this alcohol change into acetic ester, at room temperature stirred then about 1 to 10 hour, and made it most of alkene that generates.Generally speaking, water stops this reaction, and (II n=2), is purified in case of necessity to isolate required product with extraction process then.

(II) formula that makes according to above-mentioned method or the product of (II III) formula are some esters, wherein R ¹It is the carboxy protective radicals R of putting down in writing above ^a, or the sort of residue R of the ester group of easy hydrolysis in vivo that puts down in writing above ^bWith aforesaid method will be wherein R ' be the ester class of Ra, change into corresponding carboxylic acid class (R ^bBe hydrogen), certainly, in the case of necessary, also be used in the method for putting down in writing above, with the carboxylic acid of (II) formula or (VIII) formula, be transformed into wherein R ¹It is the easy corresponding compounds of the ester group residue of hydrolysis in vivo.

Initial 6-is alpha-brominated-1, and the typical method for making of 1-dioxy penam acid esters (IX) is: handle 6 with sodium bicarbonate and sodium bisulfite, and 6-two bromos-1,1-dioxy penicillanic acid carries out acidifying then.The 6-that is generated is alpha-brominated-1, and 1-dioxy penicillanic acid then is converted into certain ester of (IX) formula.

The initial ester class that (X) formula of using among the method C that outline is in the above represented is a compound known, for example referring to United States Patent (USP) 4,234,579.The typical operation process of this method is as follows, will be at the starting ester (X) in the inert solvents such as toluene, dimethylbenzene, pentane, tetrahydrofuran (THF), ether or its mixture, at low temperatures, contact with the alkyl lithium reagents that waits mole number, make it to generate penicillin lithium intermediate product, operable alkyl lithium reagents comprises n-Butyl Lithium, tert-butyl lithium or lithium methide or the like.Make penicillin lithium and equimolar amount aldehyde immediately, R ¹²R ¹³CO(wherein, R ¹²And R ¹³With defined above identical) react, and (be preferably under-78 ℃) about 1 to 4 hour of stirring under-100 to-50 ℃.This reaction is stopped, and for example separate the represented bromination alcohol intermediate product of (XI) formula with the method in the solvent, use silica-gel carrier or florisil (Magnesium Silicate q-agent) post chromatography purification extraction liquid then with making it to be allocated in water.

The above-mentioned raw materials two bromo esters that (X) formula is represented and wait the low-molecular-weight Grignard reagent reaction of mole number, with the bromhydrin that preparation (XI) formula is represented, are reflected under reagent among the top method B and the condition and carry out.

Bromination alcohol (XI) acidylate is in addition made corresponding compounds (XII), wherein R ¹⁸It is the group outside the dehydrogenation of top record.Usually in room temperature or be lower than under the room temperature and exist under the condition of reactionlessness organic solvent (preferentially selecting methylene dichloride, tetrahydrofuran (THF) or ethyl acetate for use); by the intermediate product bromhydrin and tertiary amine (for example pyridine, the N-methylmorpholine etc.) reaction of mole number acyl chlorides, acylbromide or corresponding acid anhydrides and (XI) formulas such as making, carry out acidylate.Utilize known separation methods such as extraction and evaporating solvent then, isolate required diester (XII), for example purified in case of necessity with the post chromatography.

Then, can make bromhydrin ester intermediate product (XI) or brominated diester (XII) hydrogenolysis under the hydrogenolysis condition, to remove bromine atoms.Use arbitrary known reductive agent and reductive condition to finish this hydrogenolysis, for example in the presence of noble metal catalyst, make bromhydrin debrominate hydrogenation, perhaps make it to be reduced by some organotin hydride.

Preferred organotin hydride reductive agent be dialkyl tin dihydride, trialkyltin hydride (in said each alkyl, containing 1 to 6 carbon atom) and triaryl tin hydride (wherein said aryl be phenyl or by nitro, alkyl or have the phenyl of the alkoxyl group replacement of 1-3 carbon atom).Particularly preferably be triphenyltin hydride and three-normal-butyl tin hydride.On economy and efficient, preferably select tri-n-butyl tin hydride for use.

Use the reaction of said tin hydride, will exist in the inert solvent usually and carry out.Being suitable for the solvent that the organotin hydride reductive agent uses is, dissolving (XI) or (XII) formula starting compound basically, but itself again not with the solvent of this hydride reducer reaction.This kind solvent comprises: aromatic hydrocarbons such as benzene, dimethylbenzene, toluene, chlorobenzene and naphthalene and ether, isopropyl ether, tetrahydrofuran (THF), diox and 1, ethers such as 2-glycol dimethyl ether.Preferably select benzene and toluene for use, because they are cheap, efficient is high.

When using the organotin hydride reductive agent to carry out hydrogenolysis, need bromhydrin (XI) or the brominated diester (XII) and the hydride of mole numbers such as usefulness in theory.But actually, in order to guarantee to react completely, usually use excessive hydride, the hydride of for example excessive 5-50% mole.

Use the organotin hydride hydrogenolysis, (do not use catalyzer) under the disclosed optimum condition in the above and carry out fully substantially.But, by radical is provided, for example utilize the Diisopropyl azodicarboxylate of ultraviolet ray, catalytic amount or this class superoxide of benzoyl peroxide for example, make this reaction quickening.Preferentially select the Diisopropyl azodicarboxylate of catalytic amount for use, reaction provides radical for this reason.

Typical hydrogenolysis working method is as follows.With the compound dissolution of (XI) formula or (XII) formula in inert solvent, this solution is remained under the inert atmosphere, for example under nitrogen or the argon atmospher, and add an amount of organotin hydride and free arbitrarily radical source, for example Diisopropyl azodicarboxylate stirs under certain temperature in about 0 ℃ of temperature range that optimizes between solvent boiling point then.Usually, just this reaction reaches fully within several minutes was to about several hours, complete as 5 minutes to 0 ℃ following about 20 hours internal reactions under the benzene boiling temperature.Isolate (II, X with the known method of personnel skilled in this technical field then ₃=H) the product of formula.For example, with evaporating solvent with resistates is separated as silica gel chromatography.

(II, the X that make according to the organotin hydride debrominate method of putting down in writing above ₃=H) in the formula compounds, it is found that it mainly is 6-β type isomers, i.e. 6-R ¹²R ¹³C(OR ¹⁸) substituting group belongs to beta configuration.

In the presence of noble metal catalyst, when carrying out hydrogenolysis step with hydrogen, the conventional process that realizes this transformation is under nitrogen atmosphere or under inert dilution gas mixed-gas atmospheres such as hydrogen and nitrogen or argon, and there is the compound solution of stirring down or vibration (XI) formula or (XII) formula in the precious metal hydrogenolysis catalyst.The solvent of suitable this hydrogenolysis is dissolve the starting compound of (XI) formula or (XII) formula basically, but the solvent of hydrogenolysis or hydrogenization not to take place but for itself.This solvent comprises: ether, tetrahydrofuran (THF), diox and 1, ethers such as 2-glycol dimethyl ether, low-molecular-weight ester classes such as ethyl acetate, butylacetate, N, tertiary amines such as dinethylformamide, N,N-dimethylacetamide and N-Methyl pyrrolidone, water and composition thereof.In addition, often wish this reaction mixture of buffering so that PH from about 4 to 9, be preferably under about condition of 6 to 8 and operate.Often use borate, supercarbonate and phosphate buffered saline buffer.In the closed reaction vessel that contains (XI) formula or (XII) formula compound, solvent, catalyzer and hydrogen, carry out this reaction, in reaction process, generally will simultaneously hydrogen be fed among this reaction medium.The pressure of reaction vessel interior can be about 1 to 100Kg/cm ²Change in the scope.When the atmosphere of reaction vessel interior was pure hydrogen basically, the preferred pressure scope was about 2 to 5Kg/cm ²Carry out hydrogenolysis under general certain temperature in about 0 ° to 60 ℃ scope, preferred hydrogenolysis temperature is about 25 ° to about 50 ℃.Adopt preferred temperature and pressure, hydrogenolysis took place within several hours, for example about 2 to about 20 hours.The preferred noble metal catalyst that uses in this hydrogenolysis is the reagent of realizing the known type of this class conversion usefulness in this technical field, for example nickel, palladium, platinum and rhodium.Best catalyzer is the amount of this catalyzer of palladium, when calculating according to (XI) formula compound weight, is typically about 0.01 to about 25%, and preferred amount is about 0.1 to 10%.Preferably this catalyzer is suspended on certain inert support, preferably palladium catalyst for example is suspended on the inert support such as carbon.

After hydrogenolysis is complete substantially, utilize general method to isolate required (II, X ₃=H) formula product is for example removed catalyzer with filtration method, boils off solvent, and for example utilizes known method such as recrystallization where necessary or use the chromatography purified product.

When the starting compound of (XI) formula or (XII) formula is benzyl ester (R ¹=Ra=phenmethyl) time, above-mentioned catalytic hydrogenolysis operation also may cause dissociating of phenmethyl, and this product has (II) formula structure, wherein X ₃And R ¹Be hydrogen.

6-(replaces) methylol penicillanic acid or (XII) formula or (II, X ₃=H) the ester of (wherein n be zero) formula can be with in addition oxidation of any currently known methods that sulfide is changed into sulfoxide class or sulfone class, and for example the 3-chloro peroxybenzoic acid by means of top record carries out oxidation, so that make (XII) formula or (II, X ₃=H) the corresponding sulfoxide class or the sulfone class of formula, n is respectively 1 and 2 in this two formula.But it is suitable 6 that the preferred method of producing (XI), (XII) or (II) formula sulfone class is to use, 6-two bromos-1, and 1-dioxy penam acid esters (X) (wherein n is 2) is as the raw material among the method C that puts down in writing above.

Molecular formula R ¹²R ¹³The raw material aldehydes that CO represents (R wherein ¹²And R ¹³With defined above identical), both can buy from the market, can simply produce by the raw material that can buy with known following method in this technical field again: for example

1, adopt oxygenants such as potassium bichromate, chromic acid-pyridine, the corresponding primary alconol class as the Wittig reagent parent that oxidation provides is above carried out catalyzed oxidation in the presence of precious metal, Manganse Dioxide.

2, make corresponding methyl substituted aromatic hydrocarbon and for example tin anhydride reaction.

3, under the condition of low temperature and ether solvent existence, with the corresponding (C of metal hydride reduction ₁-C ₄) alxoxycarbonyl compounds.Suitable metal hydride has lithium aluminium hydride, diisobutylaluminium hydride (DIBAL-H).

4, suitable aromatic hydrocarbon parent and n-Butyl Lithium and dimethyl formamide reaction.

As noted above (I) formula or (II) formula compound (wherein R ' is H) and salt thereof are used in combination with penicillin antibiotic like that, show synergistic activity in the in-vitro antibacterial test.(M-IC ' S) (mcg/ml) has obtained proof to such activity by measuring minimum inhibitory concentration for various microorganisms.The operation steps of being followed is (Ericcson and the S-herris about antibiotic sensitivity test that is recommended by international cooperating research, Acta.Pathologica et Mi-crobiologia Scandinav, addendum 217, B part: 64-68 page or leaf (19717)), use brain heart infusion (BHI) nutrient agar and microbionation liquid copying equipment.With after 100 times of the test tube of the grow overnight dilutions as the microbionation liquid of standard (will in about 0.002 milliliter, have 20,000-10,000 cell is placed on the agar surface, 20 milliliters of BHI agar/wares).Use the test compound of 12 doubling dilution, the starting point concentration of trial drug is that 37 ℃ of 200 mcg/ml are observed substratum after following 18 hours, and this moment, single bacterium colony was ignored.With the naked eye judge the test compound that can produce complete bacteria growing inhibiting or the minimum concentration of compound composition, be defined as the susceptibility of institute's test organism.

Those compounds of (I) formula or (II) formula (wherein R ' is H) and salt thereof; when being used in combination with known penicillin antibiotic; be used for industrial antibacterial (for example water treatment is used), sludge control, coating protection and wood preservation, and more typically be to use as sterilizing agent.In such application, when using these compounds, this active ingredient usually mixed suiting with non-toxic carrier, employed non-toxic carrier for example has vegetables oil, mineral oil or skin cream.Equally, also can or for example be dispersed in liquid diluent such as water, alkanol, glycols or its mixture or the solvent their dissolvings.In most of the cases, the suitable concentration of this active ingredient is from about 0.1% to about 10% when calculating according to total composition weight.

As pointing out above, as effective inhibitor of microorganism penicillinase, the compound of (I) formula and (II) formula (R wherein ¹Be R ^b) have crucial value.For this reason, these compounds have increased penicillin antibiotic (penicillins and cephalosporins) for a lot of microorganisms, particularly for the anti-microbial effect of the microorganism that produces penicillinase.The ability of the increase penicillin antibiotic action effect that said (I) formula or (II) formula compound are had, can be evaluated with reference to experiment, measure the MIC value of this antibiotic itself during experiment, measure (I) formula or (II) formula compound (R wherein then ¹Be hydrogen) MIC value own.Then with these two groups of MIC values, the MIC value that records during with the composition that uses given antibiotic and (I) formula or (II) formula compound (wherein R ' is a hydrogen) composition compares.When the antibacterial effect of this composition with from the effect institute expectability of individualized compound wherein to value compare when much higher, just think to have constituted active increase.The MIC value of composition is to use Barry and Sabath in " Clinical microorganism handbook (" Manual of clinical Microbiology ".Lenette, Spaulding and Truant compile, second edition, 1974, AAM) the middle method mensuration of putting down in writing.

(I) formula and (II) formula compound (R wherein ¹Be the hydrogen or the easy residue of the ester group of hydrolysis in vivo) increased penicillin antibiotic antibacterial effect in vivo.In other words, these compounds have reduced and make mouse avoid the dead required antibiotic amount of bacterium that produces because of the penicillinase of inoculating some lethal dose.Measure thisly when active, make mouse produce acute experiment and infect, concrete grammar is the test organism stdn culture that is suspended in its intraperitoneal inoculation in the 5% pig stomach mucous membrane albumen.Make under the standardized condition of infection intensity, make test mice accept the biology of lethal dose (lethal dose be consistent kill 100% infected and cure test compound and the antibiotic composition that the required minimum quantity bacterization thing of the control mice of processing puts in poison various dosage levels for the oral or intraperitoneal of the infected mouse of array.After test stops, evaluate the activity of this mixture with the number under surviving in the mouse of given dose drug treating.This activity is used in the percentage ratio of survival animal under the given dose to be represented, perhaps the dosage that makes 50% animal avoid infecting by PD50() calculate.

Said (I) formula or (II) formula compound have the ability of the bacterium of improving the anti-penicillinase generation of penicillin antibiotic, this effect makes said compound cure Mammals, particularly can put in poison with penicillin antibiotic during the human body infectation of bacteria.When curing infectation of bacteria, (I) formula or (II) formula compound and penicillin antibiotic can be mixed together, perhaps work as R ^bBe CH(R ⁴) OCOR ¹⁴(R wherein ⁴And R ¹⁴Definition is as above) time, penicillin antibiotic is linked on the compound of (I) formula or (II) formula with chemical mode, thereby these two medicines are put in poison simultaneously.Perhaps during using the medical treatment of penicillin antibiotic, (I) formula or (II) formula compound are put in poison as drug alone.In some cases, before using the penicillin antibiotic therapy, the compound of putting in poison (I) formula or (II) formula in advance for sick body also is a kind of method preferably.

When using (I) formula or (II) formula compound (R wherein ¹Be R ^b, R ^bDefinition is as above) when improving penicillin antibiotic curative effect, preferably the mixture of said compound and penicillin antibiotic, perhaps separately R wherein ^bBe CH(R ⁴) OCOR ¹⁴Those The compounds of this invention, put in poison with dosage form with standard pharmaceutical carrier or thinner.Contain pharmaceutically suitable carrier, penicillin antibiotic and (perhaps) said (I) formula or the medical composition of (II) formula compound, calculate by weight, contain about 5～80% the carrier that pharmaceutically is suitable for usually.

When being used in combination with said (I) formula or another penicillin antibiotic of (II) formula compound, said compound both can be oral, also can put in poison i.e. intramuscular injection, subcutaneous injection or peritoneal injection by non-enteron aisle.Though the dosage that the meeting final decision is used on one's body patient during doctor's evolution.(but I) formula or (II) formula compound (R wherein ¹Be R ^b) and the per daily dose ratio of penicillin antibiotic, general big about 1: 3 to 3: in the scope 1(weight ratio).In addition, when (I) formula or (II) formula compound are used in combination with penicillin antibiotic, the day oral dosage of every kind of composition generally is approximately 10 to about 200 milligrams/kg body weight, and pharmaceutical quantities is typically about 10 to about 40 milligrams/kg body weight under day non-enteron aisle of every kind of composition.These per daily doses are divided into use several times usually.In some cases, the doctor of evolution need can determine the dose that exceeds above-mentioned dose limitation of use.

Skilled professional will determine in this technical field, the oral or non-enteron aisle prescribe medicine of some penicillin compound was all effective, and other penicillin compound is only just effective when non-enteron aisle is put in poison.(if I) formula or (II) formula compound will with only when the non-enteron aisle prescribe medicine just effectively penicillin antibiotic use (mixed together) simultaneously, then need to use to be suitable for the preparation that non-enteron aisle is put in poison.(if I) formula or (II) formula compound, with oral or non-enteron aisle prescribe medicine condition under effectively penicillin antibiotic use (being mixed together) simultaneously, then can make and not only be suitable for oral but also be fit to the composition of non-enteron aisle prescribe medicine.In addition, can be in oral (I) formula or (II) formula active agent preparations, non-enteron aisle prescribe medicine penicillin antibiotic; Also can be in non-enteron aisle prescribe medicine (I) formula or the said compound formulation of (II) formula, oral penicillin antibiotic.

The present invention will be described in detail by the following example.But, should know that the present invention is not limited to the specific detail among these embodiment.Proton NMR spectrum and C ¹³Nuclear magnetic resonance spectrum be 60,90,250 or the 300MHz condition under to deuteriochloroform (CDCl ₃), water-d2 (D ₂O), full deuterium acetone (CD ₃COCD ₃) or full deuterium dimethyl sulfoxide (DMSO) (DMSO-d ₆) solution measures, and the peak position be the PPm(1,000,000 that when using tetramethylsilane to make standard, moves at low field orientation/) numerical table shows.Use following shortenings: S-is unimodal, and d-is bimodal, and the dd-two-fold is bimodal, the t-triplet, and the q-quartet, the m-multiplet, b-is wide.

Embodiment 1

6-Alpha-hydroxy penam acid esters class

The A allyl ester

Handle 85 gram 6-α hydroxyl penicillanic acids with 34 milliliters of (0.39 mole) allyl group bromination things, 54 milliliters of (0.39 mole) triethylamines and 2 gram sodium bicarbonates ^*(0.39 mole) is dissolved in the solution that 300 milliliters of dimethyl formamides are made, and at room temperature stirs this mixture 15 hours.After the water stopped reaction, use extracted with diethyl ether, be collected in together ether layer, concentrate, make the thick finished product of 43 grams with dried over mgso and in vacuum with saturated sodium bicarbonate solution, water washing.Purify with silica-gel carrier post chromatography,, make the allyl ester of 22.75 grams (23%) with chloroform-eluent ethyl acetate of 9: 1. ¹H nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.42(S, 3H), 1.60(S, 3H), 4.45(S, 1H), 4.5-5.0(m, 3H), 5.2-6.2(m, 4H).

* adopt people's such as Hauser method preparation, Helv.Chim.A-Acta, 50,1327 pages (1967).

B pivalyl oxygen methyl ester

To under room temperature, stir 15 hours by the mixture that 9 gram (0.041 mole) 6-Alpha-hydroxy penicillanic acids, 40 milliliters of dimethyl formamides, 7.4 milliliters of (0.041 mole) diisopropyl ethyl amines, 6 milliliters of (0.041 mole) Chloro methyl pivalates and 6.15 gram (0.041 mole) sodium iodides are formed.Add entry, with this mixture of extracted with diethyl ether, dry this extract and concentrated produces the thick ester products of 9 grams, purifies with the silicagel column chromatography then, uses chloroform-ethyl acetate (9: 1) wash-out.The product of collecting reaches 4.384 grams (32%).

The C benzene methyl

12.0 milliliters of (0.101 mole) phenmethyl bromines of adding in the mixture of forming by 20 gram (0.092 mole) 6-Alpha-hydroxy penicillanic acids, 12.9 milliliters of (0.092 mole) triethylamines, 1.105 gram (0.013 mole) sodium bicarbonates and 200 milliliters of dimethyl formamides (DMF).At room temperature this mixture was stirred 20 hours, make it to be allocated among ether layer and the water layer, regulate ph value of aqueous phase to 2.0 with 6 equivalent hydrochloric acid.With two-phase separately after, with extracted with diethyl ether water twice, the ether layer with sodium bicarbonate aqueous solution, water washing merge makes solvent evaporation remove after the drying.Make residue crystallized with hot chloroform-hexane, product weighs 9.1 grams, is colourless crystallization, and fusing point is 165-167 ℃.

D(5-methyl-2-oxygen-1, dioxy cyclopentenes-4-yl between 3-) methyl ester

With 15 gram (0.078 mole) (5-methyl-2-oxygen-1,3-dioxole-4-yl) monobromomethane, 18.7 gram (0.078 mole) 6-Alpha-hydroxy penicillanic acid sodium are dissolved in 225 milliliters of tetrahydrofuran (THF)s, at room temperature stirred this mixture four hours, be poured in the ice, handle to make required ester according to above-mentioned method.

Embodiment 2

6-oxapenam esters of gallic acid

A 6-oxapenam allyl propionate

To stir 10 minutes down in-78 ℃ by the mixture that 2.84 milliliters of (0.04 mole) dimethyl sulfoxide (DMSO), 3.67 milliliters of (0.026 mole) trifluoroacetic anhydrides and 50 milliliters of methylene dichloride are formed.Under-78 ℃, adding is dissolved in the solution of making in 10 milliliters of ethylene dichloride by 5.14 gram (0.02 mole) 6-Alpha-hydroxy penicillanic acid allyl esters, and this mixture was stirred 40 minutes.Under this temperature, add triethylamine (7.24 milliliters, 0.052 mole), and slowly with this mixture heating up to room temperature, the water stopped reaction.After dichloromethane extraction, the organic layer that water (3X) washing merges, dry and under vacuum this solvent of evaporation, obtain product 5.1 grams (100%), be the title compound that is yellow oily. ¹H nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.60(S, 6H), 4.75(m, 2H), 4.82(S, 1H), 5.1-6.3(m, 3H), 5.82(S, 1H).

B pivalyl oxygen methyl ester

To stir 30 minutes down at-78 ℃ by the mixture that 0.36 milliliter of (5.06 mmole) dimethyl sulfoxide (DMSO), 0.47 milliliter of (3.29 mmole) trifluoroacetic anhydride, 839 milligrams of (2.53 mmole) 6-Alpha-hydroxy penicillanic acid pivalyl oxygen methyl esters and 5 milliliters of methylene dichloride are formed, add 0.92 milliliter of (6.58 mmole) triethylamine.Method by record in top " A " is handled this product, makes the required ketone of 788 milligrams (95%). ¹H nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.3(S, 9H), 1.65(S, 6H), 4.85(S, 1H), 5.8(m, 3H).

Embodiment 3

6(E)-(2-pyridyl) methylene radical penicillanic acid allyl ester

To be dissolved in the mixture that obtains in 6 milliliters of anhydrous tetrahydro furans (THF) by 2.64 gram (6.8 mmole) 2-picolyl San Ben Phosphonium muriates and 0.265 gram (6.8 mmole) sodium amide, under room temperature, stir 30 minutes.The brown suspension that obtains is cooled to-78 ℃, once is added in and is dissolved with the solution that 1.8 gram (7.0 mmole) 6-oxapenam allyl propionates obtain among 4 milliliters of anhydrous THF, stirred this mixture 3 minutes down at-78 ℃.Add the saturated ammonium chloride solution termination reaction, use ethyl acetate extraction, the organic layer that water (3X) washing merges is used dried over mgso, is concentrated into output 3.3 gram red oil in vacuum.With chromatography this oily matter of purifying, output 1.35 grams (60.7%) are the required product of yellow oily on silicagel column. ¹H nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.50(S, 3H), 1.58(S, 3H), 4.57(S, 1H), 4.65(d, 2H), 5.15-6.15(m, 3H), and 6.17(d, 1H, J=1Hz), 6.87(d, 1H, J=1Hz), 7.2-7.4(m, 2H), 7.60(td, 1H), 8.62(dd); ¹³C-nucleus magnetic resonance (CDCl ₃) PPm(δ): 26.04,32.99,62.77,65.75,70.01,70.54,119.10,123.24,124.02,125.86,131.06,136.34,144.66,149.94,152.13,167.54,168.73.

Embodiment 4

Adopt the working method of embodiment 3, with suitable Wittig reagent (its molecular formula is:

Replace making under the muriatic condition of 2-picolyl San Ben Phosphonium following compounds:

Embodiment 5

6(E)-(2-pyridyl) methylene radical penicillanic acid sodium

To contain 0.120 gram (0.38 mmole) 6-(E)-mixture of (2-pyridyl) methylene radical penicillanic acid allyl ester, 20 milligram of four (triphenyl phosphine) palladium (0) and 20 milligrams of triphenyl phosphines is dissolved in 3 milliliters of ethyl acetate, and under nitrogen atmosphere, be dissolved with the ethyl acetate solution of the 2 ethyl hexanoic acid sodium of 0.76 milliliter (0.38 mmole) 0.5 mole to adding wherein.At room temperature this mixture was stirred two hours, filter collecting precipitation,, obtain 57 milligrams of (48%) title compounds, be yellow solid with ethyl acetate washing and dry in vacuum. ¹H-nucleus magnetic resonance (D ₂O) PPm(δ): 1.55(S, 6H), 4.33(S, 1H), and 6.17(d, 1H, J=0.5HZ), and 7.03(d, 1H, J=0.5HZ), 7.17-8.07(m, 3H), 8.57(m, 1H); Infrared spectra (KBr): 3433,1756,1605Cm ^-1

Embodiment 6

The suitable raw material that use is picked out from the allyl ester class that embodiment 4 provides, make following sodium salt equally according to the working method of embodiment 5:

R ³Isomer productive rate % physical properties

Cl (E) 95 yellow solids; ¹H-nucleus magnetic resonance (D ₂O)

ppm（δ）：1.50（s，

3H），1.58（s，3H），4.3（s，

1H），5.83（d，1H），7.1（d，

1H); Infrared spectra

（KBr）cm ^-1：1573，1607，

1688，1775，3460。

Cl (Z) 89 infrared spectras (KBr)

cm ^-1：1580，1609，1679，

1753，3491。

CH ₃S (E) 80 white solids: ¹H-nucleus magnetic resonance (D ₂O)

ppm（δ）：1.48（s，3H），

1.56（s，3H），2.50（s，3H），

4.20（s，1H），5.88（s，1H），

7.2(s, 1H); Infrared spectra

（KBr）cm ^-1：1396，

1606，1749，2926，2963，

3552。

C ₆H ₅(Z) 60 buff powders

C ₆H ₅(E) 80 white powders; ¹H-nucleus magnetic resonance (D ₂O/

DMSO）ppm（δ）：1.5（s，

6H），4.25（s，1H），6.1（d，

1H），7.0（d，1H），7.4（s，

5H); Infrared spectra

（KBr）cm ^-1：1626，1642，

1655，1742，3434。

Embodiment 6A

6-phenyl thio-methylene penicillanic acid

Will be by 93 milligrams of (0.26 mmole) 6-phenyl thio-methylene penicillanic acid allyl esters (isomer mixture), 10 milligram of four (triphenyl phosphine) palladium (0) and 10 milligrams of mixtures that triphenylphosphine is formed, be dissolved in 1 milliliter of ethyl acetate, at room temperature, the ethyl acetate solution that adds the 2 ethyl hexanoic acid sodium that is dissolved with 0.52 milliliter of 0.5M stirred 10 hours under nitrogen atmosphere.When salt was seldom sedimentary, the water termination reaction was used dichloromethane extraction then.The acidifying water to PH be 3.5, extract with methylene dichloride.The concentrate drying extract obtains 6.3 milligrams of (75%) free acid isomer mixtures in a vacuum. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.5(S, 2.1H), 1.55(S, 0.9H), 1.6(S, 2.1H), 1.65(S, 0.9H), 4.4(S, 0.7H), 4.5(S, 0.3H), 5.38(d, 0.7H), 5.7(S, 0.3H), 6.7(S, 0.3H), 7.1(d, 0.7H), 7.5(m, 5H).

Embodiment 7

1.1-dioxy-6-(E)-(2-pyridyl)-

Methylene radical penicillanic acid allyl ester

To in 15 milliliters of methylene dichloride, being dissolved with the 1.30g(4.09 mmole) 6(E)-solution of (2-pyridyl) methylene radical penicillanic acid allyl ester in, add 1.70 and restrain the pure metachloroperbenzoic acid that (8.2 mmole) purity reach 80-85%, under nitrogen atmosphere and during room temperature, stirred this mixture 3 hours.After saturated sodium thiosulfate solution and water termination reaction, with this mixture of dichloromethane extraction, regulating organic layer PH with saturated sodium bicarbonate solution is 7.5, wash with water, use dried over mgso, and in vacuum, boil off solvent, obtain 1.4 gram (98% yellow oil product.Adopt silicagel column chromatography this oily product of purifying,, obtain 0.78 sulfone that restrains in the title that is the colourless crystallization shape of (55%) with hexane-eluent ethyl acetate of 7: 3. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.48(S, 3H), 1.63(S, 3H), 4.45(S, 1H), 4.73(d, 2H), 5.1-6.2(m, 3H), 5.77(d, 1H, J=0.5Hz), and 7.27(d, 1H, J=0.5Hz), 7.1-8.1(m, 3H), 8.6(m, 1H); ¹³C-nucleus magnetic resonance (CDCl ₃) PPm(δ): 18.53,20,43,63,18,64.25,66.63,72.04,119.91,124.64,126.03,130.68,132.83,136.77,150.31,166.86,168.11.Infrared spectra (KBr) Cm ^-1: 1323,1586,1759,1783,3437.

Embodiment 8

1.1-dioxy-6(E)-(2-hydroxy ethylene)

The penicillanic acid allyl ester

Under-78 ℃, in the solution of the 1.1-dioxy-6(E) that in 4 milliliters of anhydrous tetrahydro furans, is dissolved with 0.190 gram (0.61 mmole)-formyl methylene radical penicillanic acid allyl ester, add the hexane solution of 0.61 milliliter of (0.61 mmole) 1M diisobutyl alanate.Under-78 ℃, stirred this mixture 10 minutes, use the methyl alcohol termination reaction, at room temperature stir and filtered then in 20 minutes.Concentrated filtrate obtains 0.258 gram crude product in a vacuum.With this crude product dilute with water, use chloroform extraction then, drying (is used MgSO ₄) this organic phase.Chloroform is removed in evaporation, has made 160 milligrams of materials, to its further purification, with chloroform-eluent ethyl acetate of 4: 1, makes 113 milligrams of compounds in the title with the silicagel column chromatography, and productive rate is 60%. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.40(S, 3H), 1.60(S, 3H), 2.60(bs, 1H), 4.3(m, 2H), 4.4(S, 1H), 4.7(d, 2H), 5.1-6.0(m, 3H), 5.25(d, 1H), 6.38(m, 1H).

Embodiment 9A

6(E)-((1-oxygen quinoline-2-yl) methylene radical)-

11-dioxy penicillanic acid allyl ester

124 milligrams of (0.313 mmole) 6(E of dissolving in 5 milliliters of methylene dichloride)-((quinoline-2-yl) methylene radical)-1-Oxapenam allyl propionate (obtains as by product when preparing corresponding sulfone, the embodiment of face sees before, the band asterisk), add 195 milligrams of (0.904 mmoles) 80% between the chloro peroxybenzoic acid.At room temperature, stir this mixture 48 hours, after the water termination reaction, use dichloromethane extraction.Wash this extract with saturated sodium bicarbonate aqueous solution, wash with water then, drying and the concentrated yellow oil that obtains in vacuum.Utilize silicagel column chromatography this oily matter of purifying, make the title N-oxide compound that 45 milligrams (35%) are yellow solid. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.45(S, 3H), 1.6(S, 3H), 4.45(S, 1H), 4.7(m, 2H), 5.0-6.0(m, 3H), 5.85(d, 1H), 7.3-8.0(m, 7H).

Embodiment 10

The 11-dioxy-6(E)-the 2(2-pyridyl)-

Methylene radical penicillanic acid sodium

To be dissolved in 2 milliliters of acetic ester by the mixture that 0.14 gram (0.4 mmole) 11-dioxy-6(E)-(2-pyridyl)-methylene radical penicillanic acid allyl ester, 20 milligrams of tetrakis triphenylphosphine palladiums (0) and 20 milligrams of triphenylphosphines constitute, adding is dissolved with the ethyl acetate solution of the 2 ethyl hexanoic acid sodium of 0.8 milliliter of (0.4 mmole) 0.5M under nitrogen atmosphere.Under the room temperature this mixture was stirred 5 minutes.Filter the precipitation that generates, with the ethyl acetate washing, drying is made 0.13 gram (95%) and is yellow solid shape sodium salt. ¹H-nucleus magnetic resonance (D ₂O) PPm(δ): 1.50(S, 3H), 1.60(S, 3H), 4.23(S, 1H), and 5.90(d, 1H, J=1Hz), 7.1-8.0(m, 4H), 8.57(m, 1H).Infrared spectra (KBr) Cm ^-1: 1590,1621,1770,3454.

Embodiment 11

1, the 1-dioxy-6(E)-(1-oxygen-2-

Pyridyl)-methylene radical penicillanic acid allyl ester

To in 5 milliliters of methylene dichloride, be dissolved with 100 milligrams of (0.286 mmoles) 1, the solution of 1-dioxy-6(E)-(2-pyridyl)-methylene radical penicillanic acid allyl ester, handle with chloro peroxybenzoic acid between 120 milligrams (0.59 mmoles), at room temperature stirred three days.With saturated sodium thiosulfate solution termination reaction, and use dichloromethane extraction.With saturated sodium bicarbonate solution this organic layer that neutralizes, wash with water, dry and concentrate and generate 82 milligrams of yellow oil.Use silicagel column chromatography and eluent ethyl acetate liquid this yellow oil of purifying, title compound and 14 milligrams of (13%) by products-1 of 22 milligrams (21%) have been made, the methylene radical penicillanic acid-2 of 1-dioxy-6(E)-(1-oxygen-2-pyridyl), 3-epoxy propyl ester.

1, the methylene radical penicillanic acid allyl ester of 1-dioxy-6(E)-(1-oxygen-2-pyridyl): ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.5(S, 3H), 1.6(S, 3H), 4.45(d, 1H), 4.7(d, 2H), 5.1-6.0(m, 3H), 5.8(S, 1H), 7.1-8.4(m, 5H).

Embodiment 13

6(E)-(methyl sulfo-)-methylene radical green grass or young crops

Mould alkanoic acid pivalyl oxygen methyl esters

2.4 mmoles (methylthiomethyl) triphenyl phosphonium muriate, the mixture of 2.4 mmole sodium amides in 5 milliliters of anhydrous tetrahydro furans (THF) were stirred 20 minutes under room temperature.In the yellow solution that obtains, adding the solution of 788 milligrams of (2.4 mmole) 6-oxapenem alkanoic acid pivalyl oxygen methyl esters in 10 milliliters of anhydrous THF under-78 ℃.Down stirred these mixtures one minute at-78 ℃, in its impouring saturated ammonium chloride solution, and extracted with ethyl acetate.Use Na ₂SO ₄Dry this organic layer boils off solvent in a vacuum, makes 774 milligrams of crude products, purifies with the silicagel column chromatography, and the chloroform wash-out is made 220 milligrams of (24.5%) straight products. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.25(S, 9H), 1.50(S, 3H), 1.65(S, 3H), 2.45(S, 3H), 4.45(S, 1H), 6.85(m, 3H), 7.0(d, 1H).

Embodiment 14

6-(E) sulfonyloxy methyl methylene radical penicillanic acid

Pivalyl oxygen methyl esters-1-oxygen

Change thing (A) and corresponding 11-two

Oxide compound (B)

To in 5 milliliters of methylene dichloride, being dissolved with 215 milligrams of (0.58 mmole) 6(E)-solution of (methylthiomethyl) methylene radical penicillanic acid pivalyl oxygen methyl esters in, add 375 milligrams of (1.74 mmoles, 3 equivalents) 80% between the chloro peroxybenzoic acid.At room temperature stirred this mixture 4 hours, water, saturated sodium thiosulfate solution, hydrogen-carbonate hook solution termination reaction are used chloroform extraction.Wash organic phase with water three times, use MgSO ₄Drying, and concentrate in a vacuum, 200 milligrams of product mixtures made.With silica gel chromatography this crude product mixture of purifying,, make 25 milligrams of 1-oxide compounds (A) and 45 milligrams of 11-dioxide products (B) with chloroform-ethyl acetate (9: 1) wash-out.

(A): ¹H-nucleus magnetic resonance (CDCl ₃PPm(δ): 1.21(S, 9H), 1.3(S, 3H), 1.7(S, 3H), 3.1(S, 3H), 4.7(S, 1H), 5.8(ABq, 2H), 5.85(d, 1H), 7.1(d, 1H); Infrared spectra (CHCl ₃) Cm ^-1: 1333,1759,1807,2927,2960.

(B): ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.2(S, 9H), 1.45(S, 3H), 1.6(S, 3H), 3.15(S, 3H), 4.5(S, 1H), 5.6(d, 1H), 5.8(ABq, 2H), 7.2(d, 1H); Infrared spectra (CHCl ₃) Cm ^-1: 1324,1758,1800,2929,2956.

Embodiment 15

6-α-(N-methylpyrrole-2-yl) methylol-

1,1-dioxy penicillanic acid allyl ester

With 520 milligrams of (1.48 mmole) 6-alpha-brominated-11-dioxy penicillanic acid allyl ester is dissolved in 10 milliliters of anhydrous tetrahydro furans (THF), be cooled to-78 ℃ and add (0.52 milliliter of methyl-magnesium-bromide, 2.85M solution in THF stirs this mixture 5 minutes under-78 ℃.Add N-methylpyrrole-2-formaldehyde (CarbOXaldehyde) (162 milligrams, 0.16 milliliter), and continue to stir 20 minutes down at-78 ℃.This mixture is poured in the saturated ammonium chloride solution, used ethyl acetate extraction, drying (is used MgSO ₄) this organic layer.Evaporating solvent is made 466 milligrams of crude products in a vacuum, twists chromatography with silica gel and purifies, and with chloroform-ethyl acetate (9: 1) wash-out, make 180 milligrams (32%) pure title product compound. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.4(S, 3H), 1.62(S, 3H), 3.68(S, 3H), 4.0-4.4(m, 1H), 4.42(S, 1H), 4.5-4.8(m, 3H), 5.0-6.0(m, 4H), 6.0-6.7(m, 3H).

Embodiment 16

6(E)-(N-methylpyrrole-2-yl) methylene radical-

11-dioxy penicillanic acid allyl ester

6-α-(N-methylpyrrole-2-yl) methylol-11-dioxy penicillanic acid allyl ester (180 milligrams, 0.47 mmole) is dissolved in 3 milliliters of tetrahydrofuran (THF)s, adds 0.15 ml acetic anhydride and 0.2 milliliter of pyridine then.At room temperature stirred 1 hour.Water stops this reaction, and uses ethyl acetate extraction.Dry this organic layer, and evaporation is made 162 milligrams of products that still contain raw material except that desolvating in a vacuum.This crude product is dissolved in 3 milliliters of methylene dichloride, and adds 0.15 milliliter of Acetyl Chloride 98Min. and 0.2 milliliter of pyridine.At room temperature stir 2 hours, and handle according to the method described above, make 140 milligrams of thick products, purified, make the straight product of 72 milligrams (42%) with the silicagel column chromatography.After re-crystallizing in ethyl acetate, obtain colourless acicular substance. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.45(S, 3H), 1.65(S, 3H), 3.7(S, 3H), 4.4(S, 3H), 4.6-4.9(m, 2H), 5.1-6.4(m, 4H), 6.6-7.0(m, 2H), 7.5(dd, 1H).

Embodiment 17

6(E)-(N-methylpyrrole-2-yl) Asia

Methyl isophthalic acid 1-dioxy penicillanic acid sodium

To contain 46 milligrams of 6(E)-solution of (N-methylpyrrole-2-yl) methylene radical-11-dioxy penicillanic acid allyl ester, 5 milligrams of tetrakis triphenylphosphine palladiums (0), 4 milligrams of triphenylphosphines and 1 milliliter of methylene dichloride, under nitrogen atmosphere, stirred 5 minutes.With 1 milliliter of ethyl acetate dilution, add the ethyl acetate solution that is dissolved with 0.25 milliliter of 2-ethyl acetic acid sodium then.Stir under the room temperature after 1 hour, filter,, make 30 milligrams of yellow solids with ethyl acetate and ether washing precipitation.

¹H-nucleus magnetic resonance (D ₂O) PPm(δ): 1.50(S, 3H), 1.60(S, 3H), 3.65(S, 3H), 4.10(S, 1H), 5.4(S, 1H), 6.1-6.5(m, 1H), and 7.0(S, b, 2H), 7.2-7.4(m, 1H); Infrared spectra (KBr) Cm ^-1: 1568,1616,1660,1745,3465.

Embodiment 18

With molecular formula is R ¹³The suitable aldehyde of CHO is equivalent to the compound of following structural formula according to the preparation of the working method of embodiment 15:

Silica gel

R ¹³Productive rate % elutriant ^{* 1}H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

30 A 6-alpha-isomers. 1.4(s,

0.39H），1.5（s，2.61H），

1.62（s，0.39H），1.7（s，

2.61H），3.0（bs，1H），

4.0-4.4（m，1H），4.45

（s，1H），4.5-4.9（m，

2H），5.1-6.1（m，4H），

6.3-6.6（m，2H），7.45

（m，1H）.

6 A 6-α-, 8R and 6-α-, 8S

-mixture of isomers

38 A 1.4（s，3H），1.60（s，

3H），2.50 and 2.60（s，

3H），4.1-4.4（m，1H），

4.4 and 4.5（s，1H），

4.6-5.0（m，3H），5.1-

6.0（m，4H），6.0-7.2

（m，4H）.

Embodiment 18(is continuous)

R ¹³Productive rate % elutriant ^{* 1}H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

C ₆H ₅78 A 1.4（s，3H），1.6（s，3H），

3.28（bs，1H），3.8-4.2

（m，1H），4.35（s，1H），

4.45-4.8（m，3H），5.0-6.1

（m，4H），7.3（s，5H）.

33 B 1.3（s，3H），1.55（s，

3H），4.04（bs，1H），4.35

（s，1H），4.5-4.85（m，3H），

5.1-6.1（m，4H），7.1-7.4

（m，1H），7.6-8.0（m，1H），

8.2-8.7（m，2H）.

35 B 1.3（s，3H），1.55（s，3H），

4.0（m，1H），4.35（s，1H），

4.4-4.8（m，3H），5.1-6.2

（m，4H），7.2-7.5（m，2H），

8.2-8.6（m，2H）.

50 B 1.25（s，0.75H），1.35（s，

2.25H），1.55（s，3H），3.3

（bs，1H），4.05（dd，1H），

4.3（s，1H），4.3-4.8（m，

3H），5.0-6.2（m，4H），

6.8-7.4（m，3H）.

Embodiment 18(is continuous)

Silica gel

R ¹³Productive rate % elutriant ^{* 1}H-nucleus magnetic resonance (CDCl ₃) ppm(δ):

CH ₂＝CH 21 1.4（s，3H），1.6（s，3H），

3.0（bs，1H），3.7-4.0（m，

1H），4.4-4.8（m，4H），

5.0～6.3（m，6H）.

25 D 1.36（s，1.5H），1.40（s，

1.5H），1.60（s，1.5H），

1.65（s，1.5H），3.7（s，

3H），4.0-4.5（m，2H），

4.4（s，1H），4.5-4.8

（m，2H），5.0-6.0（m，

4H），6.7（s，1H），6.85

（s，1H）.

52 D 6-α, 8S isomer: 1.4

（s，3H），1.6（s，3H），

4.38（dd，1H），4.43（s，

1H），4.67-4.75（m，2H），

4.76（d，1H），5.3-5.5

（m，2H），5.63（d，1H），

5.85-6.05（m，1H），7.4

（d，1H），7.8（d，1H）.

6-α, 8R isomer 1.36

（s，3H），1.60（s，3H），

4.22（d，1H），4.4（s，1H），

4.65（m，2H），4.88（s，

1H），5.25-5.5（m，2H），

5.55（d，1H），5.8-6.0

（m，1H），7.35（d，1H），

7.75（d，1H）.

Embodiment 18(is continuous)

Silica gel

R ¹³Productive rate % elutriant ^{* 1}H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

42 E 6-α, 8S isomer :-1.44

（s，3H），1.62（s，3H），

3.68（bs，1H），4.31（dd，

1H），4.5（s，1H），4.74

（d，2H），4.86（d，1H），

5.4（m，3H），5.9（m，1H），

7.5（m，3H），8.02（s，

1H), 8.14(m, 2H), infrared light

Spectrum: 3482,1802cm ^-1.

57 crude product A(low-pole low-pole 6-α, 8S

9 low polar isomers) isomer: 1.41(s, 3H),

The strong polarity 1.6(s of the polarity F(of the Final 8,3H), 4.45(s, 1H),

Isomer) 4.4-4.8(m, 4H), 5.2-

5.6（m，3H），5.7-6.3

（m，1H），7.35（t，1H），

8.85（d，2H）.

Strong polarity 6-α,, 8R

Isomer: 1.45(s, 3H),

1.6（s，3H），4.4（s，1H），

4.45（dd，1H），4.7-4.9

（m，2H），4.95（d，1H），

5.2-5.6（m，3H），5.7-

6.3（m，1H），7.35（t，

1H），8.85（d，1H）.

Embodiment 18(is continuous)

Silica gel

R ¹³Productive rate % elutriant ^*H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

First part of 25%, the first part of D: 1.4(s, 3H),

(a kind of isomer) 1.6(s, 3H), 4.2-4.4(m,

12%, the second part of 2H), 4.5-5.0(m, 3H), 5.1-

(6.1(m of two kinds of isomer, 6H), 7.6(d, 1H),

Mixture 8.87(d, 1H), 9.23(s, 1H).

56 D 1.4（s，3H），1.57（s，3H），

(the mixed 4.25(m of isomer, 1H), 4.37(s,

Compound (70: 30) 0.7H), 4.42(s, 0.3H),

4.75（m，2H），4.8（d，

0.3H），4.85（d，0.7H），

5.25-5.5（m，3H），5.9

（m，1H），8.52（m，2H），

8.84（m，1H）.

22 D 1.4（s，1H），1.46（s，2H），

1∶2 1.6（s，1H），1.63（s，2H），

Isomer 4.12(m, 1H), 4.22(m,

Mixture 1H), 4.41 and 4.46(s, 1H),

4.6-4.8（m，2H），4.95（d，

1H），5.2-5.5（m，3H），5.9

（m，1H），6.95 and 7.05（s，

1H），7.28 and 7.36（s，

1H）.

Embodiment 18(is continuous)

R ¹³Productive rate % elutriant ^*H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

35 G 1.38-1.40（d，3H），1.56-

1.57（d，3H），4.20-4.40

Three kinds of isomer (m, 2H), 4.59-4.72(m,

2H），4.86-4.88（d，0.5H），

5.04-5.06（d，0.5H），

5.26-5.42（m，2H），5.50-

5.62（m，1H），5.82-6.00

（m，1H），7.50-7.86（m，

1H），7.90-8.08（m，1H），

9.02-9.10（m，1H），

Infrared spectra

1800cm ^-1.

The used raw material aldehyde of * is 1-diethoxymethyl imidazoles-2-methyl (Carboxalde

-nyde）

A*-chloroform-ethyl acetate (9: 1)

B-ethyl acetate-chloroform (7: 3)

C-chloroform-ethyl acetate (19: 1)

D-chloroform-methanol (19: 1)

E-chlorine is hindered

F-chloroform-ethyl acetate (1: 1)

The G-ethyl acetate

Embodiment 19

6-(furans-2-yl) methylene radical-1.1-two oxapenems

The alkanoic acid allyl ester, (E) isomer and (Z) isomer

To in 5 milliliters of methylene dichloride, being dissolved with 310 milligrams of (0.84 mmole) 6-α-(furans-2-yl) methylol-1, in the solution of 1-dioxy penicillanic acid allyl ester, add 0.14 milliliter of (1 mmole) triethylamine and 0.1 milliliter of (0.924 mmole) trifluoromethyl SULPHURYL CHLORIDE, under nitrogen atmosphere and room temperature, stirred 2 hours.The water termination reaction, dichloromethane extraction, MgSO ₄Drying, evaporation is made 330 milligrams of crude products after removing and desolvating in a vacuum.This product is purified with the silicagel column chromatography, behind the chloroform wash-out, obtain 130 milligrams of products.Through high pressure liquid chromatographic analysis, this product is (E) isomer and (Z) mixture of isomers, and it is than being 4: 1.

¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.47(S, 3H), 1.61(S, 3H), 4.47(S, 1H), 4.75(d, 2H) 5.1-6.2(m, 4H), 5.52(dd, 1H), 6.8(m, 1H), 7.15(d, 1H), 7.6(d, 1H).

Embodiment 20

6(E)-(N-acetyl-pyrrole-2-yl) methylene radical-

11-dioxy penicillanic acid allyl ester

A, 6-(N-acetyl-pyrrole-2-yl) acetyl-o-methyl-

11-dioxy penicillanic acid allyl ester

With 210 milligrams of (0.51 mmole) 6-(N-acetyl pyrrole-2-yls) methylol-1,1-dioxy penicillanic acid allyl ester is dissolved in 3 milliliters of tetrahydrofuran (THF)s, adds 0.16 ml acetic anhydride and 0.2 milliliter of pyridine then, at room temperature mixes 24 hours.Water termination reaction, dichloromethane extraction, extraction liquid are in addition dry and concentrate, and make 171 milligrams of (75%) yellow crystals. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.4(S, 3H), 1.6(S, 3H), 2.15(S, 3H), 2.55(S, 3H), 4.15-4.3(dd, 1H), 4.4(S, 1H), 4.6-4.8(m, 3H), 5.1-6.0(m, 3H), 6.1-6.6(m, 2H), 6.6-7.4(m, 2H).

B, with the N that obtains in 170 milligrams (0.38 mmole) " A ", the O-diacetate esters is dissolved in the methylene dichloride, adds 47 milligrams of (0.38 mmole) 15-diazabicylos (430) ninth of the ten Heavenly Stems-5-alkene (DBN) then.At room temperature stirred 1 hour.Add entry, use dichloromethane extraction then.This extraction liquid is in addition dry and concentrate, make 158 milligrams of oily crude products.Purified with the silicagel column chromatography, used the chloroformic solution wash-out that 2% ethyl acetate is arranged, make 108 milligrams and be flaxen oily product. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.5(S, 3H), 1.6(S, 3H), 2.55(S, 3H), 4.4(S, 1H), 4.65(d, 2H), 5.0-6.0(m, 4H), 6.3(t, 1H), 6.8(dd, 1H), 7.2(m, 1H), 8.2(d, 1H).

Embodiment 21

6(E)-and phenylmethylene-1,1-dioxy penicillanic acid

Allyl ester with and corresponding (Z)-isomer

A, according to the method for A among the embodiment 20, use 1.98 mmole 6-phenyl methylols-1,1-dioxy penicillanic acid allyl ester, 4.2 mmole Acetyl Chloride 98Min.s and 0.4 milliliter of pyridine are made 0.7 gram (84%) and are faint yellow gummy 6-phenyl acetyl-o-methyl-1,1-dioxy penicillanic acid allyl ester.

¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.3 and 1.4(S, 3H), 1.62(S, 3H), 2.08 and 2.2(S, 3H), 4.2(dd, 1H), 4.4(S, 1H), 4.5(d, 1H), 4.65(d, 2H), 6.25(m, 1H), 7.3(m, 5H).

B, in being dissolved with A portion, in the dichloromethane solution of product (0.7 gram, 1.66 mmoles), adds 0.25 milliliter of (1.67 mmole) 1.5-diazabicylo (540) hendecene-(5) (DBU), then at room temperature with this mixture stirring 10 minutes.Add entry and methylene dichloride, separate this organic layer and washed with 0.1 equivalent hydrochloric acid, salt solution and water.Organic extract liquid is through Na ₂SO ₄Drying, evaporation removes and desolvates, and makes 660 milligrams of crude products.Carry out chromatograph with 100 gram silica gel as carrier and purify, the chloroform wash-out has been made (the Z)-isomer of 68 milligrams (11%).

¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.45(S, 3H), 1.60(S, 3H), 4.45(S, 1H), 4.68(d, 2H), 5.37(d, 1H), 5.1-6.05(m, 3H), 7.35(d, 1H), 7.45(S, 1H).From elutriant, make title (E)-isomeric compound that 100 milligrams (16.7%) are colorless oil, become crystal after the placement. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.45(S, 3H), 1.58(S, 3H), 4.45(S, 1H), 4.75(d, 2H), 5.45(d, 1H), 5.2-6.2(m, 3H), 7.36(d, 1H), 7.45(S, 5H).

Embodiment 22

Select suitable oxy-compound in the material that utilization provides from embodiment 18, the working method that adopts according to embodiment 19 is prepared as follows compound:

R ³Productive rate % silica gel elutriant ¹H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

22(E) ether (E)-isomer: 1.5(s, 3H),

19（Z） 1.7（s，3H），4.5（s，1H），

4.7（d，2H），5.5（d，1H），

5.1-6.2（m，3H），7.3-7.5

（m，2H），7.7-8.0（m，1H），

8.53-8.83（m，2H）.

(Z)-isomer: 1.48(s, 3H),

1.6（s，3H），4.5（s，1H），

4.7（d，2H），5.25（s，1H），

5.1-6.2（m，3H），6.88（s，

1H），7.2-7.5（m，1H），

8.43-9.0（m，3H）.

36 ethyl acetate-mixed isomers: 1.45(s,

Hexane 3H), 1.62(s, 3H), 4.5

（1∶1） （s，1H），4.7（d，2H），5.2-

6.2（m，4H），6.75（s，

0.3H），7.2-7.5（m，1.7H），

7.6-7.85（m，1H），8.5-

8.83（m，2H）.

Embodiment 22(is continuous)

R ³Productive rate silica gel elutriant ¹H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

14 chloroform 1.45(s, 3H), 1.6(s ,-3H),

4.4（s，3H），4.7（d，2H），

5.0-6.2（m，3H），5.25（d，

1H），7.0-7.65（m，4H）.

CH ₂=CH-18 chloroform 1.45(s, 3H), 1.65(s, 3H),

3.7-4.2（m，1H），4.45（s，

0.6H），4.5（s，0.4H），

4.75（d，2H），5.1-6.4

（m，7H）.

Embodiment 23

With the 6-R that provides among the embodiment 19-22 ³-methylene radical-1,1-dioxy penicillanic acid allyl ester be as raw material, prepares following sodium salt according to the method for embodiment 17.Use under the condition of 2 ethyl hexanoic acid potassium, can make corresponding sylvite.

Embodiment 24

6(E) Ben Yajiaji penicillanic acid-1, the 1-dioxide

Be dissolved with 0.1 gram (0.28 mmole) 6(E)-Ben Yajiaji-1, in 3 milliliters of ethyl acetate solutions of 1-dioxy penicillanic acid allyl ester, 20 milligrams of triphenyl phosphines and 20 milligram of four (triphenyl phosphine) palladium (0), add concentration and be 0.5 mole, volume and be 0.57 milliliter 2 ethyl hexanoic acid sodium, this mixture was at room temperature stirred 1 hour.Place in refrigerator after 65 hours, do not have precipitation, with ethyl acetate and water dilution, it is 1.8 that dilute hydrochloric acid is regulated the PH that isolates water layer, with fresh ethyl acetate extraction, extraction liquid is carried out drying (N ₂SO ₄), under vacuum, boil off solvent, obtain 62 milligrams of (69%) products, be yellow crystal (from acetone).H '-nucleus magnetic resonance (CD ₃COCD ₃) PPM(δ): 1.55(S, 3H), 1.65(S, 3H), 4.43(S, 1H), 5.93(d, 1H), 7.3-7.9(m, (6H), 8.7(bS, 1H); Infrared spectra (Potassium Bromide) cm ^-1: 1327,1685,1737,1772,2929,2961,3108,3477.

Embodiment 25

6(E)-and (1-Methylimidazole-2-yl)-methylene radical-1,1-dioxy penicillanic acid potassium

A, 6-(1-Methylimidazole-2-yl) acetoxyl methyl isophthalic acid, 1-dioxy penicillanic acid allyl fat

With 6-(1-Methylimidazole-2-yl) methylol-1; 1-dioxy penam acid esters (472 milligrams, 1.23 mmoles) carries out acetylize with the method for embodiment 20A; obtain 392 milligrams of (75%) acetoxyl compounds, this compound is the mixture of two isomerss. ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.4(S, 1.5H), 1.5(S, 1.5), 1.6(S, 1.5H), 1.7(S, 1H), 2.2(S, 3H), 3.7(S, 1.5H), 3.75(S, 1.5H), 4.0-6.0(m, 8H), 6.3-6.5(m, 1H), 6.8(m, 1H), 7.0(m, 1H).

B, 6(E)-(1-Methylimidazole-2-yl) methylene radical-1,1-dioxy penicillanic acid allyl ester

With the method for embodiment 20B, with the product (392 milligrams, 0.920 mmole) that obtains among the above-mentioned A, 5 milliliters of methylene dichloride and 0.115 milliliter 1,5-diazabicylo (4,3,0)-ninth of the ten Heavenly Stems-its productive rate of fat that 5-alkene (DBN) changes this title into is 53%. ¹H-nucleus magnetic resonance (CDCL ₃) PPM(δ): 1.5(S, 3H), 1.6(S, 3H), 3.7(S, 3H), 4.35(S, 1H), 4.7(m, 2H), 5.0-6.1(m, 3H), 5.7(d, 1H), 6.9(m, 1H), 7.1(d, 1H), 7.2(m, 1H).

The method of C, usefulness embodiment 17, the allyl ester (163 milligrams, 0.45 mmole) that obtains among the B is changed into the sylvite of this title, wherein replace corresponding sodium salts with the 2 ethyl hexanoic acid potassio, this that obtains kind of product reaches 143 milligrams (productive rates of 87%), is single (E) isomers. ¹H-nucleus magnetic resonance (dimethyl alum) PPm(δ): 1.38(S, 3H), 1.45(S, 3H), 3.8(S, 4H), 5.68(S, 1H), 7.15(S, 1H), 7.35(m, 2H); ¹³C-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)) PPm(δ): 18.5,20.2,32.5,64.4,66.2,70.55,115.2,124.6,129.9,130.6,141.2,167.9,169.0.Infrared spectra (Potassium Bromide) Cm ^-1: 1614,1762,3428.

Embodiment 26

Repeat the step of embodiment 10, with 50 milligrams of (0.12 mmole) 6-(3-allyl oxygen-2-pyridyl) methylene radical-1,1-dioxy penicillanic acid allyl ester and 5.2 milligrams of triphenyl phosphines that are dissolved in 1.5 milliliters of ethyl acetates, 5.2 milligram four (triphenyl phosphine) palladium (0) and 0.24 mmole 2 ethyl hexanoic acid potassium (2 moles of initiator acrylate) mix, stirred this mixture 18 hours, remove ethyl acetate with transfer pipet and resistates is carried out washed twice with ethyl acetate (1 milliliter every part), obtain the solid product of a black, weigh 43 milligrams, this black solid product is 6-(E)-(3-hydroxyl-2-pyridyl) methylene radical 1, the di-potassium of 1-dioxy penicillanic acid. ¹H-nucleus magnetic resonance (D ₂O) PPm(δ): 1.56(S, 3H), 1.62(S, 3H), 4.27(S, 1H), 6.00(d, 1H), 7.29(m, 2H), 7.80(d, 1H), 8.04(d, 1H).

Embodiment 27

6(E)-(2-pyrimidyl) methylene radical penicillanic acid allyl ester

A, 2-oxymethylpyrimidine

To add 18 gram (163 mmole) hydrochloric acid hydroxyl acetamidines, 8.06 milliliters of (81 mmole) 3-with the pulpous state sodium ethylate cool to room temperature of 7.44 gram (323 mmole) sodium Metal 99.5s and 300 milliliters of dehydrated alcohol preparations

Methyl ammonia propenal refluxes this mixture heating up, slowly distills out dimethylamine, meanwhile regularly adds ethanol to keep solvent volume.Reflux after 9 hours, this mixture was at room temperature stirred 18 hours again, reduction vaporization injects silicagel column with resistates, carries out wash-out with ethyl acetate/methanol (19: 1), obtains 4.1 gram products (productive rate is 46%)

B, chlorination 2-pyrimidine Jia base San Ben Phosphonium

With 80 milliliters of methylene dichloride dissolvings, 4.096 gram (37.2 mmole) 2-oxymethylpyrimidine, drop by drop add 8.6 milliliters of thionyl (two) chlorine (3.72 mmole) (heat release) again.This mixture was stirred 15 minutes,, use dichloromethane extraction with saturated sodium hydrogen carbonate solution neutralization.Dry this extraction liquid boils off solvent and obtains 2-chloromethyl pyrimidine 3.67 grams. ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 4.82(S, 2H), 7.3(t, 1H), 8.9(d, 2H).

To be dissolved in 30 milliliters of 2-chloromethyl pyrimidines 3.565 grams (27.7 mmole) and mixture reflux of triphenyl phosphine 7.269 grams (27.7 mmole) 18 hours in the toluene, filter, dry resulting throw out, product weighs 9.06 grams (65%, two goes on foot)

C, the Wittig reagent among the above-mentioned B 2.187 gram (5.6 mmole), sodium amide 218.4 milligrams (5.32 mmole) and anhydrous tetrahydro furan (THF) are mixed for 30 milliliters, at room temperature stirred 1.5 hours, add at-78 ℃ next time and to be dissolved in 10 milliliters of anhydrous THF(tetrahydrofuran (THF)s) in 1.44 gram (5.65 mmole) 6-oxapenam allyl propionate solution, after mixture stirred 5 minutes, be poured in the saturated ammonium chloride solution, use chloroform extraction.Organic phase is washed with saturated ammonium chloride washing, salt, dry (MgSO ₄), under vacuum, boil off solvent, make carrier with silica gel, carry out the oily matter that purifying obtains with column chromatography, carry out wash-out with chloroform/ethyl acetate of 9: 1, straight product weighs 560 milligrams. ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.5(S, 3H), 1.6(S, 3H), 4.6(S, 1H), 4.7(m, 2H), 5.1-6.3(m, 3H), 6.2(d, 1H), 7.0(d, 1H), 7.0-7.35(m, 1H), 8.8(d, 2H).

Embodiment 28

1,1-dioxo-6(E)-(2-pyrimidyl-) methylene radical penicillanic acid allyl ester and sylvite

A, with 10 milliliters of methylene dichloride dissolving 6(E)-(2-pyrimidyl)-methylene radical penicillanic acid allyl ester (560 milligrams, 1.69 mmoles) and 730 milligrams of 3-chlorine peroxybenzoic acid (3.38 mmole), stirring is 4 hours under nitrogen atmosphere.The water termination reaction, dichloromethane extraction, Sulfothiorine washing extract, the sodium bicarbonate neutralization, drying and concentrated is carried out in the salt water washing under vacuum, obtain 460 milligrams of thick oily matter.With this oily matter of silica gel column chromatography purifying, with chlorine part/eluent ethyl acetate of 9: 1, obtain the allyl ester of 180 milligrams of needs, be faint yellow solid. ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.45(S, 3H), 1.65(S, 3H), 4.5(S, 1H), 4.75(m, 2H), 5.2-6.3(m, 3H), 5.75(S, 1H), 7.1-7.5(m, 2H), 8.9(d, 2H).

B, with the method for embodiment 10, make above-mentioned allyl ester and triphenyl phosphine, four (triphenyl phosphine, palladium (0) and 2-second caproic acid potassium react, and obtain the sylvite of needs, productive rate is 89%, is the light red solid. ¹H-nucleus magnetic resonance (D ₂O) PPm(δ): 1.6(S, 3H), 1.68(S, 3H), 4.4(S, 1H), 6.1(S, 1H), 7.48(S, 1H), 7.54(t, 1H), 8.88(d, 2H); ¹³C-nucleus magnetic resonance (D ₂O) PPm(δ): 20.9,22.7,68.8,68.9,74.6,124.5,132.5,139.9,160.9,163.2,172.5,175.5.Infrared spectra (Potassium Bromide) cm ^-1: 1560,1615,1771,3439.

Embodiment 29

With 50 milligrams of di-isopropyl carbodiimide, 0.5 milliliter 2,2, the 2-ethapon joins in 25 milliliters of methylene dichloride that are dissolved with 1.0 gram 6-Alpha-hydroxy penicillanic acids, stirring is spent the night, and evaporation removes and desolvates in a vacuum, is carrier with silica gel, use the column chromatography purifying crude product, obtain 6-Alpha-hydroxy penicillanic acid-2,2, the 2-trichloro ethyl ester.

B, 0.5 right-toluenesulphonic acids of gram and 0.4 gram dihydropyrane are joined in 50 milliliters of dioxs of the 1.0 gram 6-Alpha-hydroxy penicillanic acids that are dissolved with, add ratio of specific heat mixture to 50 ℃, at room temperature stir then and spend the night, boil off solvent, make carrier with silica gel, chromatography purification obtains 6-Alpha-hydroxy penicillanic acid-2-tetrahydropyrans ester.

Embodiment 30

6-oxapenam acid benzyl ester

2.12 milliliters of (0.015 mole) trifluoroacetic anhydrides are dissolved in the solution that obtains in 5 milliliters of methylene dichloride, under-60 ℃, are added drop-wise to and are dissolved with 2 milliliters, in the 2ml α dichloromethane solution of 1.8 milliliters of (0.025 mole) methyl-sulphoxides.Under-60 ℃, this mixture was stirred 20 minutes, add 350 milligrams (1.14 mmoles), the 6-Alpha-hydroxy penam acid benzyl ester in 5 milliliters of methylene dichloride, continue to stir 60 minutes down at-60 ℃.Add (0.50 milliliter) triethylamine, remove cryostat, be heated 0 ℃ and pour in the frozen water, use dichloromethane extraction.Dry this organic layer, simmer down to one small volume dilutes with benzene in a vacuum, frozen water washing three times.The dry benzene layer boils off solvent and obtains 230 milligrams of (67%) yellow crystal products, at CDCL in the vacuum ₃In, proton-nmr analysis shows that this product is very pure.

Embodiment 31

The 6-(2-pyridyl) methylol penam acid benzyl ester

A, 6-bromo-6(2-pyridyl) methylol penam acid benzyl ester

Be dissolved in 9.0 in 200 milliliters of new toluene distillations grams (0.02 mole) 6,6-dibromo penicillanic acid benzyl ester solution is cooled to-78 ℃, and to drip concentration be 2.2 moles, be dissolved in 9 milliliters of spy-butyllithiums in the pentane.This mixture is stirred adding in 30 minutes 2.14 gram (0.02 mole) 2-pyridine-formaldehyde, continue again and stirred 40 minutes.Splash into the acetic acid that is dissolved in the toluene and stop this reaction.Stirred 1 hour, and removed cryostat and be heated to-10 ℃, with 200 milliliters of dilution with toluene, wash (5 times), dry (Na with water ₂SO ₄).This toluene solution is injected Magnesium Silicate q-agent (1 kilogram) carrier post, with 2: 1 toluene/ethyl acetate wash-out.The elutriant that contains product is merged, and evaporation obtains the brown pulpous state product of 4.2 grams in a vacuum, for next step usefulness.

B, the brown pulpous state product among the A (4.2 gram) is dissolved in 50 milliliters of benzene, add tributyltin chloride 2.65 grams, reflux 2 hours, add tributyltin chloride ← (1.65 gram) again, continue reflux and spend the night, boil off solvent in the vacuum, with this resistates of hexane wash, be injected in the post of 500 gram silica gel,, obtain 425 milligrams of the compounds of this title with 2: 1 toluene/ethyl acetate wash-out. ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.35(S, 3H), 1.7(S, 3H), 4.0(dd, 1H), 4.5(S, 1H), 5.1(S, 2H), 5.2(d, 1H), 5.4(d, 1H), 7.0-7.8(m, 3H), 8.5(m, 1H).

Embodiment 32

The 6-(2-pyridyl) methylol penicillanic acid 1, the 1-dioxide

A, 6-(2-pyridyl) methylol-1,1-dioxy penam acid benzyl ester

With 0.20 gram--the chlorine peroxybenzoic acid, be added to and be dissolved with 0.40 gram 6-(2-pyridyl)-the 5mL dichloromethane solution of methylol penam acid benzyl ester in, at room temperature, stirred this mixture 1 hour.Thin-layer chromatographic analysis show this mixture contain sulfoxide add again 0.2 the gram between-the chlorine peroxybenzoic acid, stirring is spent the night.With the methylene dichloride dilution, more successively with saturated thiosulfonic acid sodium solution, water, saturated sodium bicarbonate solution washing, organic layer concentrates in a vacuum subsequently.Residue is leached with ethyl acetate, with sodium hydrogen carbonate solution, water, salt water washing, dry (Na ₂SO ₄).Boil off solvent, obtain 330 milligrams of desired, brown oily benzyl esters, carry out purifying,, obtain 60 milligrams of yellow oily products with 11: 9 ethyl acetate/hexane wash-out with silica gel column chromatography. ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.25(S, 3H), 1.52(S, 3H), 4.1(dd, 1H), 4.5(S, 1H), 4.72(d, 1H), 5.5(d, 2H), 5.8(d, 1H), 7.1-8.0(m, 3H), 8.5(m, 1H).

B, in three atmospheric nitrogen atmosphere, make the suspension of 118 milligrams of 10%pd/C catalyzer in 10 milliliters of tetrahydrofuran (THF)s and 4 ml waters give hydrogenation 20 minutes, with obtain among the A in the above, be dissolved in 4 milliliters of benzyl esters in same tetrahydrofuran (THF)/water mixture and be added in this suspended substance for 130 milligrams, at 50 pounds/inch ²(3.5 kilograms per centimeter ²) pressure under, hydrogenation 30 minutes.The Pd/C catalyzer that adds 129 milligram 10% again, and at 50 pounds/cun ²Under the pressure, continue hydrogenation 2 hours.Remove by filter its catalyzer, boil off solvent in a vacuum, resistates is distributed in water and the ethyl acetate and the water layer lyophilize is obtained 85 milligrams of the acid that need. ¹H-nucleus magnetic resonance (D ₂O) PPm(δ): 1.3(S, 3H), 1.5(S, 3H), 4.4(S, 1H), 5.0-5.35(m, 2H), 5.9(d, 1H); Infrared spectra (Potassium Bromide) Cm ^-1: 1620,1731,3407.

C, adopt above-mentioned steps, but need with the amount among the A reach 175 milligrams between-chlorine peroxybenzoic acid (etc. gram molecular weight), separate the product that obtains and be corresponding α-and mixture of β-Ya.

Embodiment 33

Following material is mixed by the weight ratio of following provisions, to obtain forming uniform powder:

(a) (6-α, 8R)-the 6-(thiazol-2-yl)-the acetoxyl methyl isophthalic acid, 1-dioxy penicillanic acid potassium 1.0

(b) ampicillin 3 hydrates 1.0

(c) lactose 0.5

(d) polyoxyethylene glycol, molecular-weight average are 4,000 3.0

Being filled in suitable, the hard gelatine capsule of size mixture (1375 milligrams) to obtain each active ingredient is 250 milligrams glue.As making the more or less capsule of active ingredient, as long as the weight of suitable capsular size of adjusting and weighting material is just passable.For the relative weight of making active ingredient than the capsule that is not 1, as long as adjusted the relative weight of active ingredient.For example, by 0.75,1.5,0.5,3.0 weight mixed active material recently, stopping composition weight is 1700 milligrams/capsule respectively, and (a) active substance composition is 225 milligrams in the capsule that obtains, and (b) the active substance composition is 450 milligrams.

With same way, prepare other penicillinase inhibitor for oral use by other habitual beta-Lactam antibiotics.

Another kind of way is, with (the 6-(D-2-amino-2-phenylacetyl amido) of 2 parts of weight) penicillanic acid methylol 6-(2-pyridyl) methylene radical-1,1-dioxy penicillanic acid hydrochloride replaces the active ingredient (a) and (b) in the above-mentioned prescription.

Embodiment 34

Injectable preparation

With heavy Cefoperazone sodium and 1 such as equal portions, the 1-dioxy-6(E)-(2 pyrazinyl) methylene radical penicillanic acid potassium mixes with the water of 20 parts of weights, with the standard method in the medical technology, this solution is carried out sterile filtration, pack in the phial, its tubular bottle cap places the pallet lyophilize with the soft rubber ball of pine, and the volume of packing into make the content of (seal this moment) every kind of active ingredient in each lyophilize phial under vacuum be 500 milligrams.Before injection, in bottle, inject 10 milliliters of Injectable sterile water by soft rubber ball, shake and make it dissolving, during use with hypodermic needle via soft rubber ball sucking-off 1-10 milliliter injection therefrom.

Embodiment 35

The 6-(2-thiazolyl) acetoxyl methylene radical-1,1-dioxy penicillanic acid allyl ester

Method with embodiment 20A; with 0.5 gram (1.29 mmole) 6-(2-thiazolyl) methylol-1; 1-dioxy penicillanic acid allyl ester (embodiment 18 preparations); in 5 milliliters of tetrahydrofuran (THF)s 0.396 restrain (3.88 mmole) second (acid) acid anhydride and 0.307 gram (3.88 mmole) pyridine carries out acetylize with being dissolved in; at room temperature stirred 4 hours; with the methylene dichloride dilution, wash with water up to neutral (pH6.0-6.5), dry organic phase (Na ₂SO ₄), will obtain the required acetic ester of 0.688 gram after the solvent evaporation. ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.52(S, 3H), 1.70(S, 3H), 2.35(S, 3H), 4.4-4.6(m, 2H), 4.6-5.0(m, 3H), 5.2-6.4(m, 3H), 6.65(d, 1H), 7.4(d, 1H), 7.8(d, 1H).

Embodiment 36

The 6-(2-thiazolyl)-and methylene radical-1,1-dioxy penicillanic acid allyl ester and it are hydrolyzed to sylvite

With above-mentioned acetoxyl ester (0.688 gram, 1.29 mmoles) and 0.16 gram (1.29 mmole) 1,5-diazabicylo (430)-ninth of the ten Heavenly Stems-5-alkene (DBN) and 5 milliliters of methylene dichloride mixing, at room temperature stirred 1 hour, with methylene dichloride dilution, water washing (2 * 50 milliliters), dry (Na ₂SO ₄), boil off solvent and obtain an oily matter.Make carrier with silica gel, carry out chromatographic separation, to obtain 0.189 gram product (39%), be light yellow oil with 1: 1 ethyl acetate/hexane wash-out. ¹H-nucleus magnetic resonance (CDCL ₃)-PPm(δ): 1.53(S, 3H), 1.65(S, 3H), 4.33(S, 1H), 4.55(d, 2H), 5.0-5.4(m, 2H), 5.45(S, 1H), 5.4-6.0(m, 1H), 7.1(m, 1H), 7.75(m, 1H), 7.65(d, 1H).

The allyl ester that B, hydrolysis embodiment 25C make then can obtain the 6-(2-thiazolyl) methylene radical-1,1-dioxy penicillanic acid potassium, a step productive rate is 84.7%, product is a yellow solid. ¹H-nucleus magnetic resonance 250MHZ(DMSO-D ₆) PPm(δ): 1.40(S, 3H), 1.45(S, 3H), 3.80(S, 1H), 5.83(S, 1H), 7.66(S, 1H), 8.04(m, 2H).

Embodiment 37

6-(D-(2-(1-methyl-2 methoxycarbonyl vinyl amino)-2-phenyl kharophen)) penicillanic acid TBuA

In 300 milliliters of chloroforms, add 39.3 gram 6-(D-(2-amino-2-phenylacetylamino)) the penicillanic acid trihydrate, add 50 ml waters, it is 8.5 that the tetrabutylammonium with 40% is regulated pH.Two separate is come out, and its water layer adds sodium sulfate makes it saturated, extracts with fresh chloroform.Extract is mixed with initial bottom, boil off solvent and obtain about 250 milliliters of product.

In 250 milliliters of products, add 150 milliliters of methyl acetoacetates and 30 gram anhydrous magnesium sulfates.Reflux mixture 3 hours allows it clarify, and the organic layer of decantation heat in order to obtain this title crystalline compounds, makes the cooling of clarification chloroformic solution, and productive rate is 52%.Fusing point 182-184 ℃ (decomposition). ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 0.8-2.0(m, 4H), 1.88(S, 3H), 3.1-3.6(m, 8H), 3.6(S, 3H), 4.17(S, 1H), 4.58(S, 1H), 5.05(d, 1H), 5.38-5.6(m, 2H), 6.78(d, 1H), 7.35(S, 5H), 9.4(d, 1H).

Embodiment 38

6-(D-(2-(1-methyl-2-methoxycarbonyl vinyl amino)-2 (4-hydroxyl-phenyl) kharophen)) penicillanic acid tetrabutylammonium

In 300 milliliters dichloro-methane, add 4.19 gram 6-(2-amino-2-(4-hydroxyphenyl) kharophens) penicillanic acid trihydrate and 50 ml waters, the tetrabutylammonium hydroxide aqueous solution with 40% is transferred to 8.5 to pH.At this moment be three layers, the superiors of removal add sodium sulfate and make it saturated, with the extraction of dichloro-methane, middle layer, orlop are mixed with this extraction liquid, and this mixture of vacuum-evaporation obtains oily matter, this oily matter crystallization when developing with acetone.It heavily is 44.6 grams, is 6-(2-amino-2-(4-hydroxyphenyl) kharophen)-the penicillanic acid tetrabutylammonium.

This salt is added in 150 milliliters of methyl acetoacetates, this suspended substance be heated to about 65 ℃ till the solution that varnish occurs (8 minutes).Allow its cooling, with this solid of reclaiming by filtration, wash with methyl acetoacetate, and then, obtain 49.25 gram 6-(2-(1-methyl-2-methoxycarbonyl vinyl amino)-2-(4-hydroxyphenyl) acetamidos with the diethyl ether washing) penicillanic acid tetrabutylammonium crystal.

Embodiment 39

(6-α, 8S)-the 6-pyrimidine-2-base) methylol-1,1-dioxy penicillanic acid potassium

Be dissolved with 300 milligrams (0.79 mmoles) the at first isomer 6-α of wash-out-(pyrimidine-2-base) methylol-1, in the 4ml ethyl acetate solution of 1-dioxy penicillanic acid allyl ester (embodiment 18 obtains), add 30 milligram of four (triphenyl phosphine palladium (0) and 30 milligrams of triphenyl phosphines, under nitrogen atmosphere, stir this mixture and make it solvation (5-10 minute), add 1.57 milliliters of (0.79 mmole) 2 ethyl hexanoic acid potassium that are dissolved in the ethyl acetate.After at room temperature stirring 20 minutes, filter, use the ethyl acetate washing leaching cake, drying obtains 53 milligrams of yellow solids.Filtrate is handled to carry out the precipitation second time with ether, can obtain 152 milligrams of solids again, and total productive rate is 69%. ¹The H-nucleus magnetic resonance, 250MHz, (DMSO-d ₆) PPm(δ): 1.33(S, 3H), 1.44(S, 3H), 3.77(S, 1H), 3.95(d or d, J=2, J=6,1H), 4.89(d, J=2,1H), and 5.1(d, J=6,1H), 6.33(S, 1H), 7.48(t, t=4,1H), and 8.84(d, J=4,2H).

B, (6-α, 8R)-the 6-pyrimidine-2-base) methylol-1,1-dioxy penicillanic acid potassium

Use aforesaid method, isomer 6-α-(pyrimidine-2-base) methylol-1 of wash-out 300 milligrams (0.79 mmole) second time, 1 dioxy penicillanic acid allyl ester (obtaining among the embodiment 18) solution changes its sylvite into, obtains 236 milligrams of products (79%). ¹The H-nucleus magnetic resonance, 250MHz(dimethyl sulfoxide (DMSO)-d ₆) PPm(δ): 1.30(S, 3H), 1.42(S, 3H), 3.65(S, 1H), 4.60(dd, J=2, J=8,1H), and 4.75(d, J=2,1H), and 5.15(d, J=8,1H), and 7.47(t, J=4,1H), and 8.85(d, J=4,2H).

Embodiment 40

A, (6-α, 8S)-the 6-(pyrimidine-2-base) acetoxyl-methyl isophthalic acid, 1-dioxy penicillanic acid allyl ester

In 4 milliliters of methylene dichloride, dissolve 785 milligrams (2.1 mmoles) the at first isomer 6-α of wash-out-(pyrimidine-2-base) methylol-1, in the solution that 1-dioxy penicillanic acid allyl ester obtains (obtaining among the embodiment 18), add 0.45 milliliter of (5.6 mmole) pyridine and 0.53 milliliter of (5.6 mmole) diacetyl oxide again, this mixture at room temperature stirred 2.5 hours.With 30 milliliters of methylene dichloride dilutions, anhydrous magnesium sulfate drying is used in water extraction (7 * 60 milliliters), filters, and vaporising under vacuum obtains 813 milligrams of described compounds of (92%) this exercise question. ¹H-nucleus magnetic resonance (CDCI ₃) PPm(δ): 1.4(S, 3H), 1.6(S, 3H), 2.2(S, 3H), 4.45(S, 3H), 4.45(dd, 1H), 4.75(m, 2H), 4.95(d, 1H), 5.2-5.6(m, 2H), 5.7-6.3(m, 1H), 6.45(d, 1H), 7.35(t, 1H), 8.85(d, 1H).

B, (6-α, 8R)-the 6-pyrimidine-2-base)

The acetoxyl methyl isophthalic acid, 1-dioxy penicillanic acid allyl ester

Isomer 6-α-(pyrimidine-2-base) methylol-1 of the wash-out second time, 1-dioxy penicillanic acid allyl ester (obtaining in embodiment 18) carries out acetylize, has obtained the described compound of exercise question with aforesaid method, and productive rate is 88%. ¹H-nucleus magnetic resonance (CDCI ₃) PPm(δ): 1.4(S, 3H), 1.6(S, 3H), 4.45(S, 1H), 4.50(dd, J=1, J=8,1H), 4.75(m, 2H), 4.8(d, J=1,1H), 5.25-5.6(m, 2H), 5.7-6.3(m, 1H), 6.4(d, J=8,1H), 7.35(t, J=6,1H), 8.8(d, J=6,1H).

Embodiment 41

A, (6-α, 8S)-the 6-(pyrimidine-2-base) the acetoxyl methyl isophthalic acid, 1-dioxy penicillanic acid potassium

Step with embodiment 54, make 789 milligrams of (1.86 mmole) (6-α that are dissolved in 4 milliliters of ethyl acetate, 8S)-and the 6-pyrimidine-2-base) the acetoxyl methyl isophthalic acid, 1-dioxy penicillanic acid allyl ester solution reaction, obtain 342 milligrams of sylvite that (43%) is required, with medium pressure liquid chromatography method purifying, 9: 1 water/acetonitrile wash-out, obtain 105 milligrams of products (through high pressure liquid chromatographic analysis, purity is 85%).

B, (6-α, 8R)-the 6-(pyrimidine-2-base) the acetoxyl methyl-

1,1-dioxy penicillanic acid potassium

With same step, make 666 milligrams of (1.57 mmole) (6-α, 8R)-and the 6-(pyrimidine-2-base) the acetoxyl methyl isophthalic acid, 1-dioxy penicillanic acid allyl ester solution reacts, obtain the thick product of 339 milligrams (51%), through medium pressure liquid chromatography method purifying, 9: 1 water/acetonitrile wash-out obtains 162 milligrams of pure isomers. ¹The H-nucleus magnetic resonance, 250MHz, (DMSO-d ₆) PPm(δ): 1.34(S, 3H), 1.44(S, 3H), 2.17(S, 3H), 3.65(S, 1H), 4.15(dd, J=2, J=8,1H), and 4.97(d, J=2,1H), 6.27(d, J=8,1H), 7.50(t, J=5,1H), and 8.85(d, J=5,2H).

Embodiment 42

With the method for embodiment 20 or 55, be used in the suitable initial reactant of embodiment 18 preparations, i.e. 6-R ¹³CHOH(replaces)-1,1-dioxy penam acid esters prepares following acetic ester:

C ₆，C ₈

R ¹³Stereochemistry productive rate % ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ):

6-α，8S 100 1.43，（s，3H），1.63（s，

And 3H), 2.25(s, 3H), 4.51

6-alpha，8R （m，2H），4.79（m，2H），

Mixture 5.43(m, 2H), 5.98(m,

1H），6.65（d，1H），7.5

（m，3H），7.98（s，1H），

8.20（m，2H）.

69 1.4（s，1.8H），1.43（s，

6-α, 8S and 1.2H), 1.56(s, 1.2H),

6-α，8R 1.62（s，1.8H），2.2（s，

60: 40 mixture 1.2H), 2.3(s, 1.8H),

4.35（m，1H），4.4（s，

0.6H），4.43（s，0.4H），

4.78（d，0.6H），4.8（d，

0.4H），5.3-5.5（m，2H），

5.8-6.05（m，1H），6.3

（m，1H），7.45（d，1H），

8.82（d，1H），9.25（m，

1H）.

C ₆，C ₈

R ¹³Stereochemistry productive rate % ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ):

66 1.4（s，1.8H），1.5（s，

6 α, 8S and 1.2H), 1.6(s, 1.8H),

6α，8R 1.65（s，1.2H），2.2（s，

1.2H），2.26（s，1.8H），

Mixture 4.23(dd, 0.4H), 4.35

（60∶40） （dd，0.6H），4.4（s，

0.6H），4.45（s，0.4H），

4.68（m，2H），4.74（d，

0.6H），5.0（d，0.4H），

5.35（m，2H），5.9（m，1H），

6.45（m，1H），8.6（m，

2H），8.75（m，1H）.

Embodiment 43

With the method for embodiment 54, the 8-acetoxyl-3-ketonic oxygen allyl ester of preparation in embodiment 25A and 57 is converted into the sylvite of following structural formula.

C ₆，C ₈

R ¹³Stereochemistry productive rate % ¹H-nucleus magnetic resonance (D ₂₀) PPm(δ):

65: 35 57, be purified: 1.45(s, 3H),

6-α, 8S(is thick) (crude) 1.58(s, 3H), 1.25(s,

6-α，8R 21， 1.05H），1.32（s，1.95H），

(chromatogram is divided 4.25(s, 0.65H), and 4.28

From purifying (s, 0.35H), 4.37(dd,

0.65H），4.45（dd，0.35H），

Mix with dividing 5.15(d, 0.65H), 5.2(d,

Isomer) 0.35H), 6.25(d, 0.65H),

6.35（d，0.35H），7.73

（m，1H），8.85（m，1H），

9.15（m，1H）.

6∶1 64 1.44（s，3H），1.5（s，

6-α，8S 3H），1.62（s，3H），2.2

6-α，8R （s，0.4H），2.24（s，2.6H），

3.8（s，3H），4.27（s，1H），

4.4（dd，1H），4.96（d，

1H），6.45（d，0.15H），

6.5（d，0.85H），7.07（s，

0.15H），7.1（d，0.85H），

7.16（s，0.15H），7.2（d，

0.85H）.

Infrared spectra (Potassium Bromide): 3409,

1786，1740，1650Cm ^-1

C ₆，C ₈

R ¹³Stereochemistry productive rate % ¹H-nucleus magnetic resonance (DMS ₀-d ₆) PPm(δ):

30∶70 84， 1.3（s，2.1H），1.34（s，

6 α, 8S (slightly) 0.9H), 1.42(s, 3H), 2.13

43，

6 α, 8R (the chromatogram branch (s, 0.9H), 2.2(s, 2.1H),

From the back) 3.66(s, 0.7H), 3.7(s,

0.3H），4.1（dd，0.3H），

4.95（d，0.7H），5.07（d，

0.3H），6.24（d，0.3H），

6.36（d，0.7H），8.7（s，

2H），8.8（s，0.7H），8.83

（s，0.3H）.

Infrared spectra (Potassium Bromide): 3468,

1781，1746，1623Cm ^-1

* adopt C ₁₈(C ₁₈Be silicic acid list stearyl) post.

Embodiment 44

With the method for embodiment 20B, following and 8-acetic ester that provide are above changed into corresponding 6-methylene compound, and remove allyl group to obtain the following sylvite of structural formula, wherein R with the method for implementing 54 ¹Be potassium.

Embodiment 45

6-(imidazoles-2-yl) methylol-1.1-dioxy penicillanic acid potassium

In nitrogen atmosphere, with 141 milligrams of (0.38 mmole) 6-(imidazoles-2-yls) methylol-1, the mixture that 1-dioxy penicillanic acid allyl ester (mixed isomers that obtains in embodiment 18), 12 milligram of four (triphenyl phosphine) palladium (0), 12 milligrams of triphenyl phosphines, 0.76 milliliter of (0.38 mmole) 2 ethyl hexanoic acid potassium and 2 milliliters of ethyl acetate are formed stirred 1 hour, use the reclaiming by filtration precipitated product, be yellow solid, weigh 143 milligrams (100%), high pressure liquid chromatographic analysis shows that it contains two kinds of isomerss.Infrared spectra (Potassium Bromide): 3382,1780,1728 and 1615 centimetres ^-1

Embodiment 46

The 6-(2-thiazolyl) methylol-1,1 dioxy penam acid benzyl ester

Under-78 ℃, in 250 milliliters of anhydrous tetrahydro furans 17.79 gram (44 mmole) 6-alpha-brominated-1 will be dissolved in, the methyl-magnesium-bromide reaction of 1-dioxy penicillanic acid benzyl ester solution and equimolar amount, stir after 1 minute, thiazolyl-2-the formaldehyde (Carboxaldehyde) that adds equimolar amount continues to stir 10 minutes.Add the acetic acid of equimolar amount, stir after 5 minutes, this mixture is poured in 500 ml waters, use ethyl acetate extraction, extract washes with water, dry (MgSO ₄), under vacuum, boil off solvent, obtain 16.93 gram thick products (89%), tlc shows two spot, and this thick product silica gel chromatography was with chloroform/eluent ethyl acetate of 96: 4, obtain the strong polar isomer of 4.72 grams, 2.98 isomer that gram polarity is more weak and 0.5 gram blended isomer, (overall yield is 43%).

The isomer that polarity is stronger: ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.25(S, 3H), 1.55(S, 3H), 4.3(dd, 1H), 4.45(S, 1H), 4.65(bS, 1H), 4.9(d, 1H), 5.2(m, 2H), 5.55(d, 1H), 7.35(m, 6H), 7.75(d, 1H).

The isomer that polarity is more weak: ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.2(S, 3H), 1.5(S, 3H), 4.35(m, 2H), 4.75(d, 1H), 5.1(m, 2H), 5.55(d, 1H), 7.2(m, 6H), 7.6(d, 1H).

B, 6-(2-thiazolyl) methylol-1,1-dioxy penicillanic acid benzhydryl ester

With the 6-α-bromo-1 of 20 mmoles, 1-dioxy penicillanic acid benzhydryl ester, the step above repeating, use the silica gel chromatography purifying, with chloroform/eluent ethyl acetate of 9: 1, obtaining the more weak isomer of polarity was 2.464 grams, and the isomer that polarity is stronger is 3.029 grams.

The isomer that polarity is stronger: ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.06(S, 3H), 1.52(S, 3H), 4.1-4.3(m, 1H), 4.42(S, 1H), 4.76(d, 1H), 5.45(d, 1H), 6.82(S, 1H), 7.05-7.3(m, 11H), 7.56(d, 1H).

The isomer that polarity is more weak: ¹H-nucleus magnetic resonance (CDCL ₃) PPm(δ): 1.2(S, 3H), 1.65(S, 3H), 4.35(dd, 1H), 4.55(S, 1H), 4.83(d, 1H), 5.65(dd, 1H), 6.95(S, 1H), 7.2-7.4(m, 11H), 7.75(d, 1H).

Embodiment 47

Adopt the method for embodiment 20A, making suitable chemical formula above using is R ¹⁸Cl chloride of acid or corresponding acid anhydrides and suitable with 6-R ¹³CHOH(replaces)-1, the compound below 1-dioxy penam acid esters has made.

Embodiment 48

(6-α, 8R)-the 6-(thiazol-2-yl) the propionyloxy methyl isophthalic acid, the mould alkanoic acid of 1-dioxy base

Be dissolved in 20 milliliters, 9: the 7(volume/volume) in the palladium carbon catalysis agent composition of the gram of 1.89 in tetrahydrofuran (THF) and the water mixture 10%, pass to hydrogen and make it saturated, add (the 6-α that is dissolved in 13 milliliters of tetrahydrofuran (THF)s and 7 ml waters again, 8R)-and the 6-(thiazol-2-yl) the propionyloxy methyl isophthalic acid, 689 milligrams of ester solutions of 1-dioxy penicillanic acid benzyl (1.4 mmole), under the pressure of 3 crust, with this mixture hydrogenation 20 minutes, filtration is to remove catalyzer, filtrate is used ethyl acetate extraction (3 * 200 milliliters), dry extraction liquid (MgSO ₄), under vacuum, boil off solvent, obtain 330 milligrams of yellow solids.

B, (6-α, 8R)-the 6-(thiazol-2-yl) benzoic acid methyl-1,1-dioxy penicillanic acid

Step above adopting has obtained the compound of this exercise question with corresponding benzyl ester, and its productive rate is 57%. ¹H-nucleus magnetic resonance (D ₂O) PPm(δ): 1.38(S, 3H), 1.55(S, 3H), 4.25(S, 1H), 4.44(dd, 1H), 5.05(d, 1H), 6.68(d, 1H), 7.4(t, 7H), 7.55(t, 1H), 7.58(d, 1H), 7.7(d, 1H), 7.95(d, 1H), infrared spectra (Potassium Bromide): 3473,1782,1729,1622cm ^-1

Embodiment 49

(6-α, 8S)-the 6-(thiazol-2-yl) ethoxy carbonyl methylol-1,1-dioxy penicillanic acid

In 5 milliliters of methylene dichloride, be dissolved with 557 milligrams of (0.954 mmole) (6-α, 8S)-and the 6-(thiazol-2-yl) ethoxy carbonyl methylol-1, in the solution of 1-dioxy penicillanic acid benzhydryl ester, add 0.62 milliliter of (5.72 mmole) phenylmethylether, it is cooled to-5 ℃, more than 15 minutes, slowly add the mixture of 382 milligrams of (2.86 mmole) Aluminum chloride anhydrouss and 2 milliliters of Nitromethane 99Min.s.Reaction mixture dilutes with 50 milliliters of ethyl acetate, adds water and regulates pH to 7.5.Separate water layer, being acidified to pH is 3, uses ethyl acetate extraction.Boil off solvent and obtain a glass resistates, it is dissolved in the ether, filter, add hexane in the filtrate to precipitate, behind the filtered and recycled solid, carry out drying, obtain 211 milligrams of products (53%). ¹The H-nucleus magnetic resonance, 300MHZ, (CDCl ₃) PPm(δ): 1.40(t, 3H), 1.53(S, 3H), 1.67(S, 3H), 4.28-4.42(m, 3H), 4.50(S, 1H), 4.92(S, 1H), 6.58(d, 1H), 7.53(d, 1H), 7.93(d, 1H), and infrared spectra (Potassium Bromide): 3443,1797,1754cm ^-1

B, according to top step, with embodiment 62 (6-α, 8R) isomers prepare corresponding 6-(thiazol-2-yl) ethoxy carbonyl methylols-1 preparation, the initiator benzhydryl ester, (6-α, 8R) isomers of 1-dioxy penicillanic acid. ¹The H-nucleus magnetic resonance, 300MHZ, (CDCl ₃) PPm(δ): 1.34(t, 3H), 1.53(S, 3H), 1.65(S, 3H), 4.2-4.4(m, 3H), 4.44(S, 1H), 5.04(S, 1H), 6.67(d, 1H), 7.53(d, 1H), 7.90(d, 1H), and infrared spectra (Potassium Bromide): 3418,1803,1750cm ^-1

Embodiment 50

Suitable allyl ester with embodiment 62 preparations is made parent material, adopts the method for embodiment 60 to make following sylvite.

Embodiment 51

A, 6-bromo-6-(2-thiazolyl) methylol-1,1-dioxy penicillanic acid allyl ester

To be dissolved in the gram of 8.84 in 100 milliliters of anhydrous tetrahydro furans (20 mmole) 6,6-two bromo-1,1-dioxy penicillanic acid allyl ester solution is cooled to-78 ℃, adds 7.02 milliliters of (20 mmole) methyl-magnesium-bromides, stirs 5 minutes.Under-78 ℃, adding is dissolved in the gram of 2.69 in 10 milliliters of same solvents (20 mmole) thiazole-2-formaldehyde (Carboxaldehyde), stirs 20 minutes, add (1.2 milliliters) acetic acid, pour in the water, with ethyl acetate and chloroform extraction, with organic layer merging, dry (Na ₂SO ₄), under vacuum, boil off solvent and get thick product 8.5 grams of vitreous state.With silica gel is the carrier chromatography purification, with chloroform/eluent ethyl acetate of 89: 11, obtains 6.2 gram (72%) pure, single isomer products. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.4(S, 3H), 1.6(S, 3H), 4.0(bS, 1H), 4.42(S, 1H), 4.6(d, 2H), 5.3(S, 1H), 5.55(S, 1H), 5.1-6.3(m, 3H), 7.35(d, 1H), 7.75(d, 1H).

B, 6-bromo-6-(2-thiazolyl) methylol-1,1-dioxy penam acid benzyl ester

Step above adopting, with 6,6-two bromo-1,1-dioxy penam acid benzyl ester replace allyl ester to make the described compound of this number topic in large quantities, and product is the oily foams. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.32(S, 3H), 1.60(S, 3H), 4.5(S, 2H), 5.2-5.8(m, 4H), 7.3(d, 1H), 7.4(S, 5H), 7.8(d, 1H).

C, prepare following compound equally with the step of A

¹The H-nucleus magnetic resonance

R ^aR ¹³Productive rate % (CDCl ₃) ppm(δ)

Benzyl 100 1.25(s, 3H), 1.54(s, 3H),

Yellow bubble 4.5(s, 1H), 5.02(s, 2H),

Foam shape 5.43(s, 1H), 5.68(s, 1H),

7.32（m，7H），8.00（m，2H）.

Benzyl

88 1.4(2s, 3H), 1.6(s, 3H),

Yellow solid 4.0(s, 1H), 4.9(2,1H),

Body 5.18(m, 2H), 5.5-5.8(m,

2H），7.5（s，5H），8.0 and

8.5（2s，1H）.

Allyl group

100 1.25(s, 3H), 1.52(s, 3H),

4.45（s，0.75H），4.52（s，

0.25H），5.1-5.4（m，4H），

7.3（s，5H），8.6（m，2H），

9.0（m，1H）.

Benzyl

38 1.38(s, 3H), 1.60(s, 3H),

4.38-4.73（m，3H），5.0-6.0

（m，5H），7.10（s，1H），8.51

（s，1H）.

Embodiment 52

The compound of A, usefulness front embodiment adopts the method for embodiment 57 or 62 to carry out acidylate, the compound below having obtained equally.

A.R ^aBe allyl group, R ¹⁸Be CH ₃During CO:

R ¹³%Yield ¹H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

2-thiazolyl 49 1.4(s, 3H), 1.6(s, 3H),

Clear crystal 2.25(s, 3H), 4.45(s,

1H），4.65（m，2H），5.4

（s，1H），5.2-6.3（m，3H），

6.7（s，1H），7.4（d，1H），

7.8（d，1H）

¹³C-nucleus magnetic resonance (CDCl ₃) ppm(δ):

18.4，19.8，20.4，60.7，

63.1，64.4，66.5，66.9，

73.3，120.3，120.4，130.6，

143.6，163.7，165.5 166.2，

168.6.

59 1.40（s，3H），1.60（s，

（+21% 3H），2.25（s，3H），4.48-

Isomers

4.70（m，3H），5.2-6.2（m，

Product 5H), 6.92(s, 1H), 8.83

（s，1H）.

B, R ^aBe benzyl, R ¹⁸Be CH ₃During CO:

R ¹³Productive rate % ¹H nucleus magnetic resonance (CDCl ₃) ppm(δ):

2-thiazolyl 100 1.25(s, 3H), 1.55(s, 3H),

Transparent 4.50(s, 0.9H), 4.55(s,

9∶1

Isomers 0.1H), 5.2(m, 2H), 5.40

Mixture (s, 0.9H), 5.57(s, 0.1H),

6.42（s，0.1H），6.60（s，

0.9H），7.3（m，6H），7.75

（d，1H）.

100 1.3（s，3H），1.52（s，3H），

Orange-yellow 2.25(s, 3H), 4.54(s, 1H),

Foams 5.02(s, 2H), 5.52(s, 1H),

6.8（s，1H），7.3（m，7H），

7.9（m，2H）.

19 1.25（s，3H），1.5（s，3H），

2.19（s，3H），3.95（s，3H），

4.4（s，1H），5.15（s，2H），

5.45（s，1H），6.3（s，1H），

7.35（s，5H），7.73（s，1H）.

90 1.25（s，2.25H），1.35（s，

3∶1 0.75H），1.4（s，2.25H），

Isometry 1.42(s, 0.75H), 2.2(s,

Body mixture 2.25H), 2.3(s, 0.75H),

4.45（s，0.75H），4.55（s，

0.25H），5.1-5.3（m，2H），5.3

（s，0.75H），5.6（s，0.25H），

6.25（s，0.25H），6.4（s，

0.75H），7.3（m，5H），8.67

（m，2H），9.67（s，1H）.

C, also can carry out acidylate with another kind of way.Promptly use the way of embodiment 66, before product separation, reaction mixture is carried out acidylate by following general method; The compound of preparation said structure formula:

In temperature is-78 ℃, is dissolved with in the tetrahydrofuran solution of 1.0 normal 6.6-dibromo penicillanic acids, ester, add be dissolved in the same solvent, 1.3 normal methyl-magnesium-bromides, stirred 5-10 minute.Under-78--68 ℃, add and be dissolved in aldehyde (R in the same solvent, that 1.3 equivalents are suitable ¹³CHO) 30-60 minute, add 1.3 normal Acetyl Chloride 98Min.s, continue down to stir 10 minutes at-78 ℃, pour product separation in the frozen water into, use ethyl acetate extraction, drying boils off solvent under vacuum.

R ¹⁸Be CH ₃During CO:

¹The H-nucleus magnetic resonance

R ^aR ¹³Productive rate % (CDCl ₃) PPm(δ)

Benzyl C ₆H ₅100 light yellow foams

Allyl group

77 1.35(s, 3H), 1.56(s,

3H），2.22（s，3H），4.42

Yellow oily (s, 1H), 4.60-4.74(m,

Thing 2H), 5.24-5.42(m, 3H),

5.79-5.96（m，1H），6.52

（s，1H），7.32-7.34（d，

1H），8.70-8.74（d，1H）.

Infrared spectra 1810,

1760 centimetres ^-1.

¹The H-nucleus magnetic resonance

R ^aR ¹³Productive rate % (CDCl ₃) ppm(δ)

Allyl group

59 1.42(s, 3H), 1.62(s,

3H），2.28（s，3H），2.48

Yellow oil (s, 3H), 4.5(s, 1H),

Shape 4.6-4.8(m, 2H), 5.28-

5.47（m，2H），5.82-6.0

（m，1H），6.3（s，1H），

6.97（s，1H）.

Infrared spectra: 1810,1760,

1730 centimetres ^-1.

Benzyl

59 1.6(s, 3H), 1.8(s,

3H），2.2（s，3H），2.3

（s，6H），4.4（s，1H），

5.2（d，2H），5.3（s，

1H），6.4（s，1H），7.3

（s，5H）.

Benzyl

22 1.22(s, 3H), 1.5(s,

3H），2.18（s，3H），2.42

（s，3H），4.5（s，1H），

5.16-5.36（m，3H），6.18

（s，1H），6.48（s，1H），

7.4（s，5H）.

¹The H-nucleus magnetic resonance

R ^aR ¹³Productive rate % (CDCl ₃) ppm(δ):

Benzyl 44 1.26(s, 3H), 1.5(s,

Yellow 3H), 2.2(s, 3H), 2.4

Foams (s, 3H), 4.4(s, 1H),

5.16（d，2H），5.3（s，

1H），6.6（s，1H），6.8

（s，1H），7.3（s，5H）.

Allyl group

36 1.40(s, 3H), 1.60(s,

Foams 3H), 2.27(s, 3H),

2.65（s，3H），4.20-4.8

（m，3H），5.1-6.2（m，

4H），6.41（s，1H）.

Infrared spectra: 1815,

1760 centimetres ^-1.

Embodiment 53

A, 6-β-(thiazol-2-yl) acetoxyl methyl isophthalic acid, 1-dioxy penam acid benzyl ester

In 850 milliliters of benzene, be dissolved with 74.6 gram (134 mmole) 6-bromo-6(thiazol-2-yls) the acetoxyl methyl isophthalic acid, in the solution of 1-dioxy penam acid benzyl ester, add 43.99 gram (151.2 mmole) three-normal-butyl stannic hydrides.With this mixture reflux 5.5 hours, placement was spent the night.Under vacuum, boil off solvent, resistates is immersed in the hexane, with acetonitrile extraction (2 * 250 milliliters).The evaporation acetonitrile layer is made the resistates of pulpous state with ether, filters, and filter cake washs with ether, obtains 33.28 gram clear crystals.The filtrate evaporation drying also can be obtained 2.8 gram products, this resistates taking-up is dipped in the benzene, add 10 gram-normal-butyl stannic hydrides, reflux 1 hour, and handle by the method for first part of product, overall yield is 56.3%.

Above-mentioned first part of product made carrier with silica gel, uses chromatography purification, with chloroform/eluent ethyl acetate of 9: 1, concentrates the elutriant that merges, and makes the pulpous state product with ether/ethyl acetate of 4: 1.Filter,, obtain 22.6 gram white solids with the ether washing. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.25(S, 3H), 1.53(S, 3H), 2.1(S, 3H), 4.58(S, 1H), 4.80(d, 1H), 5.2(dd, 1H), 5.22(q, 2H), 6.75(d, 1H), 7.35(S, 5H), 7.4(d, 1H), 7.8(d, 1H). ¹³C-nucleus magnetic resonance (CDCl ₃) PPm(δ): 17.7,19.9,20.5,54.5,63.06,63.6,63.8,64.5,68.1,121.8,128.8,128.9,134.3,142.6,164.6,166.5,169.2,170.5.

B, use similar way, the compound below the compound debrominate that embodiment 67 is obtained has made:

¹The H-nucleus magnetic resonance

R ^aR ¹³Productive rate % (CDCl ₃) ppm(δ)

Benzyl

39 1.3(s, 3H), 1.55(s, 3H),

2.19（s，3H），4.5（s，1H），

4.79（d，1H），5.2（m，3H），

6.79（d，1H），7.32（m，7H），

7.9（m，2H）.

Benzyl 72 1.29(s, 3H), 1.55(s, 3H),

2.10（s，3H），4.03（s，3H），

4.5（s，1H），4.78（d，1H），

4.87（dd，1H），5.25（q，

2H），6.53（d，1H），7.38（s，

5H），7.89（s，1H）.

Benzyl

46 1.3(s, 3H), 1.55(s, 3H),

4.45（s，1H），4.6-5.1（m，

Yellow 2H), 5.2(m, 2H), 6.6(dd,

Solid 1H), 7.35(s, 5H), 8.6(m,

2H），8.83（m，1H）.

¹The H-nucleus magnetic resonance

R ^aR ¹³Productive rate % (CDCl ₃) ppm(δ)

Allyl group

70 1.44(s, 3H), 1.62(s, 3H),

Oily matter 2.10(s, 3H), 4.51(s, 1H),

4.60-4.80（m，2H），4.89-

4.91（d，1H），5.26-5.42（m，

3H），5.86-5.99（m，1H），

6.88-6.92（d，1H），8.82（s，

1H）.

Infrared spectra: 1795,1750.

Strong polarity together

Allyl group

51(is strong, and the utmost point divides isomer: 5.84-6.00(m,

Property is with differentiation 1H), 6.28-6.42(m, 2H),

The structure thing) 6.62-6.77(d, 1H), 7.38-

+ 7.48（d，1H），8.64-8.70

The weak utmost point of 11((d, 1H). white crystal

Property is with the differentiation infrared spectra: (Potassium Bromide): 1807,

1760 centimetres of structure things ^-1.

Allyl group 31 1.46(s, 3H), 1.64(s, 3H),

Yellow 2.14(s, 3H), 2.48(s, 3H),

Oily 4.5(s, 1H), 4.6-4.9(m,

3H），5.2-5.26（dd，1H），

5.3-5.6（m，2H），5.86-6.1

（m，1H），6.7（d，1H），7.0

（s，1H）.

Infrared spectra: 1810,1760 centimetres ^-1.

¹The H-nucleus magnetic resonance

R ^aR ¹³Productive rate % (CDCl ₃) ppm(δ)

Benzyl 43 1.3(s, 3H), 1.58(s, 3H),

Molten some 2.12(s, 3H), 2.36(d, 6H),

194.5-

195.5℃. 4.5（s，1H），4.75（d，1H），

5.2-5.4（dd，3H），6.6（d，

1H），7.4（s，-5H）.

Benzyl

16 1.28(s, 3H), 1.55(s, 3H),

Colourless solid 2.1(s, 3H), 2.4(s, 3H),

Body, single 4.5(s, 1H), 4.8(dd, 1H),

One isomery 5.25(q, 1H), 6.15(s, 1H),

Body 6.5(d, 1H), 7.4(s, 5H).

Benzyl

43 1.3(s, 3H), 1.58(s, 3H),

2.14（s，3H），2.48（s，3H），

4.52（s，1H），4.8（d，1H），

5.16-5.36（AB quartet and

dd，3H），6.7（d，1H），7.0

（s，1H），7.4（s，5H）.

Allyl group

44 1.37-1.40(d, 3H), 1.58-

3: 1 1.60(d, 3H), 2.12-2.14(d,

Mix with dividing

Isomer 3H), 2.58(s, 3H), 4.48(s,

1H），4.58-4.88（m，4H），5.24-

5.46（m，2H），5.82-6.00（m，

1H），6.64-6.67（d，0.75H），

7.05-7.08（d，0.25H）.

Infrared spectra: 1810,1765cm ^-1.

B, 6-β-(thiazol-2-yl) acetoxyl methyl isophthalic acid that in present embodiment A, obtains, the water slurry of 1-two oxapenem propylhomoserins, handle with equimolar saleratus soluble in water and to be converted into corresponding sylvite, make carrier with the octadecyl silicon ester, medium pressure liquid chromatography carries out purifying, just can obtain corresponding sylvite with 9: 1 water/acetonitrile wash-out, its productive rate is 60%. ¹H-nucleus magnetic resonance (dimethyl alum-d ₆) PPm(δ): 1.37(S, 3H), 1.48(S, 3H), 2.07(S, 3H), 3.80(S, 1H), 4.92(dd, 1H), 5.12(d, 1H), 6.55(d, 1H), 7.89(m, 2H).Infrared spectra (Potassium Bromide): 3454,1788,1630cm ^-1

Embodiment 55

6-(benzothiazole-2-yl) methylene radical-1,1-dioxy penicillanic acid, the mixture of E and Z isomers.

400 milligrams of (0.91 mmole) 6-(benzothiazole-2-yls in being dissolved in 5 ml waters) acetoxyl methyl isophthalic acid, in the 1-dioxy penicillanic acid solution, add and be dissolved in the gram of 0.15 in 2 ml waters (1.82 mmole) sodium hydrogen carbonate solution, stirred this mixture 2 hours, lyophilize, take out the lyophilic salt of this kind and be placed in 8 ml waters, regulate pH to 3.5 with dilute hydrochloric acid.Use ethyl acetate extraction, dry (MgSO ₄) organic layer, boil off solvent in a vacuum.Nuclear magnetic resonance spectroscopy shows, this kind product is (E) and (Z) mixture of isomers, and their ratio is 60: 40. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.55(S, 1.2H), 1.6(S, 1.8H), 1.65(S, 1.2H), 1.67(S, 1.8H), 4.55(S, 0.6H), 4.58(S, 0.4H), 5.38(S, 0.4H), 5.74(S, 0.6H), 7.44(S, 0.4H), 7.48(S, 0.6H), 7.5(m, 4H), 7.89(d, 1H), 8.07(d, 0.4H), 8.15(d, 0.6H).

B, to obtain above, should fit with 6-R ¹³-CH(OAC)-replace 1,1-dioxy penicillanic acid carries out similar processing, making structural formula is following mixture, it is (E) and (Z) mixture of isomers

R ¹³Productive rate % ¹H-nucleus magnetic resonance (D ₂O) ppm(δ):

84 1.54（s，3H），1.62（s，3H），

60∶40 4.04（s，3H），4.35（s，1H），

(E) and (Z) divide 5.7(s together, 0.6H), 5.95(s,

The mixed 0.4H of (sodium salt) isomer), 7.26(s, 0.6H), 7.55

Compound (s, 0.4H), 8.09(s, 2H).

Embodiment 56

A, 6-bromo-6-(thiazol-2-yl) the acetoxyl methyl isophthalic acid, 1-dioxy penicillanic acid potassium

Method with embodiment 60, with 96 milligrams of (0.2 mmole) 6-bromo-6-(thiazol-2-yls) the acetoxyl methyl isophthalic acid, 1-dioxy penicillanic acid allyl ester (providing among the embodiment 67) reaction 10 minutes, and by described method processing, obtain 46 milligrams of products (48%), be yellow solid. ¹H-nucleus magnetic resonance (D ₂O) PPm(δ): 1.45(S, 3H), 1.6(S, 3H), 4.4(S, 1H), 5.55(S, 1H), 6.85(S, 1H), 7.72(d, 1H), 7.86(d, 1H).

B, 6-bromo-6-(thiazol-2-yl) methylol-1,1-dioxy penicillanic acid potassium similarly, with aforesaid method with 220 milligrams of 6-bromo-6-(thiazol-2-yls) methylol-1,1-dioxy penicillanic acid allyl ester (embodiment 66 provides) reaction 20 minutes, obtain the alleged salt of this title, product is a light yellow solid, and productive rate is 52%. ¹H-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)-d ₆) PPm(σ): 1.35(S, 3H), 1.47(S, 3H), 3.75(S, 04H), 3.83(S, 0.6H), 5.3(d, 0.4H), 5.32(d, 0.6H), 5.45(S, 0.6H), 5.5(S, 0.4H), 7.6-8.0(m, 2H).Infrared spectra (Potassium Bromide): 3442,1794,1633Cm ^-1

Embodiment 57

(6-β, 8S)-the 6-(thiazol-2-yl)-methylol penicillanic acid potassium

A, 6-bromo-6-(thiazol-2-yl) methylol penicillanic acid allyl ester

Under nitrogen atmosphere, in being cooled to 150 milliliters of anhydrous tetrahydro furans of-78 ℃, temperature is dissolved with 9.971 gram (24.99 mmoles) 6, in the solution of 6-dibromo penicillanic acid allyl ester, add 8.77 milliliter of 2.85 volumetric molar concentration (24.99 mmole) the methyl magnesium bromine that is dissolved in the tetrahydrofuran (THF), stirred 15 minutes, be added in and be dissolved with 2.824 gram (24.99 mmole) thiazole-2-formaldehyde solutions (Carboxaldehyde) in 5 milliliters of tetrahydrofuran (THF)s, under-78 ℃, stirred this mixture once more 20 minutes, add 1.43 milliliters of (24.99 mmole) Glacial acetic acid termination reactions, stirred 10 minutes, be heated to room temperature, pour in the water, with 2 * 250 milliliters of ethyl acetate extractions, extraction liquid washes (2 * 250 milliliters) with water, dry (MgSO ₄), under vacuum, boil off solvent, obtain the clear look oily matter of 10.36 grams, make carrier with silica gel, chromatography purification, chloroform/eluent ethyl acetate of 9: 1, obtain 4.54 gram yellow solids (mixture of isomers) and 0.443 gram yellow froth product (strong polarity isomer is only arranged), (overall yield 46%) makes nuclear magnetic resonance spectroscopy to yellow foams, H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.56(S, 3H), 1.76(S, 3H), 4.60(S, 1H), 4.7(m, 2H), 4.9-6.4(m, 6H), 7.45(m, 1H), 7.8(m, 1H).

B, 6-β-(thiazol-2-yl) methylol penicillanic acid allyl ester

The isomer 200 milligram (0.462 mmoles) stronger above-mentioned A Semi-polarity is dissolved in 1 milliliter of benzene, add 0.183 milliliter of (0.693 mmole, 1.5 equivalents) the three normal-butyl stannic hydride that is dissolved in the benzene, with this mixture reflux 3 hours, at room temperature place and spend the night, boil off solvent under the vacuum, resistates is dissolved in the acetonitrile, hexane wash, evaporation concentration are separated in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column to a small volume, the chloroform wash-out obtains 73 milligrams of desired products (45%). ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.65(S, 3H), 1.87(S, 3H), 3.8-4.4(m, 1H), 4.05-4.3(dd, 1H), 4.65(S, 1H), 4.78(m, 2H), 5.3-5.6(m, 2H), 5.6-6.3(m, 3H), 7.45(m, 1H), 7.85(m, 1H).

The method of C, usefulness embodiment 60 changes into sylvite to 73 milligrams that obtain among the B (0.206 mmole) products, obtains 58 milligrams of alleged compounds of (80%) this title, is yellow solid. ¹The H-nucleus magnetic resonance, 300MHz, (D ₂O) PPm(δ): 1.36(S, 3H), 1.55(S, 3H), 4.13(dd, 1H), 4.18(S, 1H), 5.32(d, 1H), 5.41(d, 1H), 7.56(d, 1H), 7.60(d, 1H).

Embodiment 58

A, same, the method for employing embodiment 72A is with suitable aldehyde R ¹³CHO replaces thiazole-2-formaldehyde (Carboxaldehyde) to obtain the compound corresponding to following structural formula:

R ¹³Productive rate % ¹H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

20, isomers A:1.46(s, 3H), 1.64

（s，3H），4.42（d，1H），4.50

Isomers

（s，1H），4.64（m，2H），5.26-

The brilliant 5.50(m of A(white, 3H), 5.84(s, 1H),

Body) 5.8-6.0(m, 1H), 8.58(d, 2H),

8.9（s，1H），

13 ¹³C-nucleus magnetic resonance (CDCl ₃) 26.4,32.5,

Isometry 64.4,66.1,69.8,70.9,73.7,

B(yellow 74.9,119.6,131.0,143.0,

Oily matter) 144.3,144.6,152.1,166.8,

167.8ppm.

Isomers B:1.45(s, 3H), 1.63

（s，3H），4.56（s，1H），4.65

（m，2H），5.1-5.5（m，4H），5.6-

6.0（m，1H），5.91（s，1H），

8.57（m，2H），8.78（m，1H）.

¹³C-nucleus magnetic resonance (CDC ₃) 26.27,32.57,

64.30，66.19，69.94，70.77，

72.38，74.73，119.70，130.98，

143.30，144.57，144.70，

152.04，166.99，167.99ppm.

R ¹³Productive rate % ¹H-nucleus magnetic resonance (CDCl ₃) ppm(δ)

25， 1.52（s，3H），1.70（s，3H），

(isometry 4.64(s, 1H), 4.72(m, 2H),

Body A, 8S) 4.86(d, 1H), 5.34-5.48(m,

3H），5.91（s，1H），5.92-6.05

（m，1H），7.39（t，1H），8.87

（d，2H）.

40， 1.52（s，3H），1.71（s，3H），

(isometry 4.61(s, 1H), 4.72(m, 2H),

Body B, 8R) 4.98(d, 1H), 5.30-5.52(m,

3H），5.90-6.04（m，1H），6.10

（s，1H），7.40（t，1H），8.85

（d，2H）.

83 1.49（s，3H），1.69（s，3H），

Foams 3.56(d, 0.7H), 3.89(d, 0.3H),

4.7（m，3H），5.5（m，3H），5.9

（m，2H），7.53（m，3H），8.14

（m，3H）.

97

(slightly)

Isometry

The mixing of body

Thing

The method of B, usefulness embodiment 72B has obtained following compound to the above-claimed cpd debrominate

R ¹³Productive rate % ¹-nucleus magnetic resonance (CDCl ₃) ppm

57 1.5（s，3H），1.7（s，3H），4.05

Oily (dd, 1H), 4.35(s, 1H), 4.5

(from same differentiation (d, 1H), 4.65(m, 2H), 5.25-

Structure body A, 5.45(m, 3H), 5.55(d, 1H),

8S） 5.9-6.0（m，1H），8.6（m，2H），

8.85（s，1H）.

59 1.5（s，3H），1.8（s，3H），

4.15（dd，1H），4.25（bs，1H），

(isometry 4.55(s, 1H), 4.7(m, 2H),

Body B, 8S) 5.2-6.2(m, 5H), 8.67(bs,

2H），9.00（bs，1H）.

35 1.51（s，3H），1.74（s，3H），

Oily 4.01(dd, 1H), 4.44(d, 1H),

(from dividing 4.60(s together, 1H), 4.70(d, 2H),

Isomer A, 5.40(m, 3H), 5.60(d, 1H),

5.96（m，1H），7.34（t，1H），

8.80（d，2H）.

65 1.52（s，3H），1.78（s，3H），

4.23（m，2H），4.64（s，1H），

(from dividing 4.71(d together, 2H), 5.30-5.46(m,

Isomer 3H), 5.53(d, 1H), 5.90-6.04

B，8R） （m，1H），7.34（t，1H），8.85

（d，2H）.

R ¹³Productive rate % ¹H-nucleus magnetic resonance (CDCl ₃) ppm(δ):

100 1.47（s，3H），1.67（s，3H），

4.16（m，2H），4.64（m，3H），

5.47（m，4H），5.94（m，1H），

7.43（m，3H），8.02（m，3H）.

81 1.42（s，3H），1.7（s，3H），4.4

(not purifying) (d of d, J=4 and 8,1H), 4.5

（8R） （s，1H），4.65（m，2H），5.2-6.3

（m，3H），5.6（d，J＝4，1H），5.6

（d，J＝8，1H），7.2-7.6（m，2H），

7.8-8.1（m，2H）.

36 1.45（s，3H），1.55（s，3H），

(behind the purifying) 4.15(d of d, 1H), 4.5(s, 1H),

（8S） 4.65（m，2H），5.2-6.4（m，5H），

7.2-7.6（m，2H），7.8-8.2（m，

2H）.

The method of C, usefulness embodiment 60 is reacted with top allyl ester, the sylvite below having obtained

R ¹³Productive rate % stereochemistry ¹H-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)-d ₆)

75 8R 1.46（s，3H），1.56（s，3H），

3.76（s，1H），4.13（dd，

(with differentiation 1H), 5.05(d, 1H), 5.4(d,

Structure body A) 1H), 8.58(d, 2H), 8.72

(s, 1H). infrared spectra (KBr):

3478，1761，1607cm ^-1.

82 8S 1.42（s，3H），1.65（s，3H），

4.25（s，3H），4.27（dd，

(with differentiation 1H), 5.3(d, 1H), 5.35(d,

Structure body B) 1H), 8.6-8.7(m, 2H), 8.8

（m，1H）.

94 8S （D ₂O）：1.32（s，3H），1.54

（s，3H），4.18（s，1H），

(isometry 4.14-4.19(m, 1H), 5.19

Body A) (d, 1H), 5.25(d, 1H),

7.45（t，1H），8.75（d，2H）.

95 8R （D ₂O）：1.44（s，3H），1.58

（s，3H），4.12（s，1H），4.18

(isometry (m, 1H), 5.22(d, 1H), 5.49

Body B) (d, 1H), 7.46(t, 1H), 8.75

（d，2H）.

C ₈

R ¹³Productive rate % stereochemistry ¹H-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)-d ₆)

ppm（δ）：

97 8R 1.47（s，3H），1.58（s，3H），

3.79（s，1H），4.13（dd，1H），

5.2（d，1H），5.4（d，1H），

5.95（bs，1H），7.45（t，1H），

7.60（t，2H），8.03（d，2H），

8.16（s，1H）.

85 8S 1.48（s，3H），1.67（s，3H），

4.27（d of d，J＝4 and 10，

1H），4.3（s，1H），5.45（d，

J＝4，1H），5.57（d，J＝10，

1H），7.45-7.65（m，2H），

8.04（t，J＝8，2H）.

IR（KBr）：3424，1765，1746，

1592cm ^-1.

91 8R 1.42（s，3H），1.56（s，3H），

4.16（s，1H），4.25（d of d，

J＝4 and 8，1H），5.46（d，

J＝4，1H），5.5（d，J＝8，1H），

7.4-7.6（m，2H），7.8-8.05

（m，2H）.

Preparation A

Chlorination 6-chloropyridine-2-ylmethyl-San Ben Phosphonium

(1) 6-chloro-2-picoline-1-oxide compound

In 50 milliliters of methylene dichloride, be dissolved with add in 5.1 gram (40 mmole) the 6-chloro-2-picoline solution 8.625 gram (40 mmoles) 80% between the monochlor(in)ate peroxybenzoic acid, at room temperature stirred 15 hours, add 0.5 milliliter of saturated sodium thiosulfate with termination reaction, regulating pH with sodium hydrogen carbonate solution is 7.5, organic layer washes with water, dry (Na ₂SO ₄), boil off solvent and obtain 4.84 gram N-oxide compounds. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 2.6(S, 3H), 7.0-8.0(m, 3H).

(2) 6-oxygen-2-acetoxyl picoline

Under 100 ℃, the solution heating that is dissolved with above-mentioned N-oxide compound 4.8 grams (0.035 mole) in 15 ml acetic anhydride 1 hour, distill under the vacuum, obtain the product that 2.39 grams need, boiling point is 125-128 ℃/0.7 millimeter, colorless oil.

¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 2.1(S, 3H), 5.1(S, 2H), 7.0-7.8(m, 3H).

(3) 6-chloro-2-piconol

Under 70 ℃, the product that obtains in (2) hydrolysis 1 hour in 10 milliliters of 2 normal hydrochloric acid, (K again neutralizes ₂CO ₃), chloroform extraction, from anhydrous extract, boil off solvent, obtained thick pure 1.87 grams, carry out chromatographic separation with silica gel as carrier, obtain straight product 0.982 gram. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 4.8(S, 2H), 5.3(bS, 1H), 7.0-7.8(m, 3H).

(4) 6-chloro-2-chloromethylpyridine

At room temperature, with 0.814 gram thionyl chloride, handle the 6-chloro-2-piconol one hour be dissolved in the grams of 0.982 in 10 milliliters of methylene dichloride (6.84 mmole), neutralize with saturated sodium bicarbonate solution, dichloromethane extraction, dry, boil off solvent and obtain 815 milligrams of colourless crystallization products ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 4.7(S, 2H), 7.1-8.0(m, 3H).

(5) preparation of Wittig reagent: 815 milligrams of (5 mmole) products and 1.318 gram (5 mmole) triphenyl phosphines that (4) are obtained are dissolved in (10 milliliters) toluene, with this mixture reflux 6 hours, filtration is with the product of collecting precipitation, weigh 1.368 grams (65%), be the alleged product of this title. ¹H-nucleus magnetic resonance (dimethyl sulfoxide (DMSO)) PPm(δ): 5.5(S, 1H), 5.8(S, 1H), 7.2-8.2(m, 18H).

(6) chlorination 4-methoxypyridine-2-ylmethyl three benzene Phosphonium.

By the step of (2), make parent with 2.1 gram 2-methyl-4-pyridinyl methoxy-1-oxide compounds, obtained 2.5 gram 2-acetoxyl methyl-4-pyridinyl methoxies, wherein accompany 5-acetoxyl-2-methyl-4-pyridinyl methoxy of about 25%.This mixture is dissolved in the methyl alcohol that contains 1.118 gram (20.7 mmole) sodium methoxides (10 milliliters), and stirring and refluxing 1 hour boils off methyl alcohol under the vacuum, residue diluted with water, dilute hydrochloric acid neutralization, chloroform extraction.Organic layer salt water washing, drying (MgSO ₄), concentrate under the vacuum, obtain 853 milligrams of (41%) 2-methylol-4-pyridinyl methoxies. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 3.9(S, 3H), 4.72(S, 2H), 5.35(bS, 1H), 6.7(dd, 1H), 6.95(d, 1H), 8.3(d, 1H).

Method with (4), the methylol compound that obtains is above changed into 2-chloromethyl-4-pyridinyl methoxy, weigh 0.895 gram (5.68 mmole), under refluxing, with this compound and the triphenyl phosphine reaction that is dissolved in the equimolar amount in the toluene (10 milliliters) 20 hours, leach sedimentary product, weigh 860 milligrams, be yellow solid, this i.e. the alleged compound of this title.

Preparation B

Chlorination 2-quinoline methyl triphenyl phosphine

Restrain the solution reflux 3 hours of (0.035 mole) with being dissolved with 2-chloromethyl quinoline 6.26 gram (0.035 mole) and triphenyl phosphine 9.20 in 80 milliliters of methyl, filter the solid of collecting precipitation, dry under vacuum, product is a brown solid, weighs 3.5 grams (23%).

Preparation C

Chlorination 3-allyloxy-2-picolyl San Ben Phosphonium

(1) 3-allyloxy-2-4-hydroxymethylpiperidine

In sodium methoxide-carbinol mixture by 1.43 gram (62 mmole) sodium Metal 99.5s and the preparation of 100 ml methanol, add 5.9 gram (31 mmole) 3-hydroxyl-2-4-hydroxymethylpiperidines, under vacuum, remove methyl alcohol.This resistates is dissolved in 80 milliliters of DMSO(dimethyl sulfoxide (DMSO)) in, at room temperature, more than 20 minutes, add 3.0 milliliters of (34.7 mmole) allyl bromide 98s that are dissolved among 20 milliliters of DMSO, stirred 2 hours, and boiled off DMSO under vacuum, resistates is in chloroform, regulate the pH to 7.5 of water, with chloroform extraction 3 times, organic phase is lumped together, wash with water, the salt water washing, dry (Na ₂SO ₄), concentrate, obtain ether 3.48 grams (68%) that need.

(2) 3-allyloxy-2-chloromethylpyridine

Be dissolved in product (3.43 grams that obtain among 20 milliliters of A in the methylene dichloride with the processing of 1.5 equivalents (2.5 milliliters) thionyl chloride, 20.8 mmole), in nitrogen atmosphere, stirred 2 hours, remove volatile matter in the vacuum, resistates is distributed in methylene dichloride and the water, and the pH of water layer is transferred to 7.5, extracts with fresh methylene chloride, wash with water, the salt water washing, dry (Na ₂SO ₄), boil off solvent under the vacuum, obtain product, it is heavy to be 3.28 grams (86%), it will be used in next step.

(3) product in (2) (3.28 grams, 17.9 mmoles) is dissolved in 30 milliliters of toluene, add 4.69 gram triphenyl phosphines (17.9 mmole), reflux and stirred 3 hours, at room temperature stirred then 12 hours, leach product, the uncommon reagent 3.89 of dimension ladder that toluene wash needing to obtain restrains (49%).

Preparation D

6-α-bromo-1,1-dioxy penicillanic acid allyl ester

(1) 6-α-bromine penicillanic acid 1, the 1-dioxide

To 20.26 gram (0.0517 moles) 6 be arranged in 80 ml waters, 6-two bromo-penicillanic acids 1, the suspension of 1-dioxide, gradation is handled with 13 gram (0.155 mole) solid sodium bicarbonates, adds ethyl acetate, emit with the pilot-gas fierceness, gradation adds solid sodium bisulfite 6.76 grams (0.062 mole), stirs this mixture 35 minutes, regulates pH to 1.0 with concentrated hydrochloric acid and dilutes with ethyl acetate, organic phase is washed with salt, dry (Na ₂SO ₄), boiling off solvent in a vacuum, resistates adds chloroform to be developed, and filters to obtain light yellow solid 6.72 grams, and concentrated filtrate also can obtain 3.2 gram products, and resistates is handled with chloroform.

(2) in 20 milliliters of dimethyl formamides that contain above-mentioned first time of product 6.352 grams, add 1.76 milliliters of (20.3 mmole) allyl bromide 98s, 2.83 milliliter (20.3 mmole) triethylamine and 0.2 gram sodium bicarbonate, at room temperature, in the nitrogen atmosphere, stirred 15 hours, and added water, extracted with diethyl ether, extraction liquid washes with water, dry (Na ₂SO ₄), under vacuum, boiling off solvent, the ester 4.60 that needing to obtain restrains (64%), is oily matter. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.4(S, 3H), 1.6(S, 3H), 4.4(S, 1H), 4.6(d, 1H), 4.7(d, 2H), 5.15(d, 1H), 5.1-5.95(m, 3H).

(3) 6,6-dibromo penicillanic acid allyl esters

Use aforesaid method, to 6 of 0.417 volumetric molar concentration, the 6-dibromo penicillanic acid carries out esterification, then can obtain 140 grams (84%) as the buttery allyl ester. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.5(S, 3H), 1.65(S, 3H), 4.6(S, 1H), 4.75(m, 2H), 5.3-5.6(m, 2H), 5.85(S, 1H), 5.8-6.3(m, 1H).

Preparation E

2-formyl-1-Methylimidazole

(1) 2-methylol-1-Methylimidazole

The mixture of the formaldehyde (proportion 1.08) of 50 gram 1-Methylimidazoles and 100 milliliters 37% is placed on (300 milliliters) in the stainless cylinder, heated (bath temperature) 17 hours down at 150 ℃, then cylinder is placed in the ice and cools off, pour out mixture, concentrate in a vacuum, resistates was stored liquid under 4 ℃, filter gained crystal and oily mixture, with ethyl acetate washing, dry in a vacuum colourless crystal, obtain 14.60 gram products.Mother liquor is handled again, also can be obtained 6.48 gram products, product weighs 21.08 grams (31%) altogether.

(2) in 50 milliliters of dioxs that are dissolved with 4.96 gram (43.9 mmole) 2-methylol-1-Methylimidazoles, add 4.90 gram (44.1 mmole) tin anhydride, stirred 5 hours down at 85-90 ℃, at room temperature stirred 36 hours, 85 ℃ were stirred 8 hours down, at room temperature stirred at last 15 hours, filtered, under vacuum, boil off solvent, obtain thick aldehyde 4.81 grams, obtain 2.11 gram products through distillation again, be clear crystal, when 2.8 mmhg, 65 ℃ of boiling points.

Preparation F

Chlorination 6-methyl-2-picolyl San Ben Phosphonium

(1) 6-methyl-2-4-hydroxymethylpiperidine

Under 0-5 ℃, be dissolved in 6-picoline-2-formaldehyde (Carboxa dehyde) in 50 ml methanol with the sodium borohydride reduction of 20.6 mmoles, after reacting completely, neutralize (pH7.5), filter with 2 normal sulfuric acid, concentrate, chloroform extraction boils off the solvent of organic layer, and obtaining product is reddish black oily matter, weigh 3.32 grams, be used for the step down.

(2) 2-chloromethyl-6-picoline

At room temperature, be dissolved in the gram of 3.32 in 20 milliliters of methylene dichloride the said products 1 hour with 1.94 milliliters of (27 mmole) thionyl chlorides processing, this mixture (NaHCO neutralizes ₃), chloroform extraction boils off solvent, and the product that obtains is an oily matter, weighs 3.22 grams, is used in next step.

(3) will be dissolved with the solution reflux 4 hours of 3.22 in (2) grams oily matter and 5.96 gram triphenyl phosphines in 30 milliliters of toluene, the elimination precipitation obtains 3.93 gram Wittig reagents, is brown solid.

Preparation G

Chlorination 2-pyrazine ylmethyl three benzene Phosphonium

(1) 2-methylol pyrazine

Temperature for-78 ℃, in 100 milliliters of tetrahydrofuran solutions that contain 11.29 gram (79.2 mmole) 2-pyrazine carbonyl chlorides (under reflux temperature handle with the excessive thionyl chloride of 1 mmole corresponding 2-carboxylic acid preparation), add 2.0 in gradation more than 20 minutes and restrain 52.6 mmole lithium aluminum hydrides (purity 95%).Stirred 10 minutes, and be heated to room temperature.With 2M sodium hydroxide termination reaction, filter, methanol wash, this filtrate of contracting under vacuum has obtained the black solid product, weighs 4.12 grams, is used in down the step.

(2) above-mentioned black solid (4.12 grams, 37.8 mmoles) is dissolved in the methylene dichloride, adds 2.8 milliliters of thionyl chlorides down at 0 ℃, be heated to room temperature, stirred 30 minutes, add water, neutralization, dichloromethane extraction, making product is yellow oil, weighs 2.29 grams, will go on foot usefulness down.

(3) in 40 milliliters of toluene that contain above-mentioned oily matter 2.29 grams, add 4.70 gram triphenyl phosphines, refluxed three hours, handle with general method, obtain 1.995 gram Wittig reagents, be brown solid.

Preparation H

4-formyl pyrimidine

Under the room temperature, be dissolved in 100 milliliters of 4-methylpyrimidine (10 grams, 0.106 mole) solution in the diox with 11.8 gram tin anhydride processing, heated 15 hours down at 100 ℃, add after the 2.5 gram tin anhydride, continue heating 1 hour, cooling, filtration are used the ethyl acetate washing leaching cake, under vacuum, evaporation washings and filtrate, the remaining dark oil thing that obtains is dissolved in the methylene dichloride, filters, boils off solvent, and resistates crystallizes out from a small amount of methylene dichloride, obtain the aldehyde of this title ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 7.87(dd, 1H), 9.06(d, 1H), 9.43(d, 1H), 10.0(S, 1H).

Preparation I

6-α-bromo-1,1-dioxy penicillanic acid benzhydryl ester

In 400 milliliters of anhydrous tetrahydrofuran solutions that contain hexichol diazomethane 21.557 grams (0.1 mole), add 31.2 gram (0.1 mole) 6-α-bromo-1,1-dioxy penicillanic acid in gradation more than 30 minutes.Reaction has slight exotherm, stirs 1 hour, boils off solvent, resistates is dissolved in (50 milliliters) in the ethyl acetate, add 400 milliliters of ether, store down, do not have crystallization after 18 hours at 4 ℃, concentrate this mixture under the vacuum, obtain yellow solid, weigh 51.2 grams, in the separation of the enterprising circumstances in which people get things ready for a trip spectrum of silica-gel carrier, chloroform washing, obtain the glassy product of 14.86 grams, colourless. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 1.26(S, 3H), 1.57(S, 3H), 4.55(S, 1H), 4.70(d, 1H), 5.13(d, 1H), 6.9(S, 1H), 7.27(S, 10H).

Preparation J

Benzothiazole-2-formaldehyde (Carboxaldehyde)

In nitrogen atmosphere, in 250 milliliters of tetrahydrofuran (THF)s with being dissolved in, new distillatory (82 ℃ of boiling points, 2 mmhg) benzothiazoles (10 grams, 0.074 mole) are freezing to-78 ℃, stir 15 minutes under this temperature.At the n-Butyl Lithium that dropwise adds 29.6 milliliters of (0.074 mole) 2.5 volumetric molar concentrations more than 15 minutes, continue to stir 25 minutes, add 8.6 milliliters of (0.111 mole) dimethyl formamides, stirred 1 hour, be heated to room temperature, add 200 gram ice, under vacuum, boil off solvent, with 5 * 100 milliliters of ethyl acetate extraction aqueous residues, dry extraction liquid (MgSO ₄), concentrate a small volume, carry out chromatographic separation with silica gel as carrier, with chloroform/eluent ethyl acetate of 96: 4, the aldehyde 8.4 that needing to obtain restrained molten some 74.5-75 ℃. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 7.54(m, 2H), 7.79(m, 1H), 8.21(m, 1H), 10.1(S, 1H).

Preparation K

Pyrazine-2-formaldehyde (Carboxaldehyde)

Pyrazine-2-carboxylic acid and methyl alcohol in the presence of sulfuric acid, refluxes 5 hours carry out fatization, boils off methyl alcohol under the vacuum, with methylene dichloride dilution, sodium bicarbonate neutralization (pH7.5).Concentrate anhydrous organic layer and obtain pyrazine-2-carboxylic acid formicester, be pale solid, productive rate 84% with Virahol, ether recrystallization, makes yellow needle-like product. ¹H-nuclear magnetic resonance spectrum (CDCl ₃) PPm(δ): 4.1(S, 3H), 8.93(m, 2H), 9.47(m, 1H).

(20 grams, 0.145 mole, freezing to-78 ℃, more than 15 minutes, dropping is dissolved in the lithium aluminum hydride of the gram of 5.8 in the tetrahydrofuran (THF) 98% to dissolve this formicester with 600 milliliters of anhydrous tetrahydro furans.Under-78 ℃, stirred 30 minutes, add 20 milliliters of acetic acid, this mixture is carried out concentrating under reduced pressure, in 2 normal hydrochloric acid mediums (30 milliliters), use chloroform extraction, merge organic layer, wash with water, drying and evaporation obtain the thick product of 8.53 grams, make it to make the carrier post to carry out purifying by silica gel, with 4: 1 methylene dichloride/ethyl acetate wash-out, obtain lurid needle-like product 5.02 grams. ¹H-nuclear magnetic resonance spectrum (CDCl ₃) PPm(δ): 8.38(m, 2H), 8.7(bS, 1H), 9.7(S, 1H).

Preparation L

2-phenyl-1,2,3-triazoles-4-formaldehyde (Carboxaldehyde

(1) under 0-10 ℃, 0.34 mole of acetone carboxylic acid and the 0.58 mole of Sodium Nitrite that is dissolved in 100 ml waters reacted, add rare nitric acid to be settled out product, this product is a dioxime, promptly 1, and 3-dioxime-2-oxo propane, be the brown crystal, productive rate is 46%.

(2) under 70 ℃, will be dissolved in the phenylhydrazine hydrochloride of dioxime (0.158 mole) and equimolar amount in the ethanol (170 milliliters) and acetic acid sodium reaction 30 minutes, add water (170 milliliters), be heated to 85 ℃, be concentrated to 250 milliliters, cooling obtains 24.7 gram phenylhydrazones. ¹H-nucleus magnetic resonance (CD ₃COCD ₃) PPm(δ): 7.3(m, 5H), 7.9(S, 1H), 8.6(S, 1H), 10.5(bS, 1H), 11.4(bS, 1H), 12.3(S, 1H).

(3) at room temperature, above-mentioned dioxime phenylhydrazone 24.7 grams (0.119 mole) were mixed, stir 30 minutes with 500 ml acetic anhydride, it is poured in the water, stirred 20 minutes, filter.This thick solid carries out recrystallization with benzene/ethyl acetate, obtains-acetate fat HON=CH-C(=NNHC ₆H ₅) CH=NOCOCH ₃15.47 gram (52%), yellow meal.H-nuclear magnetic resonance spectrum (CDCl ₃, acetone): 1.85(S, 3H), 7.09(m, 5H), 7.95(S, 1H), 8.3(S, 1H), 10.9(bS, 1H), 12.25(S, 1H).

(4) at room temperature, with an above-mentioned acetate fat 15.40 gram (0.062 mole) that obtains be dissolved in 400 milliliters of cesium carbonates 22.16 in the tetrahydrofuran (THF) and restrain (0.068 mole) and mixed, stir 1 hour, filter, filtrate concentrating obtained yellow residue, this resistates is dissolved in isopropyl ether/hexanaphthene 700 milliliters of heat, 1: 2, be concentrated to 200 milliliters, obtain 9.41 gram (80%) 2-phenyl-1,2,3-triazoles-4-formaldehyde (Carboxaldehyde), yellow meal, the following step will be used.

The mixture reflux that (5) 9.14 gram (0.0497 mole), S-trioxanes 4.48 grams and 2 normal hydrochloric acid are 300 milliliters 3.5 hours, the water extracted with diethyl ether, the ether layer of merging washes with water, drying (MgSO ₄).Under vacuum, boil off ether, obtain crystallization aldehyde 6 grams. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 7.6(m, 3H), 8.25(m, 3H), 10.25(S, 1H); Fusing point 66-67 ℃.

Preparation M

5-methyl-isoxazole base-3-formaldehyde (Carboxaldehyde)

(1) 5-methyl-isoxazole base-3-carboxylic acid second fat

Mixture with 0.16 mole of 2.4-, two oxy pentanoic acid second fat, 0.08 mole of hydroxylamine sulfate, 50 milliliters of ethanol and 70 milliliters of toluene, under 40 ℃, stirred 4 hours, and be cooled to 15-20 ℃, add the dense ammonium hydroxide of 1.8 grams, continue at room temperature to stir 60 hours, this mixture is poured in water/toluene, and water layer extracts with toluene, merges organic layer, use the salt water washing, dry (Na ₂SO ₄).Boil off solvent under vacuum, obtain yellow liquid, this is distilled, obtain 14.68 gram products, boiling point is 120-124 ℃ under 30 mmhg, occurs crystallization during placement.

(2) under-75--70 ℃, in the nitrogen atmosphere, be dissolved in second fat in 75 milliliters of toluene, that 2.0 grams (14.4 mmole) obtain above with diisobutyl aluminum hydride reduction equimolar amount, 1M that is dissolved in the hexane, stir after 30 minutes, add the ammonium chloride solution termination reaction, be heated to room temperature, boil off solvent (under vacuum), resistates is developed with hot methanol, boils off solvent and obtains 0.85 gram colorless oil product. ¹H-nucleus magnetic resonance (CDCl ₃) PPm(δ): 2.4(S, 3H), 6.3(d, 1H), 9.0(S, 1H).

Claims (7)

1, a kind of method for preparing following compounds, said compound is: (a) structural formula is

Compound, wherein n is 0 or 2, R ¹Be R ^aOr R ^b, R ^aBe the residue that is selected from the carboxy protective group of THP trtrahydropyranyl, allyl group, benzyl, diphenyl-methyl, R ^bBe be selected from hydrogen or

(R wherein ⁴And R ⁵Hydrogen or CH respectively do for oneself ₃And R ⁶Be (C ₁-C ₅) alkyl) and the residue of ester group of facile hydrolysis in vivo; R ¹²And R ¹³In a hydrogen, another is phenyl, vinyl, furyl, thienyl, N-methylpyrrole base, N-acetyl-pyrrole base

Be 0,1 or 2, X ₁Be S, O or NR ¹¹, R ⁷Be hydrogen, (C ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group or benzyl, R ⁸Be H, (C ₁-C ₄) alkyl, phenyl or benzyl, R ¹¹Be hydrogen, CH ₃, C ₂H ₅Or CH ₃CO,

Perhaps (b) said compound (wherein, R ¹²Or R ¹³Contain a basic nitrogen atom) be suitable for medical acid salt,

Perhaps (c) said compound (R wherein ¹Be hydrogen, or R ¹²Or R ¹³Contain a carboxyl) be suitable for medical cationic salts,

It is characterized in that: temperature for-100-+25 ℃ under, in the presence of inert solvent, make structural formula be

(wherein, R ¹Be that group, n outside the H is 0 or 2) compound, with the halogenation (C that waits mole number ₁-C ₄) alkyl magnesium or (C ₁-C ₄) alkyl lithium reagents and molecular formula be R ¹²R ¹³The aldehyde contact of CO, said halogenide is Cl, Br or I, R ¹²And R ¹³Definition as above to obtain structure is

Compound, also can change R to said compound (XI) into ¹Be R described above ^aThe derivative that is protected of carboxyl, and in inert organic solvents and etc. in the presence of the mole number tertiary amine, be R with molecular formula ¹⁸Cl, R ¹⁸The acyl chlorides of Br or acylbromide or corresponding acid anhydrides carry out acylations, wherein R ¹⁸Be (C ₂-C ₅) alkanoyl, (C ₂-C ₅) alkoxy carbonyl, pyrazine carbonyl, benzoyl, CF ₃CO or CONR ⁸R ⁹

Make (XI) formula compound or its acylations form carry out hydrogenolysis with the organotin hydride hydrogenolysis or in the presence of noble metal catalyst with hydrogen in the presence of the inert solvent;

Make described compound carry out dehydration reaction or deacetylation.

2, method according to claim 1, wherein said and aldehyde R ¹²R ¹³The reaction of CO is in the presence of tetrahydrofuran (THF) or ether, carries out under temperature is-78 ℃.

3, method according to claim 2, wherein R ¹²And R ¹³, one is H, another is 2-thiazolyl, 3-isothiazolyl, 4-pyrimidyl, 4,5-dimethylthiazole-2-base, benzothiazole-2-base or 1-benzyl-benzimidazolyl-2 radicals-Ji.

4, method according to claim 1 wherein makes R ¹Be (X) formula compound of allyl group or benzyl, with methyl magnesium bromine and molecular formula be R ¹²R ¹³The aldehyde of CO react and in benzene or toluene solvant under 0 ℃ of temperature between the said solvent boiling point, carry out hydrogenolysis with three positive fourth tin hydrides.

5, method according to claim 3 wherein makes R ¹Be (X) formula compound of allyl group or benzyl, with methyl magnesium bromine and molecular formula be R ¹²R ¹³The aldehyde of CO react and in benzene or toluene solvant under 0 ℃ of temperature between the said solvent boiling point, carry out hydrogenolysis with three positive fourth tin hydrides.

6, method according to claim 1, wherein R ¹²And R ¹³One is hydrogen, and another is 2-thiazolyl or benzothiazole-2-base.

7, according to the described method of any one claim of front, wherein R in said starting compound ¹Be allyl group, in the presence of inert solvent, with four (triphenyl phosphine) palladium (O) of catalytic amount, triphenyl phosphine and etc. the sodium salt or the sylvite of mole number 2 ethyl hexanoic acid, with resulting allyl ester product reaction, make said allyl group change R into ¹It is the respective compound of H, Na or K.