CN101500992A - Method for producing 1-methylcarbapenem production intermediate - Google Patents

Method for producing 1-methylcarbapenem production intermediate Download PDF

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CN101500992A
CN101500992A CNA2007800302669A CN200780030266A CN101500992A CN 101500992 A CN101500992 A CN 101500992A CN A2007800302669 A CNA2007800302669 A CN A2007800302669A CN 200780030266 A CN200780030266 A CN 200780030266A CN 101500992 A CN101500992 A CN 101500992A
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奥江雅之
高桥正明
石川一郎
伊藤宜雄
山口齐
鷲见信二郎
味户庆一
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Meiji Seika Kaisha Ltd
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    • C07—ORGANIC CHEMISTRY
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    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
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Abstract

Disclosed is a method for producing a commercially suitable 1-methylcarbapenem production intermediate (II), which does not comprise a complicated step, while using low-cost raw material. Specifically disclosed is a method for producing an 1-methylcarbapenem production intermediate (II), wherein a compound represented by the general formula (I) below is reacted with imidazole, then reacted with a malonic acid ester, and finally if necessary, subjected to diazotization.

Description

The method for preparing 1-methylcarbapenem production intermediate
Technical field
The present invention relates to a kind of excellent antibiotic active preparation method who is used as the azetidinone derivative of the intermediate for preparing 1-beta-methyl carbapenem (1-methylcarbapenem) that has.
Background technology
1-beta-methyl carbapenem with excellent anti-microbial activity and high security is very useful material in clinical practice as the injection antimicrobial substance.They are carrying out as the exploitation of Orally administered promoting agent and recently for expecting one of more attention material from now on.
Yet the antibiotic that constitutes conventional antiseptic-germicide group simultaneously is derived from natural organic-compound, and the 1-beta-methyl carbapenem does not have other selections except relying on chemosynthesis.Therefore they relate to the major issue about the preparation cost of chemosynthesis.The intermediates preparation of antimicrobial substance or preparation antimicrobial substance was at home and abroad actively discussed so far.
The intermediate of several key intermediates as preparation 1-beta-methyl carbapenem proposed.As the example, the following compounds that exists logical formula V to represent:
[formula 1]
R wherein 1Expression hydrogen atom or hydroxyl protecting group, R 6Expression hydrogen atom or carboxyl-protecting group and OR 8The expression leaving group.
Proposed the synthetic method of the compound that the whole bag of tricks represents as logical formula V so far, the azetidinone derivative of its formula of (II) expression can classify as one of important intermediate:
[formula 2]
Figure A200780030266D00051
R wherein 1Expression hydrogen atom or hydroxyl protecting group, R 2Expression hydrogen atom or amino protecting group, R 5Expression hydrogen atom or nitrogen-atoms and R 6Expression hydrogen atom or carboxyl-protecting group.
For example, in Japanese Patent Laid public publication H06-321946 disclosed method, the compound of general formula (II) expression is described by the intermediate that comprises in the preparation of the compound of representing as logical formula V.Be that it discloses several 4-acetoxyl group azetidinone (4-actetoxyazetidinone) derivatives of compound such as following general formula (III ') expression that wherein make and (is disclosed in Japanese patent publication 3220985, Japanese patent publication 3450193 and Tetrahedron, 52, the 331-357 page or leaf, in 1996 grades and commercially available) stand the reaction that the stereoselectivity C-C forms with the compound with auxiliary base of following formula (A) expression and obtain the method for the compound of following general formula (VI) expression.In addition, it also discloses wherein by the auxiliary based structures part (R in the compound of removing following general formula (VI) expression as methods such as hydrolysis 9) and change into the compound that general formula (VII) is represented, activated carboxyl and further chainpropagation C then 2The method of the compound of unit and the expression of synthetic general formula (II).The compound that the logical formula V that further makes the compound of general formula (II) expression produce one of key intermediate of preparation 1-beta-methyl carbapenem is represented:
[formula 3]
R wherein 1Expression hydrogen atom or hydroxyl protecting group, R 2Expression hydrogen atom or amino protecting group, R 5Expression hydrogen atom or nitrogen-atoms, R 6Expression hydrogen atom or carboxyl-protecting group, OR 8Expression leaving group and R 9The auxiliary base of expression.
Yet, when wanting to prepare 1 beta-methyl carbon penicillenic that is considered to more useful in the 1-beta-methyl carbapenem, produced several problems.For example, the use imperative of expensive auxiliary base may costliness because pursue highly-solid selectively and be used for forming smoothly the reagent of C-C in the compound of general formula (VI) expression synthetic.In case also may need to remove auxiliary base,, stand the complicated like this step of chainpropagation once more after more then with regard to activated carboxyl.Therefore, ordinary method still stays as industrial suitable method and treats improved space.
Japanese Patent Laid public publication H06-256327 and Japanese Patent Laid public publication H07-82248 disclose the method for reaction that the tiron that wherein will also use in the present invention and zirconin are used for producing the compound of general formula (VI) expression especially.Yet, use compound with expensive auxiliary base in order to improve stereoselectivity.In addition, Japanese patent publication 3220985 has been advised the mode of the compound of a kind of generation general formula (VII) expression, but does not have the suggestion about the compound of being represented by the logical formula V of compound generation of general formula (I) expression.
Japanese Patent Laid public publication S63-284176, Japanese Patent Laid public publication H10-87657 also disclose improving one's methods of a kind of complex steps that does not comprise chainpropagation once more after removing auxiliary base.Disclose promptly that compound with general formula (VI ') expression begins and carried out the method (referring to following synoptic diagram) that (suppose to state pursue the required auxiliary base of highly-solid selectively in the step be a class leaving group) produces the compound that general formula (II) represents thereon without the compound of general formula (VII) expression.
[formula 4]
Figure A200780030266D00061
R wherein 1Expression hydrogen atom or hydroxyl protecting group, R 2Expression hydrogen atom or amino protecting group, R 5Expression hydrogen atom or nitrogen-atoms, R 6Expression hydrogen atom or carboxyl-protecting group, OR 8The expression leaving group, R 9The auxiliary base of expression, R 10, R 11, R 12And R 13Can be identical or different and expression hydrogen atom or the optional low alkyl group that replaces and X and Y represent Sauerstoffatom or sulphur atom.
It is complicated and expensive with preparation that yet this method has been stipulated to be assumed to be a class leaving group and had auxiliary base and its precursor compound property obtained difference of this auxiliary gene of having the auxiliary base of complicated substituent special ring texture.Therefore, this method still stays as industrial suitable method and treats improved space.There is not the mode of correlation technique suggestion by the compound or the compound that formula V is represented of compound production (II) expression of cheaply assisting base as having of Chinese style of the present invention (I) expression.
Still need in these cases to develop and do not comprise complex steps and use cheap raw material to prepare the industrial appropriate preparation method of the intermediate of 1-beta-methyl carbapenem.
The invention summary
The present inventor has realized the industrial appropriate preparation method of the azetidinone derivative that the general formula (II) of one of useful intermediates of a kind of 1-of preparation beta-methyl carbapenem is represented.
Therefore, the object of the invention is used cheap auxiliary base but is had preparation method's the method for industrial excellence of azetidinone derivative of the intermediate of excellent antibiotic active 1-beta-methyl carbapenem or 1 beta-methyl carbon penicillenic without the conduct of complex steps as preparation for providing a kind of.
One aspect of the present invention provides the method for the compound of a kind of preparation following formula (II) expression:
[formula 5]
Figure A200780030266D00071
R wherein 1Expression hydrogen or hydroxyl protecting group, R 2Expression hydrogen or amino protecting group, R 5Expression hydrogen or nitrogen-atoms and R 6Expression hydrogen or carboxyl-protecting group,
This method comprises the following steps:
(a) compound that following formula (I) is represented:
[formula 6]
Figure A200780030266D00072
(I)
R wherein 3Optional aryl and the R that replaces of expression 4The optional aryl that replaces of expression, the optional aralkyl that replaces or the optional alkyl that replaces,
Also obtain wherein R with the malonic ester reaction subsequently with the imidazoles reaction 5Be the compound of the formula (II) of hydrogen atom expression, and
(b) as needs R wherein 5During for the compound of the formula (II) of nitrogen-atoms expression, then make the compound diazotization of acquisition in step (a).
The present invention also provides the method for the compound of a kind of preparation general formula (I) expression on the other hand, and this method comprises the compound that makes following formula (III) expression:
[formula 7]
Figure A200780030266D00081
R wherein 1And R 2As above-mentioned definition and R 7The expression alkyl carbonyl oxy,
Compound with following formula (IV) expression:
[formula 8]
Figure A200780030266D00082
R wherein 3And R 4As above-mentioned definition,
The step of reaction in the presence of zirconin.
Auxiliary base (N (the R of Shi Yonging in the present invention 3) SO 2R 4) be different from the auxiliary base that in ordinary method, needs etc. with special ring texture, but can cheaply reach preparation easily and industrial suitable and can be further effectively as leaving group.The i.e. auxiliary base (N (R that uses in the present invention 3) SO 2R 4) can be easily by the material with high universalizable such as aniline and sulfonic acid preparation and sulfonanilide compound (HN (R 3) SO 2R 4) because some itself have significant versatility as industrial raw material and cheap and preparation easily.In addition, in case the inventive method is not for needing the auxiliary base of cancellation, then with regard to the method for the industrial excellence of the complex steps of activated carboxyl.
Preparation method about the compound that constitutes the otherwise general formula of the present invention (I) expression, special is under the situation of 1 beta-methyl carbon penicillenic in target, known to the inventor, with Japanese patent publication 3220985, Japanese patent publication 3450193 and Tetrahedron, 52,331-357 page or leaf, the currently known methods of describing in 1996 grades are applied to auxiliary base (N (R in the preparation of the compound of general formula (I) expression 3) SO 2R 4) time, always do not obtain enough stereoselectivities.Yet the inventive method has favourable effect when carrying out especially in the presence of zirconin, wherein always obtain high stereoselectivity.
Detailed Description Of The Invention
Definition
In the disclosure content, represent preferably to have linearity, branching or the cyclic alkyl of 1-6 carbon atom and comprise methyl as specific examples, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl etc. as the low alkyl group of group or group part.
Aryl refers to derived from the group of aromatics ring compound and for example comprises phenyl, naphthyl or pyridyl etc.
Aralkyl represent arylalkyl and in this group the preferred above-mentioned low alkyl group of expression of alkyl structure part and aryl structure division represent above-mentioned aryl.Therefore, its specific examples comprises benzyl, styroyl, 3-hydrocinnamyl, menaphthyl, pyridylmethyl etc.
Halogen atom comprises fluorine atom, chlorine atom, bromine atoms or iodine atom etc.
Preparation formula (II) compound
Step (a)
In the methods of the invention, at first make the compound of general formula (I) expression and imidazoles reaction form imidazoles (imidazolide) compound, obtain wherein R with the malonic ester reaction then 5Compound for the expression of the formula (II) of hydrogen atom.
In formula (I) and formula (II), R 1Expression hydrogen atom or hydroxyl protecting group, R 2Expression hydrogen atom or amino protecting group and R 6Expression hydrogen atom or carboxyl-protecting group.Be described in " PROTECTIVEGROUPS in ORGANIC SYNTHESIS (protecting group in the organic synthesis) ", the 3rd edition, the normally used protecting group among the Wiley etc. can be used as the protecting group separately of hydroxyl, amino and carboxyl.Example comprises silyl type protecting group such as the trimethyl silyl as hydroxyl protecting group; triethylsilyl; t-butyldimethylsilyl etc. are as the silyl type protecting group such as the trimethyl silyl of amino protecting group; triethylsilyl; t-butyldimethylsilyl etc. and benzyl type protecting group such as benzyl; to methoxy-benzyl; to nitrobenzyl; diphenyl-methyl etc. and as the benzyl type protecting group such as the benzyl of carboxyl-protecting group; to methoxy-benzyl; to nitrobenzyl; but the ester group such as the oxy acid methyl neopentyl of hydrolysis in diphenyl-methyl etc. and the body; 1-(cyclohexyloxy carbonyl oxygen) ethyl; the acetoxyl methyl; 1-(isopropoxy carbonyl oxy) ethyl; 1-(oxyethyl group carbonyl oxygen base) ethyl; the cyclohexyloxy carbonyl oxygen methyl; 1-(cyclohexyloxy carbonyl oxygen)-2-methylpropane-1-base; the isopropoxy carbonyl oxy methyl; phthalidyl etc.
In formula (I) and formula (II), R 1Preferably include hydrogen atom, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl etc., more preferably t-butyldimethylsilyl etc.
In formula (I) and formula (II), R 2Preferably include hydrogen atom, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, benzyl, to methoxy-benzyl, to nitrobenzyl, diphenyl-methyl etc., more preferably hydrogen atom, to nitrobenzyl etc.
In formula (II), R 6Preferably include benzyl, to methoxy-benzyl, to nitrobenzyl, diphenyl-methyl, oxy acid methyl neopentyl, 1-(cyclohexyloxy carbonyl oxygen) ethyl, acetoxyl methyl, 1-(isopropoxy carbonyl oxy) but the ester group of hydrolysis etc. in the ethyl, cyclohexyloxy carbonyl oxygen methyl body, more preferably to nitrobenzyl, to methoxy-benzyl etc.
R 3For the optional aryl that replaces and this aryl preferably include aromatics ring compound such as phenyl, naphthyl, pyridyl etc.Substituting group comprises halogen atom such as fluorine atom, chlorine atom, bromine atoms, iodine atom etc., optional low alkyl group that is replaced by halogen atom such as methyl, trifluoromethyl, trichloromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc., lower alkoxy such as methoxyl group, oxyethyl group etc., amino as amino, alkyl monosubstituted amino (for example comprising monomethyl amino, single ethylamino etc.), dialkyl amido (for example comprising dimethylamino, diethylamino etc.), cyano group, nitro etc.Substituting group quantity can be for single or multiple and in substituting group quantity when being a plurality of, substituting group can be identical or different, the position of substitution can be at the point that is selected from the 2-of link position, 3-or 4-position under single substituting group situation simultaneously, under two replacement situations, can be selected from 2 of link position, 3-, 2,4-, 2,5-, 2,6-, 3,4-or 3, the point of 5-position and under greater than two substituting group situations, can be selected from any point of accepting the position.Therein under two replacement situations that substituting group is adjacent, two substituent ends can connect and this situation comprises the formation of the cyclic ether compounds that the formation of the aliphatic series ring that wherein propylidene, butylidene etc. connect is connected with wherein methylene radical dioxy base, ethylidene dioxy base etc.
According to a preferred embodiment of the invention, R 3Preferably including phenyl, bromophenyl, fluorophenyl, chloro-phenyl-, aminomethyl phenyl, 3,5-dimethylphenyl, ethylphenyl, isopropyl phenyl, tert-butyl-phenyl, methyl methoxy base phenyl, chloromethyl phenyl, trifluoromethyl, p-methoxy-phenyl, cyano-phenyl, nitrophenyl, methoxycarbonyl phenyl, methylenedioxyphenyl base, ethylidene dioxy base phenyl etc. and the position of each substituting group on phenyl meets as mentioned above.
R 4Can comprise before at R for choosing aryl, aralkyl or the alkyl and the substituting group that replace wantonly 3The middle similar substituting group of describing.This alkyl is for choosing wantonly by the low alkyl group of replacements such as halogen atom and for example comprising methyl, trifluoromethyl, trichloromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc.The optional aryl that replaces is with the identical of above-mentioned definition and for example comprise phenyl, aminomethyl phenyl, naphthyl, pyridyl etc.Aralkyl is with the identical of above-mentioned definition and for example comprise benzyl, styroyl, 3-hydrocinnamyl, menaphthyl, pyridylmethyl etc.R 4Preferably include phenyl, aminomethyl phenyl, benzyl, methyl etc.
R 5Be hydrogen atom or nitrogen-atoms.
The malonic ester of the reaction after the compound that is used for formula (I) expression and the imidazoles reaction is preferably the ester structure of malonic acid monoester wherein partly corresponding to R 6Malonic acid monoester.Therefore, its ester structure partly is preferably selected from R 6The ester structure part of citation and in addition the specific examples of malonic acid monoester comprise propanedioic acid monobenzyl ester, propanedioic acid list to nitrobenzyl ester, propanedioic acid list oxy acid methyl neopentyl ester etc., preferred propanedioic acid list is to the nitrobenzyl ester etc.
In step (a), promptly obtaining wherein R 5In the reaction for the compound of the general formula (II) of hydrogen atom expression, the fs carries out existing or do not exist to work under inert atmosphere such as nitrogen, argon gas etc. in organic solvent under the alkaline catalysts by making imidazoles.
The inert solvent that does not participate in reacting can be used as organic solvent and organic solvent, for example varsol such as Skellysolve A, normal hexane, hexanaphthene, normal heptane, they are mixture of isomers etc. separately, chlorinated solvent such as methylene dichloride, 1, the 2-ethylene dichloride, chloroform etc., aromatic hydrocarbons solvent such as benzene, chlorobenzene, toluene, dimethylbenzene etc., ether solvent such as diethyl ether, Di Iso Propyl Ether, glycol dimethyl ether, tetrahydrofuran (THF), 1, the 4-diox, cyclopentyl-methyl ether etc., acetate esters solvent such as ethyl acetate, butylacetates etc., aprotic polar solvent such as acetonitrile etc. can use separately or by the multiple organic solvent of suitable mixing.Solvent preferably includes methylene dichloride, ethyl acetate, acetonitrile etc.
According to a preferred embodiment of the invention, the interpolation of alkaline catalysts is carried out reaction smoothly.Alkaline catalysts comprises organic bases such as pyridine, 4-dimethylaminopyridine, 2-picoline, 3-picoline, 4-picoline, aniline, methylphenylamine, N, accelerine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene etc., preferred 4-dimethylaminopyridine etc.
The compound of general formula (I) expression and the ratio (by weight/volume) of solvent for use are generally 1:5-100, preferred 1:10-50.The compound of general formula (I) expression and the ratio (mol ratio) of used alkaline catalysts are generally 1:0.0-0.5, preferred 1:0.05-0.2.The compound of general formula (I) expression and the ratio (mol ratio) of used imidazoles are generally 1:1-10, preferred 1:1-5.Temperature of reaction is generally-30 ℃ to 100 ℃, preferred 30 ℃ to 60 ℃.Reaction times is generally 0.5-48 hour, and preferred 2-24 hour is 3-6 hour suitably.
The glyoxaline compound that obtains by this reaction can separate with method of purification by separation commonly used, so but to stand next stage because of this compound stability difference normally favourable.Usually make the thus obtained reaction mixture that contains glyoxaline compound continue to stand next stage, but can be in suitably cooling back storage.Cooling temperature under storage case is-80 ℃ to 0 ℃, preferred-30 ℃ to-10 ℃.Period of storage is several hours to two days, preferred 24 hours or shorter.
In step (a), promptly obtaining wherein R 5In the reaction for the compound of the general formula (II) of hydrogen atom expression, subordinate phase is by carrying out making imidazoles add malonic ester after acting on the compound of formula (I) expression.
According to a preferred embodiment of the invention, being reflected at magnesium compound exists and to carry out down and the example of used magnesium compound comprises magnesium chloride, magnesium bromide, magnesium bromide-ether title complex, magnesium iodide, magnesium methylate, magnesium ethylate etc., preferred magnesium chloride etc.
According to a preferred embodiment of the invention, being reflected at alkali exists and to carry out down and the example of alkali comprises Trimethylamine 99, triethylamine, Tributylamine, trioctylamine, diisopropylethylamine, the N-crassitude, the N-methyl piperidine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, the 2-picoline, the 3-picoline, the 4-picoline, aniline, methylphenylamine, N, accelerine, 2, the 3-lutidine, 2, the 4-lutidine, 2, the 5-lutidine, 2, the 6-lutidine, 3, the 4-lutidine, 3, the 5-lutidine, 2,4, the 6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene etc., preferred triethylamine etc.
The not restricted especially and reaction mixture that contains glyoxaline compound that separation can be obtained of the addition sequence of reagent adds in the mixture that wherein magnesium compound, alkali and malonic ester react in organic solvent in the reaction, but usually magnesium compound, alkali and malonic acid monoester is added in the reaction mixture that contains glyoxaline compound that above obtains.The compound of general formula (I) expression and the ratio (mol ratio) of used magnesium compound are generally 1:0.5-3, preferred 1:0.7-1.5.The compound of general formula (I) expression and the ratio (mol ratio) of used alkali are generally 1:1-6, preferred 1:1.5-3.The compound of general formula (I) expression and the ratio (mol ratio) of used malonic acid monoester are generally 1:1-3, preferred 1:1-2.Temperature when adding magnesium compound, alkali and malonic acid monoester is generally-80 ℃ to 0 ℃, preferred-30 ℃ to-10 ℃.Temperature of reaction is generally-30 ℃ to 100 ℃, preferred 30 ℃ to 60 ℃ after all reagent of needs add.Reaction times is generally 0.5-20 hour, preferred 1-5 hour.
R wherein 5For the compound of the general formula (II) of hydrogen atom expression can obtain by will carrying out aftertreatment according to the reaction mixture that standard program obtains and use separation commonly used to separate with method of purification.Step (b)
As needs R wherein 5During for the compound of the formula (II) of nitrogen-atoms expression, then further make the compound diazotization of acquisition in step (a).
Usually be not separated in the wherein R that obtains in the step (a) 5Be the compound of the general formula (II) of hydrogen atom expression, but in fact post-treatment solution diazotization changed into wherein R 5Compound for the expression of the general formula (II) of nitrogen-atoms.Can will not participate in the inert solvent of above-mentioned reaction at this moment as organic solvent and preferred solvent and suitable normal heptane, methylene dichloride, toluene, the ethyl acetate etc. used that are suitable for the aftertreatment reaction that varsol, chlorinated solvent, aromatic hydrocarbons solvent, acetate esters solvent etc. are used as.
Triazo-compound and alkali are used for diazotization.Triazo-compound comprises sulfonyl azide such as sulfonyl methane nitrine, tolylsulfonyl nitrine, to carboxyl sulfonyl azide, dodecyl sulfonyl azide etc., preferred dodecyl sulfonyl azide etc.
With Trimethylamine 99, triethylamine, Tributylamine, trioctylamine, diisopropylethylamine, the N-crassitude, the N-methyl piperidine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, the 2-picoline, the 3-picoline, the 4-picoline, aniline, methylphenylamine, N, accelerine, 2, the 3-lutidine, 2, the 4-lutidine, 2, the 5-lutidine, 2, the 6-lutidine, 3, the 4-lutidine, 3, the 5-lutidine, 2,4, the 6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene etc. can preferably include triethylamine etc. as alkali.
The compound of general formula (I) expression and the ratio (mol ratio) of used triazo-compound are generally 1:0.7-2, preferred 1:1-1.5.The compound of general formula (I) expression and the ratio (mol ratio) of used alkali are generally 1:0.1-1, preferred 1:0.2-0.5.Reaction is carried out under preferred 0 ℃ to 50 ℃ usually at-20 ℃ to 50 ℃.Reaction times is generally 0.5-48 hour, preferred 1-24 hour, is suitably 3-15 hour.
R wherein 5The compound of representing for the general formula (II) of nitrogen-atoms can be by those skilled in the art by carrying out the gained reaction mixture aftertreatment and further separate with method of purification by separation commonly used obtaining according to standard program commonly used.In this aftertreatment, except common washing, make wherein R with the dilute alkaline aqueous solution washing 5For the separation of the compound of the general formula (II) of nitrogen-atoms expression and purify especially convenient.The dilute alkaline aqueous solution that use this moment comprises sodium bicarbonate aqueous solution, potassium bicarbonate aqueous solution, aqueous sodium carbonate, wet chemical, aqueous sodium hydroxide solution, wet chemical, ammoniacal liquor etc., preferred aqueous sodium hydroxide solution.The concentration of the dilute alkaline aqueous solution that use this moment is generally 0.1-3mol/L, preferred 0.5-1mol/L.Separation and purification are carried out but be preferably formed sedimentary method by using common method, and this can be undertaken by suitably concentrated post-treatment solution.As other method, suitably add organic solvent such as normal heptane etc., further then ageing also passes through to filter the precipitation collection that forms, and obtains the wherein R as the intermediate for preparing the 1-beta-methyl carbapenem 5Azetidinone derivative for the expression of the general formula (II) of nitrogen-atoms.
As the R of protecting group with the compound of gained general formula (II) expression 1When existing, will be described in " GROUPS in ORGANIC SYNTHESIS (protecting group in the organic synthesis) ", the 3rd edition, the deprotection method commonly used among the Wiley etc. is used for deprotection and obtains wherein R 1For hydrogen atom and R5 is the azetidinone derivative of general formula (II) expression of hydrogen atom or nitrogen-atoms.
Although can be with R wherein 1The compound of representing for the general formula (II) of hydroxyl protecting group and separation and purification is used as the deprotection target, but in fact can use the reaction soln of the mixture of the compound that contains general formula (II) expression.Organic solvent to be used is preferably and does not participate in reacting and comprise varsol such as Skellysolve A separately or by solvent and example that the multiple solvent of suitable mixing uses, normal hexane, hexanaphthene, normal heptane, they are mixture of isomers etc. separately, chlorinated solvent such as methylene dichloride, 1, the 2-ethylene dichloride, chloroform etc., aromatic hydrocarbons solvent such as benzene, chlorobenzene, toluene, dimethylbenzene etc., ether solvent such as Anaesthetie Ether, Di Iso Propyl Ether, glycol dimethyl ether, tetrahydrofuran (THF), 1, the 4-diox, cyclopentyl-methyl ether etc., acetate esters solvent such as ethyl acetate, butylacetate etc., aprotic polar solvent such as acetonitrile, N, dinethylformamide, methyl-sulphoxide etc. or alcoholic solvent such as methyl alcohol, ethanol, the 1-propyl alcohol, the 2-propyl alcohol, the 1-butanols, the 2-butanols, isopropylcarbinol, the trimethyl carbinols etc. reach other.Solvent preferably includes methylene dichloride, acetonitrile, tetrahydrofuran (THF), methyl alcohol etc., more preferably suitable mixture of methylene dichloride and methyl alcohol etc.This moment, the ratio of mixture (volume ratio) of methylene dichloride and methyl alcohol was generally 1:0-0.1, preferred 1:1-4.When protecting group was silyl, this desilylation reagent can use separately or by mixing multiple desilylation reagent.Desilylation reagent comprises organic acid such as formic acid, acetate, trifluoroacetic acid, propionic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, camphorsulfonic acid etc., the mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., Lewis acid such as boron trifluoride, boron trifluoride-Anaesthetie Ether title complex, titanium tetrachloride, zirconium tetrachloride, aluminum chloride, iron(ic) chloride, cupric nitrate, cerous nitrate (III) etc., alkaline hydrated oxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide etc., fluorochemical such as hydrogen fluoride, Neutral ammonium fluoride, hydrogen fluoride-triethylamine title complex, the hydrogen fluoride-pyridine title complex, tetrabutyl ammonium fluoride, lithium fluoride, Sodium Fluoride, Potassium monofluoride, cesium fluoride, Neutral ammonium fluoride, fluoroboric acid, silicofluoric acid etc., preferred hydrochloric acid etc.
In deprotection, R wherein 1For the compound of the general formula (II) of hydroxyl protecting group expression is generally 1:2-50 with the ratio (by weight/volume) of solvent for use, preferred 1:5-20.The amount of desilylation reagent to be used in stoichiometry to the excessive greatly scope.Temperature of reaction is generally-20 ℃ to 60 ℃, preferred 0 ℃ to 40 ℃.Reaction times is generally 0.5-24 hour, preferred 1-17 hour.
The wherein R of deprotection 1Be hydrogen atom and R 5The compound of representing for the general formula (II) of hydrogen atom or nitrogen-atoms can be by those skilled in the art by carrying out the gained reaction mixture aftertreatment and further separate with method of purification by separation commonly used obtaining according to standard program commonly used.
Preparation formula (I) compound
The compound of formula (I) expression that is used to prepare the compound of formula of the present invention (II) expression is known and can be by for example above-mentioned Japanese patent publication 3220985, Japanese patent publication 3450193 and Tetrahedron, 52, the 331-357 page or leaf, the method for describing in 1996 obtains.Yet according to a preferred embodiment of the invention, the compound of formula (I) expression can preferably constitute other aspects of the present invention according to following synoptic diagram preparation and this method:
[formula 9]
R wherein 1Expression hydrogen atom or hydroxyl protecting group, R 2Expression hydrogen atom or amino protecting group, R 3The optional aryl that replaces of expression, R 4The optional aryl that replaces of expression, the optional aralkyl that replaces or optional alkyl and the R that replaces 7The expression alkyl carbonyl oxy.
In the present invention, use the cheap and industrial useful auxiliary base (N (R that is used as the deprotection base 3) SO 2R 4).As mentioned above, use the compound that should assist basic preparation formula (I) expression in the currently known methods of describing in front, when particularly intermediate was used in the preparation of 1 beta-methyl carbon penicillenic, existence can not obtain enough stereoselective risk.The preparation method of the compound of formula of the present invention (I) expression can address this problem.The compound of the compound of this problem by making general formula (III) expression and general formula (IV) expression of preferably handling with zirconin react in the presence of zirconin and also obtains the compound that general formula (I) represents thus and solve.Processing with the compound of zirconin mutual-through type (IV) expression preferably instigates the compound of general formula (IV) expression to act in organic solvent on zirconium compounds and the alkali.
The compound of general formula (IV) expression can obtain by currently known methods.For example, this compound is by making aniline (R 3NH 2) and sulfonic acid (R 4SO 2X) reaction obtains sulfonanilide compound (HN (R 3) SO 2R 4) and make methods such as propionyl chloride, propionic anhydride etc. are applied to it and obtain.
In preparation method of the present invention, R 1And R 2Be respectively hydrogen atom or hydroxyl and amino protecting group and can be used as hydroxyl and amino protecting group usually in above-mentioned document etc., describing this protecting group of using.Hydroxyl and amino protecting group be with defined above identical, R 1Preferably include hydrogen atom, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl etc., more preferably t-butyldimethylsilyl.
R 2Preferably include hydrogen atom, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, benzyl, to methoxy-benzyl, to nitrobenzyl, diphenyl-methyl etc., more preferably hydrogen atom, to nitrobenzyl etc.
R 3Also define and be the aryl of optional replacement as mentioned, this aryl comprises that the aromatic ring structure part is as phenyl, naphthyl, pyridyl etc. and substituting group comprise halogen atom such as fluorine atom, the chlorine atom, bromine atoms, iodine atom etc., optional low alkyl group such as the methyl that is replaced by halogen atom, trifluoromethyl, trichloromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc., lower alkoxy such as methoxyl group, oxyethyl group etc., amino as amino, alkyl monosubstituted amino (for example can comprise monomethyl amino, single ethylamino etc.), dialkyl amido (for example can comprise dimethylamino, diethylamino etc.), cyano group, nitro etc.Substituting group can be for single or multiple, at substituting group when being a plurality of, substituting group can be identical or different, and substituting group position can be selected from 2 at substituting group at the point that is selected from 2-, 3-or 4-position when being single when two replacement, 3-, 2,4-, 2,5-, 2,6-, 3,4-or 3, the point of 5-position and when existing, can be selected from any point of accepting the position greater than two substituting groups.In two replacement that substituting group is adjacent therein, two substituent ends can connect, wherein can comprise the aliphatic series ring that is connected to form by propylidene, butylidene etc., by methylene radical dioxy base, ethylidene dioxy base etc. be connected to form cyclic ether compounds.
R 3The position that preferably includes on phenyl, bromophenyl, fluorophenyl, chloro-phenyl-, aminomethyl phenyl, 3,5-dimethylphenyl, ethylphenyl, isopropyl phenyl, tert-butyl-phenyl, methyl methoxy base phenyl, chloromethyl phenyl, trifluoromethyl, p-methoxy-phenyl, cyano-phenyl, nitrophenyl, methoxycarbonyl phenyl, methylenedioxyphenyl base, ethylidene dioxy base phenyl etc. and each comfortable phenyl of substituting group is as indicated above.
R 4For choosing aryl, aralkyl or the alkyl that replaces wantonly and defining conduct as mentioned and be described in R 3In the relevant substituting group of substituting group.Alkyl is for choosing wantonly by the lower aryl of replacements such as halogen atom and for example comprising methyl, trifluoromethyl, trichloromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc.The optional aryl that replaces is with defined above identical and for example comprise phenyl, aminomethyl phenyl, naphthyl, pyridyl etc.Aralkyl is with defined above identical and for example comprise benzyl, styroyl, 3-hydrocinnamyl, menaphthyl, pyridylmethyl etc.R 4Preferably include phenyl, aminomethyl phenyl, benzyl, methyl etc.
R 7The expression alkyl carbonyl oxy also preferably includes ethanoyl oxygen base etc.
Reaction can be carried out in organic solvent under atmosphere such as rare gas element such as nitrogen, argon gas ideally.The inert solvent that does not participate in reacting can be used as organic solvent, this organic solvent can be separately or is used with the suitable mixing of multiple organic solvent and comprise varsol such as Skellysolve A, normal hexane, hexanaphthene, normal heptane, their mixture of isomers etc. separately, chlorinated solvent such as methylene dichloride, 1,2-ethylene dichloride, chloroform etc., aromatic hydrocarbons solvent such as benzene, chlorine benzene,toluene,xylene etc. and ether solvent such as Anaesthetie Ether, Di Iso Propyl Ether, glycol dimethyl ether, tetrahydrofuran (THF), 1,4-diox, cyclopentyl-methyl ether etc. preferably include methylene dichloride etc.
Zirconium compounds comprises zirconium tetrafluoride, zirconium tetrachloride, tetrabormated zirconium, zirconium tetraiodide, four zirconium iso-propoxides etc., preferred zirconium tetrachloride etc.
As alkali, use dimethylamine, Trimethylamine 99, diethylamine, triethylamine, dibutylamine, Tributylamine, trioctylamine, diisopropylethylamine, two (trimethyl silyl) amine, tetramethyleneimine, the N-crassitude, piperidines, the N-methyl piperidine, morpholine, N-methylmorpholine, Tetramethyl Ethylene Diamine, pyridine, 4-dimethylaminopyridine, the 2-picoline, the 3-picoline, the 4-picoline, aniline, methylphenylamine, N, accelerine, 2, the 3-lutidine, 2, the 4-lutidine, 2, the 5-lutidine, 2, the 6-lutidine, 3, the 4-lutidine, 3, the 5-lutidine, 2,4, the 6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene etc. preferably include triethylamine, Tributylamine, diisopropylethylamine etc.
The addition sequence of reagent is not restricted especially, but preferably the compound of zirconium compounds, alkali, general formula (III) expression is then added in the solution of compound in organic solvent of general formula (IV) expression in proper order with this.The compound of general formula (III) expression and the ratio (by weight/volume) of solvent for use are generally 1:10-100, preferred 1:10-30.The ratio (mol ratio) of the compound of the compound of general formula (III) expression and used general formula (IV) expression is generally 1:1-3, preferred 1:1.2-2.The ratio of zirconium compounds (mol ratio) is generally 1:1-3, preferred 1:1-2.The ratio of used alkaline catalysts (mol ratio) is generally 1:1-3, preferred 1:1.2-2.Recommend suitably to add aprotic polar solvent such as acetonitrile, N, dinethylformamide, methyl-sulphoxide etc. makes that reaction yield and/or stereoselectivity can be improved.According on the other hand, additionally add indivisible protonic solvent such as water, methyl alcohol etc. and can improve productive rate.Temperature of reaction is generally-30 ℃ to 50 ℃, preferred-15 ℃ to 30 ℃.Reaction times is generally 0.5-24 hour, preferred 1-5 hour.
The aftertreatment of thus obtained reaction mixture according to by commonly used separate and method of purification as purifying by silica gel column chromatography, form isolating standard program such as sedimentary method and carry out, make it possible to prepare the compound that general formula (I) is represented.
Embodiment
The present invention more elaborates in following specific embodiment, but is not limited to these specific embodiments.Can use following abbreviation code name.
Ts: p-toluenesulfonyl
TEA: triethylamine
The DMAP:4-dimethyl aminopyridine
Ac: ethanoyl
TBS: t-butyldimethylsilyl
DIPEA: diisopropylethylamine
Relevant with the explanation of physical properties in each section of hereinafter setting forth 1The H nuclear magnetic resonance spectrum ( 1H NMR) uses JEOL, Ltd. JNM-AL 400 nuclear magnetic resonance analyser of making are measured, value when wherein chemical displacement value is interpreted as tetramethylsilane (TMS) is appointed as δ 0.00ppm, the spin coupling constant is expressed as J value (Hz), spin coupling division figure is respectively for the unimodal s that is expressed as, be expressed as d for doublet, be expressed as t for triplet, doublet for doublet is expressed as dd, triplet for doublet is expressed as td and is expressed as m for multiplet, and the code name with br represents that broad peak and number of hydrogen atoms are expressed as 1H, 2H.In addition, in part of compounds, the nuclear-magnetism spectrum is observed the mixture as two kinds of rotational isomer, and this is because the sterically hindered reason.At this moment, chemical displacement value, spin coupled division figure and number of hydrogen atoms only are described.
Preparation embodiment 1
N-propionyl-N-(2-trifluoromethyl)-para toluene sulfonamide (compound 3)
[formula 10]
Figure A200780030266D00191
Cool off the solution of 2-5 amido benzotrifluoride in pyridine (85mL) of 32.23g (0.2mol) with ice bath, add the Tosyl chloride of 38.52g (0.2mol) therein and make to be reflected at and carried out under the uniform temp 1 hour.Reaction mixture is poured in the water and obtains organic layer, also use anhydrous magnesium sulfate drying, vapourisation under reduced pressure solvent then with dilute hydrochloric acid and saturated brine washing organic layer successively with ethyl acetate extraction.With gained residue recrystallize and obtain 55.79g (productive rate: from ethyl acetate-hexane 96.5%) as N-(2-the trifluoromethyl)-para toluene sulfonamide (compound 2) of yellow-white powder.
1H?NMR(400MHz，CDCl 3)，δ?ppm?2.37(s，3H)，6.84(br.s，1H)，7.16-7.23(m，3H)，7.47-7.53(m，2H)，7.66(d，J＝8.3Hz，2H)，7.82(d，J＝8.3Hz，1H)。
In the solution of methylene dichloride (350mL), add the DMAP of the TEA of propionic anhydride, 40.77mL (0.29mol) of 31.25mL (0.24mol) and 1.19g (0.0097mol) at 61.49g (0.20mol) compound 2 successively and reaction mixture was at room temperature reacted 1 hour.In this reaction mixture, add entry, vigorous stirring gained mixture also leaves standstill it to tell organic layer, under reduced pressure concentrate this organic layer, then hexane is added in this concentrated solution and obtain the target compound (compound 3) of 67.41g (productive rate, 93.1%) as white powder.
1H?NMR(400MHz，CDCl 3)，δ?ppm?0.97(t，J＝7.3Hz，3H)，1.91-2.06(m，2H)，2.46(s，3H)，7.35-7.38(m，3H)，7.65-7.70(m，2H)，7.86(dd，J＝7.6，1.7Hz，1H)，8.02(d，J＝8.3Hz，2H)。
Other N-propionyl-N-phenyl-tolysulfonyl sulfonamide derivatives can be by preparing with the similar method of the method that above prepares embodiment 1.
Embodiment 1
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2-trifluoromethyl)-para toluene sulfonamide (compound 4)
[formula 11]
Figure A200780030266D00201
Under nitrogen atmosphere, cool off 22.29g (60.0mmol) N-propionyl-N-(2-the trifluoromethyl)-solution of para toluene sulfonamide (compound 3) in methylene dichloride (345mL), add 20.98g (90.0mmol) zirconium chloride therein and under uniform temp, stirred this mixture 30 minutes with ice bath.In this mixture, add 16.5mL (94.7mmol) DIPEA and under uniform temp, stirred the gained mixture 30 minutes, add therein then 17.25g (60.0mmol) (3S, 4R)-the 4-acetoxyl-3-[(R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-the 2-azetidinone.Remove ice bath and reaction was carried out 1 hour, make temperature rise to room temperature simultaneously.Reaction yield this moment (based on HPLC) be 58.4% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=93.5/6.5.Add entry in this reaction mixture, vigorous stirring gained mixture also leaves standstill it to tell organic layer, and water and 10% this organic layer of salt water washing under reduced pressure concentrate this organic layer then successively.After with toluene displacement gained concentrated solution, when adding hexane, obtaining the title compound (compound 4) of 19.28g (productive rate, 53.7%) in order to concentrate as white powder.
1H?NMR(400MHz，CDCl 3)，δ?ppm?-0.01，-0.01，0.01，0.05(s，6H)，0.77-1.04(m，15H)，2.33-2.46(m，4H)，2.62，2.70(dd，1H)，3.74，3.86(dd，1H)，4.08(m，1H)，5.49，5.86(br.s，1H)，7.24-7.43(m，3H)，7.63-7.72(m，2H)，7.85(m，1H)，7.95(m，2H)。Observe the data of the ratio of rotational isomer for about 1:1.
Embodiment 2
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2-trifluoromethyl)-para toluene sulfonamide (compound 4)
Under nitrogen atmosphere, cool off 26.75g (72.0mmol) N-propionyl-N-(2-the trifluoromethyl)-solution of para toluene sulfonamide (compound 3) in methylene dichloride (345mL) with ice bath; in the gained mixture, add 21.67g (93.0mmol) zirconium chloride, under uniform temp, stirred 30 minutes then.In this mixture, add 16.2mL (93.0mmol) DIPEA and under uniform temp, stirred the gained mixture 30 minutes, in this mixture, add 17.3mL DMF then and under uniform temp, stirred the gained mixture 30 minutes, (3S, 4R)-4-acetoxyl 3-[(R)-1-(the tertiary butyl dimethyl methyl siloxy) ethyl that adds 17.25g (60.0mmol) then]-the 2-azetidinone.Remove ice bath and reaction was carried out 30 minutes, make temperature rise to room temperature simultaneously.Reaction yield this moment (based on HPLC) be 63.0% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=97.4/2.6.Add entry in this reaction mixture, vigorous stirring gained mixture also leaves standstill it to tell organic layer, and water and 10% this organic layer of salt water washing under reduced pressure concentrate this organic layer then successively.To precipitate to form with toluene displacement gained concentrated solution in order concentrating, to obtain the title compound (compound 4) of 19.71g (productive rate, 54.9%) as white powder.
The gained compound 1Identical among H NMR spectrum and the embodiment 1.
Embodiment 3
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2-bromophenyl)-para toluene sulfonamide
Use 27.53g (72.02mmol) N-propionyl-N-(2-bromophenyl)-para toluene sulfonamide to carry out with reaction like the response class of embodiment 2, obtain the title compound of 23.38g (productive rate, 63.9%) as white powder.The reaction yield of this reaction (based on HPLC) be 72.5% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=95.4/4.6.
1H?NMR(400MHz，CDCl 3)，δ?ppm?-0.01，-0.01，0.01，0.02(s，6H)，0.81，0.83(s，9H)，0.83，0.96，1.05，1.12(d，6H)，2.25，2.44(m，1H)，2.44(s，3H)，2.68，2.80(dd，1H)，3.77，3.93(dd，1H)，4.09(m，1H)，5.65，5.85(br.s，1H)，7.31-7.47(m，5H)，7.72(m，1H)，7.96(d，2H)。Observe the data of the ratio of rotational isomer for about 1:1.9.
Embodiment 4
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-phenyl-para toluene sulfonamide
Use 3.03g (10.0mmol) N-propionyl-N-phenyl-para toluene sulfonamide to carry out with reaction like the response class of embodiment 1, obtain the title compound of 2.66g (productive rate, 50.1%) as white powder.The reaction yield of this reaction (based on HPLC) be 60.5% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=85.6/14.4.
1H?NMR(400MHz，CDCl 3)，δ?ppm?-0.01(s，3H)，0.01(s，3H)，0.81(s，9H)，0.94(d，J＝6.3Hz，3H)，1.00(d，J＝7.1Hz，3H)，2.44-2.47(m，4H)，2.61(dd，J＝4.0，2.2Hz，1H)，3.77(dd，J＝4.5，2.2Hz，1H)，4.05(td，J＝6.3，4.5Hz，1H)，5.77(br.s，1H)，7.21-7.24(m，2H)，7.32(d，J＝8.1Hz，2H)，7.46-7.50(m，3H)，7.86(d，J＝8.1Hz，2H)。
Embodiment 5
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2-ethylphenyl)-para toluene sulfonamide
Use 3.32g (10.0mmol) N-propionyl-N-(2-ethylphenyl)-para toluene sulfonamide to carry out with reaction like the response class of embodiment 1, obtain the title compound of 2.81g (productive rate, 52.8%) as white powder.Reaction yield (based on HPLC) be 50.7% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=89.1/10.9.
1H?NMR(400MHz，CDCl 3)，δ?ppm?-0.04，-0.00，0.01，0.03(s，6H)，0.79，0.82(s，9H)，0.76，0.90，0.97，1.02(d，6H)，1.30，1.32(t，3H)，2.26，2.42(m，1H)，2.44，2.45(s，3H)，2.61(m，1H)，2.62，2.84(m，2H)，3.68，3.88(dd，1H)，4.02，4.12(m，1H)，5.59，5.82(br.s，1H)，6.97，7.06(d，1H)，7.23-7.35(m，3H)，7.39(m，2H)，7.91(d，2H)。Observe the data of the ratio of rotational isomer for about 1.5:1.
Embodiment 6
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(3-aminomethyl phenyl)-para toluene sulfonamide
Use 5.67g (18.0mmol) N-propionyl-N-(3-aminomethyl phenyl)-para toluene sulfonamide to carry out with reaction like the response class of embodiment 2, obtain the title compound of 5.26g (productive rate, 64.2%) as white powder.Reaction yield (based on HPLC) be 73.0% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=94.4/5.6.
1H?NMR(400MHz，CDCl 3)，δ?ppm?-0.01(s，3H)，0.01(s，3H)，0.82(s，9H)，0.93(d，J＝6.3Hz，3H)，1.00(d，J＝6.8Hz，3H)，2.39(s，3H)，2.44-2.47(m，4H)，2.61(dd，J＝4.6，2.4Hz，1H)，3.77(dd，J＝4.6，2.2Hz，1H)，4.05(td，J＝6.3，2.2Hz，1H)，5.77(br.s，1H)，6.99(d，J＝7.6Hz，1H，7.07(s，1H)，7.28-7.36(m，4H)，7.87(d，J＝8.5Hz，2H)。
Embodiment 7
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2-ethoxyl phenenyl)-para toluene sulfonamide
Use 3.48g (10.0mmol) N-propionyl-N-(2-ethoxyl phenenyl)-para toluene sulfonamide to carry out with reaction like the response class of embodiment 1, obtain the title compound of 2.89g (productive rate, 48.8%) as white powder.Reaction yield (based on HPLC) be 51.5% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=80.0/20.0.
1H?NMR(400MHz，CDCl 3)，δ?ppm?-0.01，-0.00，0.00，0.02(s，6H)，0.79，0.82(s，9H)，0.84，0.94，0.97，1.02(d，6H)，1.18，1.19(t，3H)，2.29，2.46(m，1H)，2.42(s，3H)，2.66(m，1H)，3.78-4.10(m，4H)，5.72，5.80(br.s，1H)，6.95-7.07(m，2H)，7.27-7.45(m，4H)，7.91(d，2H)。Observe the data of the ratio of rotational isomer for about 1:1.6.
Embodiment 8
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(4-p-methoxy-phenyl)-para toluene sulfonamide
Use 16.01g (48.0mmol) N-propionyl-N-(4-p-methoxy-phenyl)-para toluene sulfonamide to carry out with reaction like the response class of embodiment 2, obtain the title compound of 11.56g (productive rate, 51.5%) as white powder.Reaction yield (based on HPLC) be 69.6% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=93.5/6.5.
1H?NMR(400MHz，CDCl 3)，δ?ppm?-0.01(s，3H)，0.01(s，6H)，0.81(s，9H)，0.96(d，J＝6.3Hz，3H)，1.00(d，J＝6.8Hz，3H)，2.44(s，3H)，2.49(m，1H)，2.61(m，1H)，3.76(dd，J＝4.6，2.2Hz，1H)，3.84(s，3H)，4.05(m，1H)，5.78(br.s，1H)，6.95(d，J＝8.5Hz，2H)，7.12(d，J＝8.5Hz，2H)，7.32(d，J＝8.3Hz，2H)，7.85(d，J＝8.3Hz)。
Embodiment 9
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2,6-diethyl phenyl)-para toluene sulfonamide
Use 3.60g (10.0mmol) N-propionyl-N-(2,6-diethyl phenyl)-para toluene sulfonamide to carry out with reaction like the response class of embodiment 1, obtain the title compound of 2.66g (productive rate, 45.4%) as white powder.Reaction yield (based on HPLC) be 56.4% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=87.1/12.9.
1H?NMR(400MHz，CDCl 3)，δ?ppm?0.01(s，3H)，0.01(s，3H)，0.81(d，J＝7.8Hz，3H)，0.84(s，9H)，0.92(d，J＝6.8Hz，3H)，1.28(t，J＝7.3Hz，6H)，2.29(m，1H)，2.45(s，3H)，2.46-2.69(m，5H)，3.79(dd，J＝2.9，2.7Hz，1H)，4.08(m，1H)，5.78(br.s，1H)，7.23-7.26(m，2H)，7.32-7.40(m，3H)，8.00(d，J＝8.3Hz，2H)。
Embodiment 10
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2, the 6-diisopropyl phenyl)-para toluene sulfonamide
Use 3.48g (10.0mmol) N-propionyl-N-(2, the 6-diisopropyl phenyl)-para toluene sulfonamide to carry out with reaction like the response class of embodiment 1, obtain the title compound of 4.18g (productive rate, 50.0%) as white powder.Reaction yield (based on HPLC) be 60.6% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=91.6/8.4.
1H?NMR(400MHz，CDCl 3)，δ?ppm?0.00(s，6H)，0.81(s，9H)，0.94-0.98(m，3H)，1.12-1.34(m，15H)，2.45(s，3H)，2.75(br.m，1H)，3.01-3.05(m，3H)，3.82(br.m，1H)，4.10(m，IH)，5.85(br.s，1H)，7.25-7.45(m，5H)，7.97(br.d，J＝7.6Hz，2H)。
Embodiment 11
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(3, the 5-3,5-dimethylphenyl)-para toluene sulfonamide
Use 15.92g (48.0mmol) N-propionyl-N-(3, the 5-3,5-dimethylphenyl)-para toluene sulfonamide to carry out with reaction like the response class of embodiment 2, obtain the title compound of 14.40g (productive rate, 64.4%) as white powder.Reaction yield (based on HPLC) be 70.6% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=94.6/5.4.
1H?NMR(400MHz，CDCl 3)，δ?ppm?0.01(s，3H)，0.01(s，3H)，0.82(s，9H)，0.93(d，J＝6.3Hz，IH)，0.99(d，J＝6.8Hz，3H)，2.34(s，6H)，2.44(s，3H)，2.47(td，J＝6.8，2.2Hz，1H)，2.60(m，1H)，3.77(dd，J＝4.6，2.4Hz，1H)，4.06(td，J＝6.3，4.6Hz，1H)，5.77(s，1H)，6.84(s，2H)，7.11(s，1H)，7.32(d，J＝8.1Hz，2H)，7.88(d，J＝8.1Hz，2H)。
Embodiment 12
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-phenylmethane sulphonamide
Use 5.45g (24.0mmol) N-propionyl-N-phenylmethane sulphonamide to carry out with reaction like the response class of embodiment 2, obtain the title compound of 3.74g (productive rate, 41.4%) as white powder.Reaction yield (based on HPLC) be 52.1% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=92.3/7.7.
1H?NMR(400MHz，CDCl 3)，δ?ppm?0.03(s，3H)，0.04(s，3H)，0.84(s，9H)，1.09(d，J＝6.3Hz，3H)，1.12(d，J＝7.1Hz，3H)，2.54(td，J＝7.1，4.4Hz，1H)，2.75(dd，J＝4.4，2.2Hz，1H)，3.42(s，3H)，3.87(dd，4.6，2.2Hz，1H)，4.12(td，J＝6.3，4.6Hz，1H)，5.94(br.s，1H)，7.25-7.28(m，2H)，7.47-7.50(m，3H)。
Embodiment 13
N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2-ethylphenyl) amsacrine
Use 1.35g (5.29mmol) N-propionyl-N-(2-ethylphenyl) amsacrine to carry out with reaction like the response class of embodiment 2, obtain the title compound of 0.45g (productive rate, 21.2%) as white powder.The reaction yield of this reaction (based on HPLC) be 60.3% and the ratio (based on HPLC) of the diastereomer that forms be beta/alpha=94.8/5.2.
1H?NMR(400MHz，CDCl 3)，δ?ppm?0.03，0.03，0.04，0.04(s，6H)，0.84，0.85(s，9H)，1.02，1.03，1.06，1.08(d，6H)，1.29，1.30(t，3H)，2.28，2.50(m，1H)，2.56-2.82(m，3H)，3.46，3.47(s，3H)，3.84，3.93(dd，1H)，4.14(m，1H)，5.86，5.94(br.s，1H)，7.10，7.17(d，1H)，7.24-7.29(m，1H)，7.41-7.46(m，2H)。Observe the data of the ratio of rotational isomer for about 1:1.
Make the compound of formula (IV) expression and make to be reflected under the mode identical to carry out to body and function with what describe in the following table with embodiment 1 or 2.The ratio (based on HPLC) that reaction yield (based on HPLC) and these react formed diastereomer is shown in Table 1.
Table 1
Figure A200780030266D00271
Figure A200780030266D00281
Comparative Examples 1
Use with the body of giving of embodiment 4 and similarly give body and TiCl 4Situation
Under nitrogen atmosphere, 303mg (1.00mmol) N-propionyl-solution of N-phenyl-para toluene sulfonamide in methylene dichloride (6mL) is cooled to-5 ℃; add 164 μ L (1.50mmol) titanium chlorides, 274 μ L (1.58mmol) DIPEA and 287mg (1.00mmol) (3S, 4R)-4-acetoxyl 3-[(R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl therein successively with 10 minutes intervals]-2-azetidinone and make to be reflected under the uniform temp and carry out.The ratio (based on HPLC) of the diastereomer that forms after 2 hours in this reaction is beta/alpha=48.9/51.1.
Embodiment 13
(4R)-4-{ (3R, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl }-3-oxopentanoic acid 4-nitrobenzyl ester (compound 5)
[formula 12]
Figure A200780030266D00291
Under nitrogen atmosphere, 200mg (3.00mmol) imidazoles and 12.5mg (0.102mmol) DMAP are added 600mg (1.00mmol) N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl propionyl]-N-(2-the trifluoromethyl)-solution of para toluene sulfonamide (compound 4) in acetonitrile (9mL) in and make mixture 60 ℃ of reactions 16 hours down.Use the ice bath reaction mixture, add successively therein 95.5mg (1.00mmol) magnesium chloride, 280 μ L (2.01mmol) TEA and 407mg (1.70mmol) propanedioic acid list to the nitrobenzyl ester and make the reaction carried out 2 hours, temperature is risen to 50 ℃ simultaneously.Reaction mixture is under reduced pressure concentrated and, wash this diluting soln successively with 1M hydrochloric acid, 5% sodium bicarbonate aqueous solution and 10% salt solution, then the vapourisation under reduced pressure solvent with dilution with toluene gained concentrated solution.(eluting solvent: hexane/ethyl acetate=1/1) purification obtains the title compound (compound 5) of 453mg (productive rate, 94.6%) as white powder by silica gel column chromatography with the gained residue.
Title compound (compound 5) be known substance and the retention time of this title compound in HPLC and 1H NMR spectrum is with to have those of article now consistent.
Embodiment 14
(4R)-4-{ (3R, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl }-2-diazonium-3-oxopentanoic acid 4-nitrobenzyl ester (compound 6)
[formula 13]
Figure A200780030266D00301
Under nitrogen atmosphere, 1.0g (15.0mmol) imidazoles and 60mg (0.491mmol) DMAP are added 3.0g (5.00mmol) N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl propionyl]-N-(2-the trifluoromethyl)-solution of para toluene sulfonamide (compound 4) in acetonitrile (9mL) in and make to be reflected at and carried out under 60 ℃ 19 hours.Use the ice bath reaction mixture, add successively therein 0.48g (5.01mmol) magnesium chloride, 1.4mL (10.0mmol) TEA and 2.04g (8.53mmol) propanedioic acid list to the nitrobenzyl ester and make the reaction carried out 2 hours, temperature is risen to 50 ℃ simultaneously.Reaction mixture is under reduced pressure concentrated, also wash this diluting soln successively with 1M hydrochloric acid, 5% sodium bicarbonate aqueous solution and 10% salt solution with methylene dichloride (48mL) dilution gained concentrated solution.2.29g (6.51mmol) dodecyl sulfonyl azide and 210 μ L (1.51mmol) TEA are added gained to be contained in the solution of compound 5 and reaction was at room temperature carried out 17 hours.Also wash this reaction mixture successively with ice-cooled this reaction mixture, under reduced pressure concentrate organic layer then with 1M aqueous sodium hydroxide solution, water, 0.5M hydrochloric acid and 10% salt solution.Normal heptane added in the gained concentrated solution and form precipitation, filter, washing and dry should precipitation, obtain the title compound (compound 6) of 1.23g (productive rate, 48.3%) as white powder.
Title compound (compound 6) be known substance and the retention time of this title compound in HPLC and 1H NMR spectrum is with to have those of article now consistent.
Embodiment 15
(4R)-4-{ (3R, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl }-2-diazonium-3-oxopentanoic acid 4-nitrobenzyl ester (compound 6)
Use the similar method of method with embodiment 14; use 3.05g (5.00mmol) N-[(2R)-2-{ (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(2-bromophenyl)-para toluene sulfonamide; obtain the title compound (compound 6) of 1.67g (productive rate, 65.9%) as white powder.Mother liquor also contains 0.39g title compound (compound 6) when filtering-depositing, makes that overall yield is 81.4%.
Embodiment 16
(4R)-4-{ (3R, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl }-2-diazonium-3-oxopentanoic acid 4-nitrobenzyl ester (compound 6)
Use the similar method of method with embodiment 14; use 5.32g (10.0mmol) N-[(2R)-2-{ (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-phenyl-para toluene sulfonamide; obtain the title compound (compound 6) of 3.70g (productive rate, 73.4%) as white powder.
Embodiment 17
(4R)-4-{ (3R, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl }-2-diazonium-3-oxopentanoic acid 4-nitrobenzyl ester (compound 6)
Use the similar method of method with embodiment 14; use 2.73g (5.01mmol) N-[(2R)-2-{ (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(3-aminomethyl phenyl)-para toluene sulfonamide; obtain the title compound (compound 6) of 1.77g (productive rate, 70.0%) as white powder.
Embodiment 18
(4R)-4-{ (3R, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl }-2-diazonium-3-oxopentanoic acid 4-nitrobenzyl ester (compound 6)
Use the similar method of method with embodiment 14; use 2.80g (5.00mmol) N-[(2R)-2-{ (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-(4-p-methoxy-phenyl)-para toluene sulfonamide; obtain the title compound (compound 6) of 1.75g (productive rate, 69.5%) as white powder.Mother liquor also contains 0.24g title compound (compound 6) when filtering-depositing, makes that overall yield is 79.1%.
Embodiment 19
(4R)-4-{ (3R, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl }-2-diazonium-3-oxopentanoic acid 4-nitrobenzyl ester (compound 6)
Use the similar method of method with embodiment 14; use 2.28g (5.01mmol) N-[(2R)-2-{ (3S; 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl } propionyl]-N-phenylmethane sulphonamide; obtain the title compound (compound 6) of 1.74g (productive rate, 68.8%) as white powder.Mother liquor also contains 0.14g title compound (compound 6) when filtering-depositing, makes that overall yield is 74.5%.
Embodiment 20
(4R)-4-{ (3R, 4R)-3-[(1R)-the 1-hydroxyethyl]-2-aza-oxo-cyclobutane-4-yl }-2-diazonium-3-oxopentanoic acid 4-nitrobenzyl ester (compound 8)
[formula 14]
Figure A200780030266D00321
Under nitrogen atmosphere, 2.05g (30.1mmol) imidazoles and 0.12g (1.00mmol) DMAP are added 5.32g (10.0mmol) N-[(2R)-2-{ (3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl methyl siloxy) ethyl]-2-aza-oxo-cyclobutane-4-yl propionyl]-solution of N-phenyl-para toluene sulfonamide (compound 7) in acetonitrile (80mL) in and make to be reflected at and carried out under 60 ℃ 6 hours.Reaction mixture is cooled to-15 ℃, add successively therein 0.95g (10.0mmol) magnesium chloride, 2.8mL (20.1mmol) TEA and 4.07g (17mmol) propanedioic acid list to the nitrobenzyl ester and make the reaction carried out 3 hours, temperature is risen to 50 ℃ simultaneously.Reaction mixture is under reduced pressure concentrated, also wash this diluting soln successively with 1M hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and 10% salt solution with methylene dichloride (96mL) dilution gained concentrated solution.4.58g (13.0mmol) dodecyl sulfonyl azide and 420 μ L (3.01mmol) TEA are added gained to be contained in the solution of compound 5 and reaction was at room temperature carried out 19 hours and is formed reaction mixture.Also wash this reaction mixture successively with ice-cooled this reaction mixture, under reduced pressure concentrate organic layer then with 1M aqueous sodium hydroxide solution, water, 0.5M hydrochloric acid and 10% salt solution.With methyl alcohol (32mL), water (5.3mL) and concentrated hydrochloric acid (2.7mL) add gained contain in the concentrated solution of compound 6 and make be reflected at stir and room temperature under carried out 4 hours.6.5% sodium bicarbonate aqueous solution is added in this reaction mixture, stir this reaction mixture simultaneously and make solution be weakly alkaline and with dichloromethane extraction gained solution.With 10% salt water washing extraction liquid, under reduced pressure concentrate organic layer, replace this organic layer in order to concentrate with ethyl acetate then.Normal heptane added in the gained concentrated solution and form precipitation, filter, washing and dry should precipitation, obtain the title compound (compound 8) of 3.12g (productive rate, 82.1%) as white powder.
Title compound (compound 8) be known substance and the retention time of this title compound in HPLC and 1H NMR spectrum is with to have those of article now consistent.
Preparation embodiment 1
(4R, 5R, 6S)-and 3-[(two phenoxy group phosphoryls) the oxygen base]-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-diazabicyclo [3.2.0] hept-2-ene"-2-formic acid 4-nitrobenzyl ester
[formula 15]
Under nitrogen atmosphere, 29.9mg (0.038mmol) capric acid rhodium added 5.00g (12.8mmol) (4R)-4-{ (3R, 4R)-3-[(1R)-the 1-hydroxyethyl]-2-aza-oxo-cyclobutane-4-yl-the 2-diazonium-solution of 3-oxopentanoic acid 4-nitrobenzyl ester (compound 8) in methylene dichloride (50mL) in and gained solution was refluxed 4 hours.The solution that will contain this compound 9 is cooled to-15 ℃, dropwise add therein 3.2mL (15.4mmol) diphenyl phosphate chloride, 3.0mL (16.9mmol) DIPEA and 31.3mg (0.256mmol) DMAP in methylene dichloride (10mL) mixing solutions and make to be reflected at and carried out under the uniform temp 50 minutes.Wash this reaction mixture successively with 0.3M hydrochloric acid, 5% sodium bicarbonate aqueous solution and 10% salt solution, under reduced pressure concentrate organic layer then.Normal heptane added in the gained concentrated solution and form precipitation, filter, washing and dry should precipitation, obtain the title compound (compound 10) of 6.91g (productive rate, 98.1%) as the ivory buff powder.
Title compound (compound 10) be known substance and the retention time of this title compound in HPLC and 1H NMR spectrum is with to have those of article now consistent.

Claims (6)

1. method for preparing the compound of following formula (II) expression:
[formula 1]
Figure A200780030266C00021
Wherein
R 1Expression hydrogen or hydroxyl protecting group,
R 2Expression hydrogen or amino protecting group,
R 5Expression hydrogen or nitrogen-atoms and
R 6Expression hydrogen or carboxyl-protecting group,
Comprise the following steps:
(a) compound that following formula (I) is represented:
[formula 2]
Figure A200780030266C00022
Wherein
R 3The optional aryl that replaces of expression and
R 4The optional aryl that replaces of expression, the optional aralkyl that replaces or the optional alkyl that replaces,
Also obtain wherein R with the malonic ester reaction subsequently with the imidazoles reaction 5Compound for the expression of the formula (II) of hydrogen; And
(b) as needs R wherein 5During for the compound of the formula (II) of nitrogen expression, then make the compound diazotization of acquisition in step (a).
2. according to the process of claim 1 wherein that step (a) carries out in the presence of magnesium compound and/or alkali.
3. according to the process of claim 1 wherein that described malonic ester is a malonic acid monoester.
4. according to the method for claim 1, it further comprises the step of the reaction product that obtains with the dilute alkaline aqueous solution washing in step (b).
5. the compound according to the formula of the process of claim 1 wherein (I) expression is the compound that makes following formula (III) expression by comprising:
[formula 3]
Figure A200780030266C00031
Wherein
R 1And R 2As above-mentioned definition and
R 7The expression alkyl carbonyl oxy,
Compound with following formula (IV) expression:
[formula 4]
Figure A200780030266C00032
R wherein 3And R 4As above-mentioned definition,
The method of the step of reaction in the presence of zirconin and the compound that obtains.
6. according to the method for claim 5, the compound that general formula (IV) is represented stands the effect of zirconium compounds and alkali, and the compound with formula (III) expression reacts then.
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CN101891666A (en) * 2010-07-20 2010-11-24 深圳市海滨制药有限公司 Preparation method of intermediate of beta methylcarbapenem antibiotics
CN101906115A (en) * 2010-08-13 2010-12-08 浙江海翔药业股份有限公司 Preparation method of beta-methyl carbapenem antibiotic intermediate
CN102690282A (en) * 2011-07-07 2012-09-26 深圳市海滨制药有限公司 Crystal-form 1beta methylcarbapenem antibiotic intermediate and preparation method thereof

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JPS63284176A (en) * 1987-05-15 1988-11-21 Nippon Redarii Kk Highly stereoselective production of (1r,5r,6s)-6-((1r)-1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid derivative
JPH0639472B2 (en) * 1991-12-21 1994-05-25 メルシャン株式会社 Azole derivative
WO1993013064A1 (en) * 1991-12-26 1993-07-08 Nippon Soda Co., Ltd. Process for producing 4-substituted azetidinone derivative
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CN101891666A (en) * 2010-07-20 2010-11-24 深圳市海滨制药有限公司 Preparation method of intermediate of beta methylcarbapenem antibiotics
CN101891666B (en) * 2010-07-20 2012-09-26 深圳市海滨制药有限公司 Preparation method of intermediate of beta methylcarbapenem antibiotics
CN101906115A (en) * 2010-08-13 2010-12-08 浙江海翔药业股份有限公司 Preparation method of beta-methyl carbapenem antibiotic intermediate
CN102690282A (en) * 2011-07-07 2012-09-26 深圳市海滨制药有限公司 Crystal-form 1beta methylcarbapenem antibiotic intermediate and preparation method thereof

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