CN1064682A - The preparation method of heterogeneous ring compound - Google Patents

The preparation method of heterogeneous ring compound Download PDF

Info

Publication number
CN1064682A
CN1064682A CN91101470A CN91101470A CN1064682A CN 1064682 A CN1064682 A CN 1064682A CN 91101470 A CN91101470 A CN 91101470A CN 91101470 A CN91101470 A CN 91101470A CN 1064682 A CN1064682 A CN 1064682A
Authority
CN
China
Prior art keywords
milliliters
gram
compound
group
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN91101470A
Other languages
Chinese (zh)
Other versions
CN1030604C (en
Inventor
布鲁诺·坦布里尼
阿尔奇德·佩邦尼
蒂诺·罗西
丹尼诺莱·多纳蒂
丹尼埃莱·安德烈奥蒂
乔瓦尼·加维拉吉
罗伯托·卡莱索
克劳迪奥·比斯马拉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline SpA
Original Assignee
Glaxo SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to GB898920337A priority Critical patent/GB8920337D0/en
Priority to MX2227590A priority patent/MX22275A/en
Priority to ZA907137A priority patent/ZA907137B/en
Application filed by Glaxo SpA filed Critical Glaxo SpA
Priority to CN91101470A priority patent/CN1030604C/en
Publication of CN1064682A publication Critical patent/CN1064682A/en
Application granted granted Critical
Publication of CN1030604C publication Critical patent/CN1030604C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to generalformula and its esters (comprising neutral salt), destabilization ester class and solvate in the metabolism, and method for making.

Description

The preparation method of heterogeneous ring compound
The present invention is the heterogeneous ring compound of relevant tool anti-microbial activity, its method for making, contains its composition and in usage medically.
Therefore, the present invention proposes down logical formula I compound
Figure 911014705_IMG5
R wherein 1Represent hydrogen atom or hydroxyl protecting group;
R 2Represent hydrogen atom, carboxyl-protecting group or derived from the positively charged ion of mineral alkali or organic bases;
R 3Represent hydrogen atom, hydroxyl, methylol or C 1-3Alkyl, or XR 4Group is X represention oxygen atom or S(O wherein) nGroup, wherein n is 0 or integer 1 or 2, and R 4Represent C 1-5Alkyl, C 3-7Cycloalkyl or phenyl, or when X be oxygen or sulphur atom, then R 4Can represent A1KNR 5R 6Group, wherein A1K represents C 2-6Straight chain or ramose alkylidene chain, and R 5And R 6Represent hydrogen atom or C independently of one another 1-4Alkyl, or R 5Can represent formyl radical, ethanoyl or formimino, and R 6Represent hydrogen atom or R 5And R 6Add that the nitrogen-atoms that joins with it forms N-pyrrolidine ring or N-hexahydropyridine ring, or R 3Group representative (CH 2) mNR 7R 8Group, wherein m is 0 or 1, and R 7And R 8Represent hydrogen atom or C independently separately 1-4Alkyl, or R 7Represent formyl radical, ethanoyl or formimino, and R 8Represent hydrogen atom, or R 3Group adds that the carbon atom that joins with it forms ketone group or its ketal derivatives; And ester class, salt and the solvate of destabilization in the metabolism.
Work as R 3Contain the basic center acid salt of this kind compound and form neutral salt (R with hydroxy-acid group 2=H), be also included within the present invention.
Except the fixedly stereochemistry that formula I defined was arranged, molecule also further contained unsymmetrical carbon on the 8-position, and another is in the 4-position, and this is to work as R 3Non-hydrogen atom or R 3And the carbon atom that joins with it forms ketone group or its ketal compound.Understand, all stereoisomerses comprise the mixture by these extra asymmetric center generations, include in formula I compound scope.
The formula I compound is antiseptic-germicide and/or can regards intermediate in order to prepare other logical formula I active compound.R wherein 1Be hydroxyl protecting group and/or R wherein 2Be the compound of carboxyl-protecting group, for can be used for preparing intermediate as one of other formula I compounds.
Suitable hydroxyl protecting group R 1And carboxyl-protecting group R 2, comprise can in hydrolysis under the buffer condition remove or anhydrous condition under the person of removing.
Work as OR 1Group is that it eligibly is ether or acyloxy through the hydroxyl of protection.Suitable especially ether example comprises wherein R 1Be hydrogen carbon silylation, as trialkylsilanyl or tertiary butyl dimethylsilyl.Work as OR 1Group is represented acyloxy, then suitable R 1The group example comprises alkyloyl, as ethanoyl, pivaloyl; Enoyl-such as allyl group carbonyl; Aroyl such as contraposition one nitrobenzyl acyl group; Carbalkoxy such as tertbutyloxycarbonyl; The fontanel carbalkoxy is as 2,2, the 2-trichloro-ethoxycarbonyl, or 1,1,1-three chloro-2-methyl-2-third oxygen carbonyl; Aralkyl oxygen carboxyl such as carbobenzoxy-(Cbz), or contraposition nitro carbobenzoxy-(Cbz); Or alkenyloxycarbonyl such as allyloxycarbonyl.
Suitable especially protecting group R 1Be tertiary butyl dimethylsilyl.
Suitable carboxyl-protecting group comprises arylmethyl, as benzyl, contraposition one nitrobenzyl or trityl, or thiazolinyl such as allyl group or the allyl group that is substituted, the tertiary butyl, fontanel alkyl are as three chloroethyls or trialkylsilanyl, as the trimethyl silane ethyl.Preferable protecting group R comprises arylmethyl, as benzyl or allyl group.
Work as R 3Add when the carbon atom that joins with it forms ketal group that then this ketal system is eligibly derived from C 1-3Alkanol is as methyl alcohol or 1,2 or 1,3 alkane glycol, as glycol or propane-1,3-glycol.
Can be as the useful especially formula I compound of antiseptic-germicide medicine, be R wherein 1Represent hydrogen atom and R 2Represent hydrogen atom, or the positively charged ion that can accept on the physiology, or its neutral salt.These compounds present anti-microbial activity, but large-scale Gram-positive of antagonism and Gram-negative, the pathogenic microbes of aerobic and anaerobism.
Work as R 2Be the positively charged ion that can accept on the physiology, suitable positively charged ion comprise basic metal (as sodium or potassium), alkaline-earth metal (as calcium), Amino acid (as relying amino acid and spermine acid) and organic bases (as Procaine, phenylbenzylamine, dibenzyl-ethylenediamin, thanomin, diethanolamine, and the N-methylglucosamine).
Work as R 2Be the positively charged ion that can accept on the non-physiology, then compound can be as intermediate in order to preparation and/or other compounds of separation the present invention.
The ester class of the metallicity destabilization of formula I compound comprises alkyl esters, as C 1-4The alkane ester is as methylethyl or isopropyl esters class, or the alkenyl esters class, as allyl group or the allyl ester class that is substituted.
Shown formula I comprises at least 4 stereoisomerses and composition thereof, and these can be represented by formula (I a, I b, I c and I d).
Figure 911014705_IMG6
Webge groove
Figure 911014705_IMG7
The expression key is on paper plane.Broken folding shape key
Figure 911014705_IMG8
The expression key is under paper plane.The represented configuration of carbon atom on formula I a and the I b8-position be called beta comfiguration hereinafter, and formula I c and I d is referred to as the α configuration.
The represented configuration of carbon atom on formula I b and I d4-position is called the α configuration hereinafter, then is called beta comfiguration in formula I a and I c.
Generally speaking, in the special compound of hereinafter name, be equivalent to the S isomer in the locational beta comfiguration of 8-, and be referred to as the R isomer at the locational beta comfiguration of 4-.The α configuration is equivalent to the R isomer on the 8-position, and the locational α configuration of 4-is equivalent to the S isomer.According to Cahn.Ingold and Prelog, Experientia 1956,12 in the appointment of 4-and locational R of 8-or S configuration system, 81 rule and going.
The preferable group of formula I is for wherein being beta comfiguration on the 8-position.And in this compounds, be α with the 4-position and be configured as Te Jia.
In the The compounds of this invention further the preferably be R wherein 3Represent hydrogen atom or particularly amido, amine methyl, methylamino, hydroxyl, methylol, methyl, cyclopentyloxy, oxyethyl group, isopropoxy, methoxyl group, amine oxyethyl group, thiophenyl, methylthio group or methylsulfinyl, or add that the carbon atom that joins with it forms ketone group or its dimethyl ketal base.
Preferable especially formula I compound, for the locational carbon atom of 8-is beta comfiguration, and the locational carbon atom of 4-is the α configuration, R 1Represent hydrogen atom, R 2Represent the positively charged ion that can accept on hydrogen atom or the physiology, and R 3Represent amido, methylamino, amine methyl, oxyethyl group, methoxyl group, isopropoxy, amine oxyethyl group, thiophenyl, methylthio group, methyl sulphonyl, hydroxyl or methylol, and destabilization ester class, salt and solvate in the metabolism.
Preferable especially compound comprise (4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] hendecene-2-base-2-carboxylic acid, and its esters such as sodium or sylvite.
(4S, 8S, 9R, 10S, 12R)-4-methylthio group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] hendecene-2-base-2-carboxylic acid and salt thereof, as potassium or sodium salt.
(4S, 8S, 9R, 10S, 12R)-4-methylsulfinyl-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] hendecene-2-base-2-carboxylic acid and salt thereof, as potassium or sodium salt.
(4S, 8S, 9R, 10S, 12R)-4-amido-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] hendecene-2-base-2-carboxylic acid and salt thereof.
The compounds of this invention not only presents the anti-microbial activity of vast scope to large-scale pathogenic microbes, simultaneously to the high resistance of the equal tool of all β-Nei Xiananmeis.The compounds of this invention is to dehydropeptidase of kidney also quite stable.
Found that The compounds of this invention has the activity of usefulness to streptococcus aureus, streptococcus faecium, escherichia coli, Pseudomonas aeruginosa, clostridium perfringens and bacteroides fragilis bacterial strain.
Therefore The compounds of this invention can be used for treating the mankind and animal because the various diseases due to the pathogenic bacteria.
Therefore, according to a further aspect of the invention, propose the formula I compound and can be used for general or localized bacterial infection in treatment or the prevention mankind or the animal individual.
According to further aspect of the present invention, the usage of formula I compound is proposed, can be used for preparing therapeutical agent, to treat whole body or localized bacterial infection in the mankind and the animal body.
According to further aspect of the present invention, the treatment mankind or the non-human class animal body method with the fight infectation of bacteria is proposed, this method comprises gives the throwing of formula I effective dose compound to health.
The compounds of this invention can be in harmonious proportion can suitable mode offeing medicine, and is used for the mankind or veterinary science, and therefore the pharmaceutical compositions that contains The compounds of this invention in addition that is included in the scope of the present invention can be used for the mankind or veterinary science.This kind formed or but helping eligibly of more than one appropriate carriers of mat or vehicle used.Constituent of the present invention comprise reconcile into especially outer, oral for intestines, through cheek, per rectum, part, implantation, eye formulation with, intranasal or urinary tract use.
The compounds of this invention can be through mediation and the mat injection system throw give to the mankind or animal doctor circle (as via intravenously bolus injection or perfusion, or via path in intramuscular, the subcutaneous or sheath), and can be unit dosage, be ampulla or other unit dose container, or multi-dose container, must the time can add preserving agent.The injection constituent can be suspension formulation formula, and solution, or emulsion in oiliness or aqueous vehicles, and can contain blender, as suspending agent, and stablizer, solubility promoter and/or dispersion agent.In addition, active ingredient can be the sterilized powder pattern, and before using with suitable solvent, as aseptic, pyrogen-free water, recombinate it.
It is oral or through cheek dispensing pattern that The compounds of this invention also can be suitable confession, be used for the mankind and veterinary medicine, as be solution, gelifying agent, syrup, mouth-washes or suspension agent, or be dry powder and before using, add water or other suitable solvents are recombinated it, wherein and can be added with perfume compound and colorant arbitrarily.Also can use solid-state composition, as lozenge, capsule, lozenge, pastille, pill, bolus, powder, paste, granule, pilule or annotate preparation in advance.Can be for oral solid-state or fluid composition according to known method preparation on the skill.This kind constituent also can contain more than one pharmaceutically acceptable carrier and vehicle, and it can be solid-state or liquid pattern.
The compounds of this invention also can be oral to veterinary science, and the agent that is in a liquid state is taken medicine, and as solution, suspension agent or dispersion agent are that activeconstituents adds pharmaceutically acceptable carrier or vehicle.
The compounds of this invention also can reconcile into suppository, as contains known suppository base being used for the mankind or veterinary science, or vaginal suppository, as contains known vaginal suppository base.
The compounds of this invention can be in harmonious proportion the confession topical administration and be applied to the mankind and veterinary science, can be ointment, emulsifiable paste, gel, lotion, shampoo, powder (comprising spraying powder), vaginal suppository, cotton balls, sprays, preserved material, aerosol, drops (using or the nose drops as eye usefulness, ear) or filling agent.
Aerosol spray is to hang oneself eligibly to deliver in the pressurizing vessel, and the helping of the suitable propelling agent of mat, as Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.
Through sucking topical administration, The compounds of this invention can be sent via atomizer, and is used for the mankind or veterinary medicine.
Pharmaceutical composition for topical administration also can contain other active ingredients, as reflunomide or suitable anti-mycotic agent.
Can contain the 0.01-99% active ingredient in the constituent.When topical administration, constituent contains 0.01-10% usually, better is the 0.01-1% active ingredient.
When general is offerd medicine, be applied to adult treatment every day dosage range at per kilogram of body weight 5-100 milligram, better be per kilogram of body weight 10-60 milligram, it can be every day 1-4 dosage throws and gives, as deciding according to dispensing path and patient status.When constituent contains unitary dose, then constituent parts preferably contains 200 milligrams of active ingredients to 1 gram.
The treatment phase decides according to speed of reaction, but not fate arbitrarily.
The formula I compound can be prepared by the cyclisation of formula II compound
Figure 911014705_IMG9
R wherein 3aThe above-mentioned R of tool 3Definition, or its group that can transform, and Y is Sauerstoffatom or phosphino-, and R 1aAnd R 2aFor as R 1And R 2Hydroxyl that is defined and carboxyl-protecting group, and need or when desiring to ask half gained compound before following more than one operation steps, or separate afterwards, to become its stereochemical isomer.
A) remove more than one protecting group.
B) with R 3aGroups converted becomes R 3Group.
C) incite somebody to action wherein R 2Be the salt that the compound of hydrogen atom or carboxyl-protecting group changes into inorganic or organic bases.
The formula II compound, wherein Y is an oxygen, its cyclic action can heat in the presence of organic phosphite and eligibly carry out.Reaction is preferably in solvent or the solvent mixture to be carried out, and temperature is in 60-200 ℃ of scope.Appropriate solvent comprises hydrocarbons, and the boiling point that its tool is suitable has toluene or dimethylbenzene as aromatic hydrocarbon.
Suitable organic phosphite comprises non-annularity and ring-type trialkyl phosphite, triaryl phosphite and blended alkylaryl phosphite.Useful especially organic phosphite is the trialkyl phosphite, as triethyl phosphite or trimethylammonium phosphite.
The formula II compound, wherein Y is a phosphino-, and its cyclic action is preferably in the solvent carries out, and temperature is between 40-200 ℃.Appropriate solvent comprises hydrocarbons, as aromatic hydrocarbon, and as dimethylbenzene or toluene, aliphatic hydrocrbon and through the hydrocarbon of fontanelization, as methylene dichloride, chloroform and trichloroethane.Suitable phosphino-example has triaryl phosphine, as triphenyl phosphine, or trialkyl phosphine is as three-tertiary butyl phosphine.
Hydroxyl and carboxyl-protecting group R 1aAnd R 2a, can prior art method and any order remove.Yet, best hydroxyl protecting group R 1aCan before removing carboxyl-protecting group, remove.Removing of protecting group also is the another characteristic of the present invention.
Hydroxyl protecting group can be removed in known standard method, as is set forth in Protective Groups in Organic Chemistry, Pages 46-119, Edited by J F W McOmie(Plenum Press, 1973).For example work as R 1aWhen being tertiary butyl dimethyl silanyl, it is removed can four fourth Neutral ammonium fluorides and acetic acid processing.This step can eligibly be carried out in as the solvent of tetrahydrofuran (THF).Similarly, work as R 1aWhen being trichloro-ethoxycarbonyl, its available zinc and acetic acid are handled and are removed.
Carboxyl-protecting group R 2aAlso can standard method remove, as be set forth in Protective Groups in Organic Chemistry, Pages 192-210, Edited by J F W McOmie(Plenum Press, 1973).For example, work as R 2aRepresent arylmethyl, it can prior art method, utilizes hydrogen and metal catalyst such as palladium to remove.Work as R 2aThe allyl group of representing allyl group or being substituted, then it is preferably handled and removes in four (triphenyl phosphine) palladium and under triphenyl phosphine exists arbitrarily with the allyl group receptor.Suitable allyl group receptor comprises sterically hindered amine, as four butylamine amine ring-type secondary amines as good fortune quinoline or sulphur good fortune quinoline, tertiary amine such as triethylamine, aliphatic series or cyclic aliphatic beta-dicarbonyl compound, as methyl ethyl diketone, ethyl 3-oxobutanoate or methone, or alkanoic acid or its an alkali metal salt, as acetic acid, propionic acid or 2 ethyl hexanoic acid, or its potassium or sodium salt.
Useful especially allyl group receptor is a 2 ethyl hexanoic acid, especially its sodium or sylvite.
Reaction is preferably in the inert solvent to be carried out, as ether such as diethyl ether or tetrahydrofuran (THF), and alkanol such as ethanol, and ester such as ethyl acetate or fontanel hydrocarbon, as methylene dichloride, or its mixture.Reaction can eligibly be carried out under 0 ° of-40 ° of temperature range, more especially at room temperature.
The compounds of this invention, wherein R 2Group is physiologically acceptable positively charged ion, and it can prepare from compound R wherein 2Be hydrogen, and with suitable alkaline purification.Eligibly, salt forms in solution, must make it precipitation by mat adding non-solvent afterwards, as nonpolar aprotic solvent.In addition, by formula I R wherein 2Represent hydrogen, and with 2 ethyl hexanoic acid sodium or potassium in the non-polar solvent of diethyl ether one class solution-treated and its sodium or sylvite.
Be preparation formula I compound, wherein R 3Representation hydroxy or methylol then can utilize formula II intermediate, wherein R 3aFor hydroxyl or methylol, reach with cyclic action through protection.Suitable to the protection hydroxyl, comprise three hydrogen carbon back silylation ethers, as TMS or tertiary butyl dimethyl silanyl ether.Hydroxyl protecting group can be in synthetic arbitrary stage of continuing remove, as with remove hydroxyl protecting group R 1aCarry out simultaneously.
Preparation formula I, wherein R 3Represent one-level or secondary amine, or contain the substituting group of this kind amido, cyclic action is often eligibly carried out with the intermediate of formula II, wherein R 3aIn amido be through the protection pattern, A is as being the allyloxycarbonyl amido.Can remove the amido protecting group with suitable method again.So for example, if R 3aBe allyloxycarbonyl amido, allyloxycarbonyl amine oxyethyl group or allyloxycarbonyl amine methyl, utilize the above-mentioned method that allyl ester is changed into suitable carboxylic acid can convert it into amido, amine oxyethyl group or amine methyl.
The formula I compound can change into other formula I compound.Therefore, formula I compound R wherein 2Group is a carboxyl-protecting group, and R 3Represent SOR 4Group, it can be prepared by suitable formula I compound oxidation, wherein R 3Represent SR 4Group.Oxygenizement preferably utilizes peracid to carry out, as benzoyl hydroperoxide, as a position one chloroperoxybenzoic acid, in organic solvent as through the hydrocarbon of fontanelization, as methylene dichloride.Preferably reaction is carried out at low temperatures, as-78 ℃ to-20 ℃.
Formula I compound, wherein R 3Group and the carbon atom that joins with it are represented ketone group, and R 1And R 2Group is represented protecting group, and it can be formed by suitable formula I ketal hydrolysis.For example, formula I compound R wherein 3Reach the carbon atom that joins with it and represent methylal, mat work in aqueous acid,, can change into suitable ketone with treatment of silica as oxalic acid aqueous solution or aqueous sulfuric acid.Reaction can be carried out in solvent, as the hydrocarbon of fontanelization, as methylene dichloride.
Formula I compound, wherein R 3The group representation hydroxy can be by formula I compound R wherein 3Group and adherent carbon atom thereof form ketone group, and reductive action forms.Reduction can utilize the borohydride reductive agent to carry out, as sodium borohydride, cyano group sodium borohydride or trialkyl borohydride, as three amyl group lithium borohydrides or three-sec-butyl lithium borohydride.Reaction can be carried out in solvent, as alkanol such as methyl alcohol, or ether, mutter or aromatic hydrocarbon as tetrahydrochysene, as toluene.Therefore, for example reductive action can utilize sodium borohydride to carry out in methanol aqueous solution, and the pH value protection of best reaction medium by adding suitable acid, keeps as spirit of salt between 4 and 7.
Formula I compound, wherein R 1Be that hydroxyl keeps base, R 2Be carboxyl-protecting group, and R 3Be alkoxyl group such as methyl, can be by suitable formula I compound R wherein 3It is hydroxyl 0-alkanisation and preparing.The carrying out of reaction can utilize suitable alkyl methylene fluoride sulphonate, exists down in suitable alkali, as two (dimethylsilyl) acid amides potassium.
The formula II compound, wherein Y=0 can be by formula III compound R wherein 1aAnd R 3aGroup is above definition, the derivative activated with formula IV (R wherein 2aBe above-mentioned definition) handle and prepare.
Figure 911014705_IMG10
The suitable activatory derivative of formula IV acid comprises suitable acyl group fontanel, as chloride of acid.
When the acyl group fontanel when the sour activated derivative of formula IV uses, then reaction is preferably in acid acceptor and carries out under existing, as three grades of organic basess, as pyridine, or trialkylamine, in aprotic solvent, as methylene dichloride.
The formula II compound, wherein Y is a phosphino-, and its preparation can be got by processing formula (V) intermediate, and wherein L is a leavings group, as fontanel such as chlorine,
Figure 911014705_IMG11
Processing can utilize suitable phosphine, as triphenyl phosphine, carries out under alkali exists.Reaction can eligibly be carried out in solvent, as diox, wherein has three grades of organic basess, as 2, and the 6-lutidine.The formula II compound is novel compound, so also constitutes further aspect of the present invention.
Formula (V) compound can prepare from the suitable hydroxy derivatives of formula VI, promptly with prior art method hydroxyl is changed into leavings group.
Figure 911014705_IMG12
Therefore, be formula (V) compound of chlorine atom as L wherein, wherein preparation can be by the formula VI compound, and with thionyl chloride, in aprotic solvent, handle and get, as diox or tetrahydrofuran (THF), and in the presence of three grades of organic basess, as 2, the 6-lutidine.The formula VI compound can be by formula III compound and gyloxylic acid ester (VII; CHOCO 2R 2a) reaction and prepare, preferably be its hydrate or half liquid aldehyde pattern.Reaction is preferably in the aprotic solvent to be carried out, as toluene, and under activated molecular sieve exists.The formula VI compound also can be by the wherein Y=0 reduction and preparing of formula II compound.Suitable reductive agent comprises zinc/acetic acid.
In addition, the formula II compound is Y=0 wherein, can be prepared by the formula VI compound oxidation, as utilize magnesium dioxide.
The formula III compound can be by the enolate ion processing of the azetidinone of formula (VIII) and formula (IX) ketone and is got.
Figure 911014705_IMG13
Reaction is preferably under the low temperature (as-78 ℃) to be carried out, in the solvent of tetrahydrofuran (THF).
The enolate ion of formula (IX) ketone, but the mat work (is handled as two (TMS) acid amides lithium, and is eligibly made in original position with suitable alkali.
In addition, formula III compound R wherein 3aBe hydrogen atom, can make with the enol ether reaction of (X) by the azetidinone of formula (VIII).
Figure 911014705_IMG14
Reaction can be carried out in solvent, as methylene dichloride or acetonitrile, and under the whole activatory ester of trifluoromethayl sulfonic acid exists, as trimethyl silane ester or lewis acid, as tin protochloride.The formula III compound also can be got by the reduction of formula (XI) compound.
Figure 911014705_IMG15
Reduction can utilize hydrogen and metal catalyst to finish, as palladium on suitable carrier as carbon or alumina.React in the solvent and carry out, as ester (as vinyl acetic monomer).
The compound of formula (XI) can and prepare by the azetidinone of formula (VIII) and ketone (XII) or enol ether (X III) reaction, utilizes aforementioned condition by formula (IX) ketone and enol ether (X) preparation formula III compound.
Figure 911014705_IMG16
The formula III compound also can prepare the oxygenizement from formula (X IV) alcohol,
Figure 911014705_IMG17
R wherein 1aAnd R 3aThe above-mentioned definition of tool.Oxygenizement utilizes conventional oxidation agent known on the skill to carry out, so that secondary alcohol (as hexalin) is changed into ketone (as pimelinketone).So, oxygenizement can utilize pyridinium chlorochromate or oxalyl chloride and methyl-sulphoxide to carry out.Reaction is preferably in the solvent to be carried out, as methylene dichloride.
The preparation of alcohol (X IV) can be formed by alpha-beta unsaturation ketone (XI) reduction.This reductive action can be reacted eligibly and be carried out the two-stage.Fs is that ketone is reduced into alcohol, utilizes proper metal hydride, as sodium borohydride.The alpha-beta unsaturation alcohol that is generated restores institute's alcohol of palpus (X IV), utilizes above-mentioned hydrogen and the metal catalyst that is used by alpha-beta unsaturation ketone (XI) preparation ketone (III).
Formula III compound, wherein R 3aRepresent the alkyl sulfenyl, but the suitable compound of mat formula III, wherein R 3aHydrogen atom, with alkali metal base such as two (TMS) acid amides lithium, and suitable methanesulfonic alkylthio ester is handled and is got.
In this reaction, alkylthio is introduced on the N-nitrogen-atoms of azetidinone, so must use two normal two (TMS) acid amides lithium alkali, and suitable methanesulfonic alkylthio ester.If reaction is progressively carried out, the nitrogen-atoms of alkylthio introducing azetidinone before 2 equivalent alkali and alkylthio reagent add then reacts major part afterwards and is created on stereoisomers on the 4-position.Yet if 2 normal alkali and alkane thioesters add together, reaction is created on the mixing of two kinds of suitable on 4-position stereoisomerses.Alkylthio on the azetidinone nitrogen-atoms can be suitable nucleophilic reagent handle and remove, as the 2-mercaptopyridine, wherein and the existence of three grades of extra organic basess is arranged, as triethylamine, and generate the compound of formula III palpus, wherein R 3Represent alkylthio.
In the modification method of present method, the formula III compound is R wherein 3aRepresent hydrogen, can prior art method change into the derivative of other N-earlier,, utilize above-mentioned condition to introduce alkylthio R afterwards as N-trimethyl silane radical derivative through protection 3a, remove the N-protected base again.
Formula III compound, wherein R 3aTool SR 4Definition, also can be via the preparation of suitable fontanel derivative from suitable compound, wherein R 3aRepresent hydrogen.So, formula III compound R wherein 3aBe hydrogen,, in solvent,, with iodine and subsequent S-WAT reaction, can get iodine derivative (III quite again as hexane and/or tetrahydrofuran (THF) with suitable alkali reaction such as two (TMS) acid amides sodium or lithium; R 3a=I).Iodate and thing are with mercaptan R 4SH reacts in the methylene dichloride aqueous solution, wherein and have suitable alkali, as phase-transfer catalyst such as TBAH, can generate the compound (III of desiring to ask; R 3a-SR 4).
The alcohol of formula (X IV) is R wherein 3aBe alkoxyl group, can be by suitable epoxide (X V) and suitable pure R 3aOH, existence is reacted down and is made as the contraposition toluenesulphonic acids under acid catalyst exists.
Figure 911014705_IMG18
The alcohol of formula (X IV) is R wherein 3aBe trinitride, can handle and make by epoxide (X V) and an alkali metal azide.React in the solvent and carry out, as in alkanol, as methyl alcohol.
Formula III compound, wherein R 3aGroup is that its preparation of amido can be by R 3The formula III compound that is azido-reduces and gets.Reductive action is utilized hydrogen and metal catalyst, carries out as vinyl acetic monomer in solvent.
Formula III compound, wherein R 3aFor or contain amido through protection, then can prepare with prior art method by suitable primary amine compound, as with suitable chloride of acid reaction, as allyloxycarbonyl chlorine.
The alcohol of formula (X IV) is R wherein 3aBe NR 7R 8R wherein 7Be hydrogen atom formula C 1-4Alkyl, and R 8Represent hydrogen C 1-4Alkyl can be by formula (X V) epoxide and suitable amine R 7R 8NH reacts and gets.Reaction is preferably in the solvent and carries out, and in alkanol, as ethanol or aqueous ethanolic solution, and the existence of ammonium salt is arranged.
The alcohol of formula (X IV), wherein R 3aBe secondary amine through protection, can be by suitable secondary amine-NHR 8Make with prior art method, as reacting, as allyloxy carbonyl chlorine with suitable chloride of acid.
The epoxide of formula (X V) can carry out epoxidation by the cyclenes of formula (X VI) and form
R wherein 1aShow definition on the tool.But the cyclenes of epoxidation mat formula II eligibly carries out with peracid treatment.Suitable peracid comprises the peroxybenzoic acid through any replacement, as a peroxybenzoic acid or a position chlorine peroxybenzoic acid, reaches alkanoic acid, as peroxyacetic acid and trifluoro peroxyacetic acid.React in the solvent and carry out, as the fontanel hydrocarbon, as methylene dichloride, and suitable temperature range is-30 to+30 ℃.
The cyclenes of formula (X VI) can be by suitable tosylhydrazone (X VII)
R wherein 1Be hydroxyl protecting group, with alkali such as methyl or butyllithium or LDA reaction and get.React in the aprotic solvent and eligibly carry out, as in ether as tetrahydrofuran (THF), temperature is between-50 ℃ and 0 ℃.
Formula (X VII) tosylhydrazone can be by the cyclohexanone derivative of formula III R wherein 1aBe hydroxyl protecting group and R 3aBe hydrogen
Figure 911014705_IMG21
With toluene sulfonyl hydrazide (X VIII), in appropriate solvent, get as the Glacial acetic acid reaction.
Formula III compound, wherein R 3aBe hydroxyl, can react as a position chlorine peroxybenzoic acid, again silylation enol ether and the hydrolysis of N-silylation protecting group are formed by silylation enol ether (X IX) and peracid.
Silylation enol ether (X IX) can prepare from suitable ketone (XX), is to have reaction down with fontanel trialkyl silane in alkali, as two-(TMS) acid amides potassium or lithium.
Ketone (XX) can be by N-through azetidinone (X XI) and the enol ether (X) of the protection activated ester at trifluoromethane sulfonic acid, and as the TMS ester, and there are reaction down in lewis acid such as tin chloride and prepare.
Figure 911014705_IMG23
N-can prepare from azetidinone (VIII) through the azetidinone (X XI) of protection, is and three suitable hydrogen carbon back silylation fontanels, in three grades of organic basess such as triethylamine, and reacts in aprotic solvent such as the methylene dichloride and forms.
To (XX), when not shown unsymmetrical carbon and when not having particular configuration, then chemical formula comprises all possible configuration in the last formula I that shows.
The special stereoisomers of formula I compound is suc as formula (I c and I d define for I a, I b, and essentially no other stereoisomerses can begin preparation with suitable formula III stereoisomers by aforesaid method.
Above-mentioned formula III compounds process for production thereof generally can generate the mixing of stereoisomers.
Formula III compound discrete stereoisomers can be disconnected from each other, utilizes conventional art such as fractional crystallization to turn usefulness into, or tubing string chromatography particularly, as utilize the silica gel tubing string, described in related example.
Formula III, (XI) and (X IV) compound are novel compound, and these compounds and indivedual stereoisomers formation further aspect of the present invention thereof.
In addition, synthetic can the mixing by two above formula III stereoisomerses begin to carry out, again in synthetic another stage with known techniques separate the special stereoisomers of palpus.Therefore, compound can turn usefulness and/or tubing string chromatographic separation into by fractional crystallization.
In formula I compound or its intermediate are synthetic, be necessary to protect R 3Functional group in the group.This kind protection and deprotection effect are suitable, and within the scope of the invention.For example, when group is one-level or secondary amine or contains this kind group, then in building-up process, must utilize known nitrogen-protecting group to be protected.
Formula VI, (IX), (X), (XII) and (X III) compound are known compound, maybe can utilize to be applied to known compound and so on and to make like method.
In order more to understand the present invention, following example is proposed but only confession explanation.
In preparation and example part, unless otherwise stated:
Fusing point (m.p.) is to utilize Gallenkamp m.p. device to decide, and not calibrated.All temperature are ℃.
Infrared spectra on the FT-IR instrument with chloroform-d 1The solution detecting.Proton magnetic resonance (PMR) ( 1H-NMR) spectrum is with the 300MHz record, in chloroform-d 1In the solution.Chemical shift with ppm downstream (δ) apart from Me 4Si and reporting, the latter be as intermediate standard product, and be marked with unimodal (s), two (d), two couple (dd) or multiple (m).
The tubing string chromatography on silica gel, carry out (Merck AG Darmstadt, Germany).
Solution is dry on anhydrous sodium sulphate.
" Petrol " means sherwood oil, b.p.40-60 ℃.
Methylene dichloride is redistillation on hydrolith; Tetrahydrofuran (THF) is redistillation on sodium; Ether is redistillation on sodium; Dimethylbenzene is dry on activated molecular sieve in redistillation and vinyl acetic monomer on five phosphorus oxide.
Below abbreviation is used for table and literary composition.The EA=vinyl acetic monomer, 40-60 ℃ of CH=hexanaphthene, P=sherwood oil, THF=tetrahydrofuran (THF), MC=methylene dichloride, EE=ether.TLC means the thin-layer chromatography on the silica plate.
Intermediate 1
(3R, 4R)-3[(R)-and 1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(R)-2 '-(1 '-oxygen basic ring hexyl)] azetidine-2-ketone (1a) and (3S, 4R)-3[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((S)-2 '-(1 '-oxygen basic ring hexyl)] azetidine-2-ketone (1b)
The A method
1-trimethyl silicane alcoxyl basic ring hexene (11 gram) is dissolved in the methylene dichloride (400 milliliters) under nitrogen.Add (3R, 4R)-the 4-acetoxy-3-((R)-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-azetidinone (9.28 grams; Intermediate A) to solution, mixture stirs down in 23 ℃, adds trifluoromethayl sulfonic acid TMS ester (0.66 gram) again.Mixture stirred 2 hours down in nitrogen, poured in the 1% ice-cold solution of sodium bicarbonate (300 milliliters) again.Tell organic layer, with water and salt solution (each 300 milliliters) washing.Can get the oily residue, in decompression down behind the evaporating solvent again chromatography (with the capable gradient of EE/P molten from) feasible title compound (1a; 2.6 solid m.p.70-80 ℃ of (t.l.c. P/EA 4/6 is white in color gram); Rf 0.5) and title compound (1b; 2.63 (t.l.c.P/EA 4/6 gram), to be white in color solid m.p.100 ℃; Rf0.45).
The B method
Two (TMS) acyl ammonium lithium 1M solution in hexane (250 milliliters) are added tetrahydrofuran (THF) (250 milliliters), and mixture stirs down in nitrogen, is cooled to-78 ℃ and added pimelinketone (15.2 gram) again in 20 minutes.Make temperature rise to-55 ℃ and go through 10 minutes, again mixture is cooled to-78 ℃ and goes through 40 fens.Add intermediate A(34 gram), the mixture of gained stirred 30 fens down at-78 ℃.Reaction mixture is poured in the saturated ammonium chloride solution (200 milliliters), and the mixture of gained extracts with vinyl acetic monomer (3 * 200 milliliters).Mix organic layer with the salt water washing, drying is reduction vaporization again.Oily is residual heat up in a steamer the thing chromatography (with the CH/EA gradient molten from) can get title compound (1a; 11.6 gram), the solid that is white in color, m.p.70-80 ° and title compound (1b; 12 grams), the solid that is white in color, m.p.100 ℃.
Utilize A method (3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4[(S)-6 '-(1 '-the oxygen basic ring oneself-2 '-thiazolinyl)]-azetidine-2-ketone (1c; 12.7 gram), m.p.125 ℃.Can prepare from 2-trimethyl silicane alcoxyl hexamethylene-1 3-diene (19.2 gram) and intermediate A(14.34 gram), except the reaction times is 18 hours, and the crystalloid product derives from the oily residue, is to replace the chromatography purification step with crystallization in EE/P.
Utilize the B method
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4[(S)-2 '-((R)-6 '-methyl isophthalic acid '-the oxygen cyclohexyl)) azetidine-2-ketone (1d; 0.5 gram), m.p.117 ℃ and (3R, 4R)-3-[(R)-and 1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4-((S)-2 '-((S)-6 '-methyl isophthalic acid '-the oxygen cyclohexyl)) azetidine-2-ketone and (3R, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((S)-2 '-((S)-6 '-methyl isophthalic acid '-the oxygen cyclohexyl)) azetidine-2-alcohol/ketone mixtures (intermediate 1e; 3.15 gram) can prepare gram from intermediate product A(14.35) and 2-methyl isophthalic acid-oxygen base-hexanaphthene 13.2 grams.
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4((S)-2 '-(6 ', 6 '-dimethoxy-1 '-cyclohexyl)) azetidine-2-ketone (1f; 0.97 gram) from intermediate A(1.8 gram) and 2,2-dimethoxy-1-oxygen hexanaphthene (2.0 gram) is except the chromatography eluent is EE and P.
(3S, 4R)-3[(R)-and 1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4(R)-6 '-(2-methoxyl group-1 '-oxygen hexamethylene-2 '-thiazolinyl))] azetidine-2-ketone (1g) and (3S, 4R)-3[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((S)-6 '-(2 '-methoxyl group-1 '-oxygen-hexamethylene-2 '-alkene))] azetidine-2-ketone (1h)
2-methoxyl group-2-cyclonene (11.9 gram) is dropwise added to anhydrous tetrahydro furan (200 milliliters) reach two (TMS) acyl ammonium lithiums in the stirred solution of hexane (200 milliliters) 1M solution, and under nitrogen reaches-78 ℃.Temperature kept under-78 ℃ 30 fens again, added intermediate A(15 gram) and make reaction mixture keep 15 fens down in-78 ℃.Reaction mixture is poured in the cold saturated solution of ammonium chloride (100 milliliters), extracts with ether again.With 1% cold solution of spirit of salt (50 milliliters) and the cold saturated solution washing of sodium bicarbonate, drying is again in decompression evaporation down respectively for organic layer.Residue is dissolved in a spot of vinyl acetic monomer, adds sherwood oil (200 milliliters) and can get title compound (1h; 7.9 (t.l.c.Rf 0.25 gram), to be white in color solid m.p.170 ℃; CH/EA 4/6).Mother liquor evaporates down in decompression can get title compound (1g behind flash chromatography; 2.9 (t.l.c.Rf0.20 gram); CH/EA 4/6).
(3S, 4R)-3-[(R)-and 1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4((R)-6 '-(2 '-oxyethyl group-1 '-oxygen hexamethylene-2 '-thiazolinyl))] azetidine-2-ketone (1i) and (3S, 4R)-3[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl [4-((S)-6 '-(2 '-oxyethyl group-1 '-oxygen hexamethylene-2 '-thiazolinyl)] azetidine-2-ketone (1j)
2-oxyethyl group-2-cyclonene (24 gram) reaches two (TMS) acid amides lithiums in the mixture of hexane (200 milliliters) 1M solution in the solution adding anhydrous tetrahydro furan (160 milliliters) of anhydrous tetrahydro furan, it also is cooled to-78 ℃ and under nitrogen, the mixture of gained remain on-78 ℃ following 1 hour.Adding intermediate A(26.3 with 10 minutes afterwards restrains) in the solution of tetrahydrofuran (THF) (80 milliliters).Successively add ammonium chloride saturated solution (320 milliliters) and spirit of salt 10% solution (70 milliliters) afterwards.Institute and mixture are with ether extraction (3 * 150 milliliters), and be successively with 10% spirit of salt (50 milliliters) and salt water washing, dry again.Decompression removes to desolvate down and can get the oily residue, and it can get 1: 1 title compound (20 gram) and pure title compound (1j through flash chromatography purifying (eluent CH/EA); 1.3 (t.l.c.Rf 0.36 for mixture gram); CH/EA 1/1).Mixture is dissolved in the amount of ethyl acetate, with the hexanaphthene dilution, can get title compound (1i after the cooling again; 4 grams) solid (t.l.c.Rf0.38 is white in color; CH/EA 1/1).
Intermediate 1k
(3S, 4R)-3-[(R)-and 1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-(1 '-oxygen cyclohexyl)] azetidine-2-ketone and (3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((S)-2 '-(1 '-the oxygen cyclohexyl)] azetidine-2-ketone
1-trimethyl silicane alcoxyl tetrahydrobenzene (11 gram) is dissolved in (400 milliliters) in the methylene dichloride, under nitrogen.(3R, 4R)-4-acetoxy-3-((R)-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl)-azetidinone (9.28 grams; Intermediate A) add in the solution, mixture stirs down in 23 ℃, adds trifluoromethayl sulfonic acid TMS ester (0.66 gram) again.Mixture stirred 2 hours down in nitrogen again, poured into afterwards in the sodium bicarbonate 1% ice-cold solution (300 milliliters).Tell organic layer, Yi Shui and salt water washing (each 300 milliliters).The solvent mixing that evaporation can get title compound under decompression is oily.
Intermediate 2
(3S, 4R)-3-[(R)-and 1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4-(R)-2 '-((S)-6 '-methoxyl group-1 '-the oxygen cyclohexyl))] azetidine-2-ketone (2a) and (3S, 4R)-3-[(R)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4-((R)-2 '-((R)-6 '-methoxyl group-1 '-the oxygen cyclohexyl))] azetidine-2-ketone (2b)
10% palladium/carbon (1.8 gram) is added to intermediate (1 gram; 2.2 gram) in the solution of vinyl acetic monomer (200 milliliters), mixture hydrogenation 2 hours under 1atm again.Catalyzer is to remove by filter, and filtrate is reduction vaporization again.Can get title compound 2a(0.6 gram behind the oily residue chromatography (eluent EA/CH 9/1)) (t.l.c.Rf 0.8; EA/CH 9/1) be pale yellow oily.Molten again from after can get title compound 2b(1.1 gram) (t.l.c.Rf 0.4; EA/CH 9/1) be oily.
In similar manner:
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethyl-silicon alcoxyl base) ethyl]-4-[(S)-2 '-((S)-6 '-methoxyl group-1 '-the oxygen cyclohexyl))]-azetidine-2-ketone (2c; 2.1 gram) can derive from intermediate 1h(2.2 gram);
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl [4-((R)-2 '-((S)-6 '-oxyethyl group-1 '-the oxygen cyclohexyl))] azetidine-2-ketone (2d; 0.95 (t.l.c.Rf0.57 gram); Eluent EA/CH 1/1) reaches
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((R)-6 '-oxyethyl group-1-oxygen cyclohexyl))] azetidine-2-ketone (2e; 3 grams) (t.l.c.Rf 0.35; Eluent EA/CH 1/1) derives from intermediate 1i(4.4 gram).
Intermediate 3
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-(1 '-the oxygen cyclohexyl))]-1-methyl sulphur azetidine-2-ketone
Intermediate 1a(9.56 gram) is dissolved in the tetrahydrofuran (THF) (60 milliliters), down and be cooled to-78 ℃ in nitrogen.In separating funnel, added two (TMS) acid amides lithiums (32.3 milliliters in the 1M of hexane solution), react on-78 ℃ and stirred 30 fens down with 8 minutes.Add methanesulfonic first thioesters (4.08 gram), mixture kept 30 fens down in-78 ℃, made it be heated to-30 ℃ again.Add ether (20 milliliters), mixture kept 30 fens down in-30 ℃, poured into (100 milliliters) in the ammonium chloride saturated solution again.Organic layer is with 1% cold hydrochloric acid solution (2 * 50 milliliters) and the first after scouring of salt solution (50 milliliters), and the oily matter of gained (eluent E/P) behind chromatography can get title compound (5.15 gram) behind the organic solvent evaporation.
IR(CDCl 3) ν Max(cm -1) 1765(β-Nei vinegar amine), 1709(c=0) 2850 and 1300(-S-CH 3) H 1-NMR(CDCl 3): 4.307(dd), 4.22(m), 2.992(t), 2.61(m), 2.46(m), 2.395(s), 2.407(m), 2.105(m), 1.935(m), 1.70(m), 1.49(m), 1.19(d), 0.86(s), 0.064(s), 0.048(s).
Intermediate 4
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((S)-6 '-methylthio group-1 '-the oxygen cyclohexyl))]-1-methylthio group azetidine-2-ketone
Two (TMS) acid amides lithiums of 1M are cooled to-78 ℃ in the 1M of hexane solution (8 milliliters), again intermediate 3(5.15 gram to be incorporated in the tetrahydrofuran (THF) (20 milliliters) in 4 minutes) solution.The mixture of gained kept 30 fens down at-78 ℃, and is following 10 minutes in-30 ℃ again.Add diethyl ether (50 milliliters), mixture is poured ammonium chloride saturated solution (200 milliliters) again into.Organic layer is with 1% cold spirit of salt (2 * 100 milliliters) and the first after scouring of salt solution (100 milliliters), the organic layer drying, and reduction vaporization, flash chromatography purifying (eluent EE/P) can get title compound (3.72 gram) and is yellow oily again.
IR(CDCl 3) ν Max(centimetre -1) 1757(β-Nei vinegar amine), 1699(c=0) H 1-NMR(CDCl 3): 4.396(m), 4.18(m), 3.5(m), 3.03(dd), 2.42(s), 2.2(m), 2.068(s), 2.1-1.6(m), 1.47(d), 1.21(d), 0.86(s), 0.077(s), 0.065(s).
Intermediate 5
(3S, 4R)-3-[(R)-and 1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((R)-6 '-methylthio group-1 '-the oxygen cyclohexyl))-1-methyl sulphur azetidine-2-ketone (5a) and (3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((S)-6 '-methylthio group-1 '-oxygen base-cyclohexyl)-1-methylthio group azetidine-2-ketone (5b)
Two (TMS) acid amides lithiums are cooled to-78 ℃ in the 1M of hexane solution (18 milliliters) under nitrogen, are incorporated in the intermediate 1b(2 gram in the tetrahydrofuran (THF) (20 milliliters) again) solution.
In adding, temperature is risen to-70 ℃.Reaction mixture kept 30 fens down at-78 ℃, afterwards to add methanesulfonic methylthio group ester (2 milliliters) in 5 minutes carefully.After stirring 15 minutes, make mixture heating up to-30 ℃ following 1 hour, dilute with anhydrous diethyl ether (40 milliliters) again.Mixture is poured (200 milliliters) in the saturated aqueous ammonium chloride solution into.Organic layer is with 1% spirit of salt cold soln (2 * 50 milliliters) and the first after scouring of salt solution (50 milliliters), and is dry again.Organic layer evaporation, residue again the flash chromatography purifying (with sherwood oil/diethyl ether molten from) can get title compound 5a(1 gram) (t.l.c.Rf 0.7; Eluent P/EE 3/7).Further molten again from after can get title compound 5b(0.84 gram and be yellow oily (t.l.c.Rf 0.035; Eluent P/EE, 3/7).
Intermediate 5a
IR(CDCl 3) ν Max(centimetre -1) 1757(β-Nei vinegar amine), 1725(c=0) H 1-NMR(CDCl 3): 4.4(dd), 4.2(m), 3.6(m), 2.9(dd), 2.6(m), 2.45(m), 2.4(s), 2.11(s), 2.01-1.7(m), 1.9(m), 1.2(d), 0.8(s), 0.04(s).
Intermediate 5b
IR(CDCl 3) ν Max(centimetre -1) 1755(β-Nei vinegar amine), 1707(c=0) H 1-NMR(CDCl 3): 4.31(dd), 4.24(m), 3.52(m), 3.33(dd), 2.96(dd), 2.45(s), 2.17(m), 2.12(s), 2.1-1.9(m), 1.75(m), 1.46(m), 1.18(d), 0.86(s), 0.06(s).
Intermediate 6
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((S)-6 '-methylthio group-1 '-the oxygen cyclohexyl))] azetidine-2-ketone (6a)
Under nitrogen, 2-mercaptopyridine (1.63 gram) and triethylamine (1.49 gram) are added to intermediate 4(5.60 gram) in the solution of methylene dichloride, and be cooled to 0 ℃.Reaction mixture stirred 2 hours down at 23 ℃, poured in the 2% cold spirit of salt (200 milliliters) again.Tell organic layer, with dilute hydrochloric acid (2 * 200 milliliters) and the first after scouring of water (2 * 200 milliliters), the residue of gained can get title compound 6a(3.87 gram with flash chromatography purifying (eluent EE/P) after the solvent evaporation) be pale yellow oily matter.H 1-NMR（CDCl 3）ppm H 32.88（dd），H 44.16（m）。
In a similar manner, (3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((S)-6 '-methylthio group-1 '-the oxygen cyclohexyl)) azetidine-2-ketone (6b; 0.6 H gram) 1-NMR(CDCl 3) ppm H 32.70(m), H 43.68(dd) can prepare the gram from intermediate 5b(0.84), and (3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((R)-6 '-methylthio group-1 '-the oxygen cyclohexyl))-azetidine-2-ketone (6c; 0.5 H gram) 1-NMR(CDCl 3) ppm H 2.73(m), H 3.59(dd) can prepare gram) from intermediate 5a(0.7.
Intermediate 7
(3S, 4R)-1-(tertiary butyl dimethylamino silane oxygen base)-4-acetoxy-3-[((R)-(tertiary butyl dimethylamino silane oxygen base)) ethyl] azetidine-2-ketone
To (3S, 4R)-4-acetoxy-3-((R)-tertiary butyl dimethyl-silicon alcoxyl base) ethyl-[azetidinone (112 gram) adds TERT-BUTYL DIMETHYL CHLORO SILANE (73 gram) and triethylamine (80 milliliters) in the ice-cold solution of stirring of methylene dichloride (800 milliliters).Mixture at room temperature stirred 20 hours, later on water (1 liter) and the first after scouring of salt solution (300 milliliters).In machine layer drying, after evaporation, can get oily matter (160 gram), it dissolves in cyclohexane/ethyl acetate (95/5) mixture (1600 milliliters), handles with silica gel (480 gram) again.Suspension stirs and refiltered in 15 minutes.Solid is with cyclohexane/ethyl acetate (95/5: 4.81) washing, and solvent can get title compound (110 gram) and be pale yellow oily matter (Rf=0.85 sherwood oil/diethyl ether=2/1) after evaporation.
IR(CDCl 3) ν Max(centimetre -1) 1747(c=0) H 1-NMR a(CDCl 3): 6.14(d), 4.15(m), 3.07(dd), 2.03(s), 1.2(d), 0.9(s), 0.84(s), 0.22(s), 0.055(s), 0.35(s), 0.005(s) ppm.
Intermediate 8
(3S, 4R)-1-(tertiary butyl dimethyl silanyl-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[2 '-(1 '-oxygen base-cyclohexyl)] azetidine-2-ketone
Under nitrogen atmosphere reaches-40 ℃, tin chloride (35.4 milliliters) is dropwise added in the acetonitrile of stirring, can form white solid and add white smoke, it can and reduce through the nitrogen flushing.Make the suspension of gained rise to-10 ℃, in 10 minutes, add 1-trimethyl silicane alcoxyl tetrahydrobenzene (60.6 milliliters) and intermediate 7(110 gram again) in the solution of acetonitrile (300 milliliters).Yellow solution stirred 10 minutes down in 0 ℃, reentered in the stirring and ice-cold mixture of 10% aqueous sodium hydroxide solution (1 liter), diethyl ether (1 liter) and ice (500 gram).Tell organic layer, with sodium hydroxide (500 milliliters) and saturated ammonium chloride solution elder generation after scouring, dry revaporization can get yellow solid (117/7 gram).Solid is dissolved in (300 milliliters) in the Virahol under 40 ℃, be cooled to room temperature again, slowly adding water (300 milliliters) can get solid down in stirring, it stirs down in 0 ℃ and refiltered in 30 minutes, after the washing of 1: 1 mixed solution (100 milliliters) of isopropanol, drying is 15 hours under 40 ℃ vacuum, can get title compound (76 gram), be 2 ' R and 2 ' S isomer, 70% to 30% ratio mixture (ratio between two isomeries with HPLC utilize hexane/ethanol (99/1) be eluent and determine with HPLC).
Intermediate 9
(3S, 4R)-1-(tertiary butyl dimethylamino silane oxygen base)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl [4(6 '-(1 '-trimethyl silicane alcoxyl basic ring oneself-1 '-thiazolinyl))] azetidine-2-ketone
Two (TMS) acid amides lithiums are added to (150 milliliters) in the tetrahydrofuran (THF) in the 1M solution of hexane (70 milliliters), mixture stirs down in nitrogen, be cooled to-70 ℃, again to be incorporated in intermediate 8 compound solutions (15.5 gram) in the tetrahydrofuran (THF) (70 milliliters) in 20 minutes.The solution stirring of gained 30 minutes added chlorine trimethyl silane (10 milliliters) again in 10 minutes.Make temperature of reaction rise to-20 ℃, mixture is poured in the saturated ammonium chloride solution (500 milliliters) again, and mixture is again with ethyl acetate extraction (300 milliliters).Organic layer is with water (200 milliliters), the ice-cold solution of 2% spirit of salt (300 milliliters).Sodium bicarbonate aqueous solution and salt solution elder generation after scouring, drying is reduction vaporization again, can get title compound, is the mixing of 6 ' R and 6 ' S isomer.
Intermediate 10
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(R)-[2 '-((S)-6 '-hydroxyl-1 '-oxygen basic ring hexyl)] azetidine-2-ketone
Intermediate 9 is dissolved under-10 ℃ in the methylene dichloride (300 milliliters), handles with sodium bicarbonate (2.85 gram) again.The suspension of gained, gradation adds 3-chlorine peroxybenzoic acid (8.5 gram) in 30 minutes.Reaction mixture stirred under 0 ℃ 1.5 hours, in room temperature following 1 hour again, added S-WAT solid (5 gram) afterwards.After stirring 30 fens, solid filtering washs with methylene dichloride (100 milliliters) again.Organic layer is with 3% sodium sulfite aqueous solution (100 milliliters), and 3% ice-cold sodium bicarbonate aqueous solution (3 * 150 milliliters) and water wash in regular turn, and dry and evaporation can get yellow oil, and it is dissolved in (250 milliliters) in the methyl alcohol again.Add Potassium monofluoride (6 gram), gained solution stirred 30 fens under room temperature again, poured saturated ammonium chloride solution (500 milliliters) afterwards into, and mixture extracts with vinyl acetic monomer (3 * 200 milliliters) again.Mix organic layer,, can get white foam (12 gram) after drying and the evaporation with the salt water washing.Recrystallize in sherwood oil and diethyl ether (8/2) (25 liters) mixture can get title compound (4.4 gram) solid that is white in color, m.p.145-147 ℃.
IR(CDCl 3) ν Max(centimetre -1) 3501(OH), 3414(NH),
1763（c＝0），1713（c＝0）
H 1-NMR a（CDCl 3）：6.29（m），4.20（m），4.02（dd），3.51（d），2.93（m），2.81（m），2.40（m），2.0-1.8（m），1.73-1.6（m），1.03（d），0.87（s），0.0（s）ppm。
Intermediate 11
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((S)-6 '-three silicomethane Oxy-1s '-the oxygen cyclohexyl)] azetidine-2-ketone
Intermediate 10(4.4 gram) compound is dissolved in the anhydrous methylene chloride (100 milliliters) under the room temperature.The triethylamine (11 milliliters) that adds TMS chlorine (7.5 milliliters) and continue, mixture stir poured water (200 milliliters) in 1 hour again into.Tell organic layer and, can contain the yellow oil of trace of triethylamine after drying and the evaporation with water (2 * 200 milliliters) washing.Oil is dissolved in (100 milliliters) in the methyl alcohol, adds silica gel (10 gram), and suspension stirs after 1 hour and refilters.The silicon gel mixes the organic layer reduction vaporization with ethyl acetate (2 * 100 milliliters) washing, under 25 ℃.The oil of gained is dissolved in (150 milliliters) in the vinyl acetic monomer, with the salt water washing, can get yellow foam after the dry and evaporation, its chromatography and be that eluent (RF=0.25) can get title compound (3.5 restrain) foam is white in color on silica gel with sherwood oil and diethyl ether (1/1).
IR（CDCl 3）ν max（cm -1）3418（NH），1755（c＝0），1717（c＝0）H 1-NMR a（CDCl 3）：5.77（s），4.16（m），4.01（m），3.95（m），3.20（m），2.867（dd），2.1（m），1.4（m），1.25（d），0.86（s），0.10（s），0.07（s），0.05（s）ppm。
Intermediate 12
(3S, 4R)-3-[(R)-and 1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-1 '-(4-aminomethyl phenyl sulfino) hydrazono-]-hexamethylene-2 '-yl]-azetidine-2-ketone (12a) and (3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((S)-1 '-(4-tolyl sulfino) hydrazono-]-hexamethylene-2 '-yl]-azetidine-2-ketone (12b)
With the solution of intermediate (1k, 12.1 grams) in Glacial acetic acid (120 milliliters), under room temperature, add tolylsulfonyl hydrazides (6.9 gram).Reaction was stirred 3 hours, with methylene dichloride (250 milliliters) dilution, made pH reach 7 with 5% sodium hydrogen carbonate solution again with salt water washing (2 * 250 milliliters) earlier afterwards, used salt water washing (2 * 150 milliliters) at last again.The organic layer drying, solvent is in decompression evaporation down.The foam of gained stirred 2 hours under room temperature with diethyl ether (60 milliliters), can get title compound 12b, the powder that is white in color, and this is to reach after the vacuum-drying after filtration to get (6 grams; M.p.187-189 ℃; T.l.c. diethyl ether Rf=0.13).
IR(CDCl 3) ν Max(CM ') 3416(N-H), 3304(NNHSO 2), vinegar amine in the 1753(), 1599(C=N, C=C) H 1-NMR(CDCl 3): 7.80(d), 7.38(bm), 7.34(d), 5.65(bs), 4.15(m), 3.58(dd), 2.63(m), 2.62(m), 2.44(s), 2.3(m), 2.08(m), 1.92(m), 1.78(d), 1.4(m), 1.20(m), 1.185(d), 0.9(s), 0.077(s), 0.067(s).
Organic layer wherein contains title compound 12a, and has a small amount of title compound 12b(to know with t.l.c.), will ly concentrate, residue flash chromatography purifying (eluent diethyl ether/sherwood oil 7: 3) can get title compound 12a, the powder that is white in color (7.6 grams; M.p.95-96 ℃; T.l.c. diethyl ether Rf=0.37)
IR(CDCl 3) ν Max(cm -1) 3410(N-H), 3306(NNHSO 2), vinegar amine in the 1755(), 1599(C-N, C=C) H 1-NMR(CDCl 3): 7.81(d), 7.40(m), 7.33(d), 5.60(bs), 4.09(m), 4.00(m), 2.81(dd), 2.52(m), 2.44(s), 2.3(m), 2.0-1.8(m), 1.6-1.4(m), 1.04(d), 0.87(s), 0.06(s), 0.03(s).
Intermediate 13
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(S)-3 '-hexamethylene-1 '-thiazolinyl] azetidine-2-ketone
With intermediate (12a, 1.12 gram) in the solution of anhydrous tetrahydro furan (20 milliliters), in adding to diisopropyl amide (preparation is from anhydrous Diisopropylamine) (1.35 milliliters) and n-Butyl Lithium under-40 ℃ lentamente in the stirred solution of the 1.6M of hexane solution (5.7 milliliters).Sluggish is heated to-20 ℃/0 ℃, and keeps 1 hour at-20 ℃/0 ℃.Reaction mixture is heated in pre-cooled spirit of salt 5% solution (20 milliliters), extracts with vinyl acetic monomer (2 * 40 milliliters) again.Organic layer is with 5% sodium hydrogen carbonate solution (20 milliliters) and salt solution (20 milliliters) washing, dry revaporization.Raw product can get title compound with flash chromatography purifying (eluent diethyl ether/sherwood oil 1/1), the powder that is white in color (0.45 gram, m.p.104-106 °; T.l.c. IR(CDCl ether Rf=0.37) 3) ν Max(CM -1) 3416(N-H), vinegar amine in the 1753(), 1603(C=C) H 1-NMR(CDCl 3): 5.82(bs), 5.81(m), 5.60(dd), 4.14(m), 3.46(dd), 2.85(m), 2.24(m), 2.00(m), 1.85-1.70(m), 1.54(m), 1.27(m), 1.23(d), 0.86(s), 0.064(s), 0.054(s).
Intermediate 14
(3S, 4R)-3-[(R ')-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(1 ' R, 2 ' S, 3 ' R)-1 ', 2 '-epoxy hexamethylene-3 '-yl] azetidine-2-ketone
A chlorine peroxybenzoic acid (3.76 grams in position between inciting somebody to action; Analyze 55%) in the solution of methylene dichloride (50 milliliters), dropwise adding intermediate 13 under 0 ℃ in the solution of methylene dichloride (50 milliliters).Solution is heated to room temperature, restir 3 hours.Reaction mixture adds to (50 milliliters) in 10% sodium sulfite solution, again with sodium bicarbonate 5% solution (2 * 50 milliliters) and the first after scouring of salt solution (50 milliliters).The solution drying is again with solvent evaporation.Raw product with flash chromatography purifying (eluent ethyl acetate/hexanaphthene 3/7) can get title compound be white in color powder (1.53 the gram, m.p.134 ℃-136 ℃; T.l.c. IR(CDCl diethyl ether Rf=0.3) 3)
ν Max(centimetre -1) 3413(N-H), vinegar amine in the 1757(), H 1-NMR(CDCl 3): 5.85(bm), 4.22(m), 3.77(dd), 3.16(t), 3.12(m), 3.01(m), 2.00-1.7(m), 1.55(m), 1.4(m), 1.24(d), 1.22(m), 0.87(s), 0.67(s).
Intermediate 15
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(R)-6 '-((S)-2 '-azido--1 '-(R)-hydroxyl hexamethylene-6 '-yl)] azetidine-2-ketone
With intermediate 14(1.5 gram) in the solution of methyl alcohol (150 milliliters), add sal epsom heptahydrate (1.135 gram) and trinitride (0.9 gram) down in nitrogen.The mixture of gained refluxes a night, pours in the water (150 milliliters) into again with methylene dichloride (3 * 150 milliliters) extraction, can get title compound (1.49 gram), m.p.124-125 ° after the dry and evaporation; T.l.c. cyclohexane/ethyl acetate 3/7(Rf 0.68); IR: ν Max(CDCl 3) 3600,3416,2101,1755cm -1; 1H-NMR(300MHz, CDCl 3) 6.02(bs), 4.16(m), 3.78(m), 3.72(m), 3.60(dd), 2.99(m), 2.27(m), 2.27(bm), 2.0-1.4(m), 1.24(m), 1.28(d), 0.89(s), 0.098(s), 0.092(s) ppm.
Intermediate 16
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(R)-6 '-((S)-2 '-azido--1 '-oxygen hexamethylene-6 '-yl)-azetidine-2-ketone
Pyridinium chlorochromate (6.67 gram) in the mixture of anhydrous methylene chloride (50 milliliters), is added intermediate 15 in the solution of methylene dichloride (200 milliliters) down in nitrogen.Mixture at room temperature stirs a night, filters the solution decompression evaporation of florisil gained.Oily residue chromatography on silica gel is an eluent with cyclohexane/ethyl acetate (1/1) mixture, can get title compound (4 grams; M.p.134-135 ℃; Decompose; T.l.c. diethyl ether Rf=0.68);
IR: ν Max(CDCl 3) 3416,2104,1759,1720 centimeters -1; 1H-NMR(300MHz, CDCl 3) 5.77(bs), 5.2(m), 4.04(m), 3.00(m), 2.9(m), 2.15-1.3(m), 1.21(d), 0.87(s), 0.074(s), 0.065(s) ppm.
Intermediate 17
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(R)-6 '-((S)-2 '-allyloxycarbonyl amido-1 '-the oxygen basic ring oneself-6 '-yl]-azetidine-2-ketone
Intermediate 16(4 gram) is dissolved in ethyl acetate (300 milliliters), adds the hydrogenation 2 hours under 3atm of 10% palladium/carbon (3 gram) mixture.Add 1 part of catalyzer (1 gram) again, and continue hydrogenation 2 hours.Mixture filtration over celite, gained solution are handled with chloroformic acid allyl ester (1.7 gram) and pyridine (1.12 gram) again.Reaction mixture at room temperature stirred 30 fens, poured into (350 milliliters) in the saturated aqueous ammonium chloride solution again.Organic layer with the 1% spirit of salt aqueous solution (2 * 150 milliliters), 5% sodium hydrogen carbonate solution (2 * 150 milliliters) and salt solution (200 milliliters) wash respectively, drying evaporates under vacuum again.Residue is the flash chromatography purifying on the silica gel tubing string, utilizes hexanaphthene-ethyl acetate (1/1) mixture can get title compound, is oily (2 grams; T.l.c. cyclohexane/ethyl acetate 3/7Rf=0.4).IR：ν max（CDCl 3）3414，1765，1709cm -1; 1H-NMR（300 MHz，CDCl 3）6.05（s），5.9（m），5.64（bd），5.36（m），4.56（m），4.4-4.1（m），4.05（dd），2.9（m），2.75（m），2.60（m），2.0-1.2（m），1.02（d），0.86（s），0.06（s）。
Intermediate 18
(3S, 4R)-3-[(R)-1 '-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(1 " S, 2 " R, 6 " R)-1 "-hydroxyl-2 " cyano group-hexamethylene-6 "-yl] azetidine-2-ketone
Intermediate 14(2.4 gram) is dissolved in the mixture of DIMETHYL FORMAMIDE (80 milliliters) and water (40 milliliters), adds potassium cyanide (1 gram), make mixture be increased to 60 ℃ and go through 8 hours, add ether (150 milliliters) dilution again with twice of washing (150 milliliters).The dry also reduction vaporization of organic layer can get rough oily matter, and it can get title compound (1.7 gram) with flash chromatography purifying (eluent ether/ethyl acetate 8/2 Rf=0.4) on silica gel solid is white in color.
The IR(centimetre -1): 3611(OH), 3416(NH), 1755(CO);
NMR（ppm）：6.12（bs），4.18-4.16（m），3.60（dd），3.0（dd），2.94（m），2.74（bs），2.0-1.87（m），0.09（s），1.85-1.6（m），1.6-1.5（m），1.29（d），0.89（s）。
Intermediate 19
(3S, 4R)-3-[(R)-1 '-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(1 " R, 2 " R, 6 " R)-1 "-hydroxyl-2 " (allyloxycarbonyl aminomethyl) hexamethylene-6 "-yl] azetidine-2-ketone
Intermediate 18(1.7 gram) be dissolved in that (15 milliliters) add platinum dioxide (40 milligrams) again in the acetic acid, mixture hydrogenation (1atm) 3.5 hours is again through kieselguhr filter, solvent and reduction vaporization.Residue is dissolved under 0 ℃ in the anhydrous methylene chloride again, adds N-ethylpyridine (1.8 milliliters) and chloroformic acid allyl ester (0.55 milliliter), and the gained mixture stirred 16 hours.Solvent removed under reduced pressure can get crude material, and it is dissolved in the ethyl acetate (100 milliliters) and with salt again washes secondary (50 milliliters).The dry also reduction vaporization of organic layer can get oily matter, and it can get title compound (0.7 gram) with flash chromatography purifying (eluent is cyclohexane/ethyl acetate 60/40 Rf=0.5) on silica gel solid is white in color.
IR（cm -1）：3454（NH），3416（NH），1751（CO）;1720（CO）;
NMR（ppm）：6.32（s），5.9（m），5.06（t），4.55（m），4.18（m），3.78-3.6（m），3.26（m），3.07-2.7（m），1.89（m），1.83-1.2（m），1.28（d），0.88（s），0.1（s），0.09（s）。
Intermediate 20
(3S, 4R)-3-[(R)-1 '-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(2 " R, 6 " R)-1 "-oxygen base-2 " (allyloxy carbonyl amine methyl) hexamethylene-6 "-yl] azetidine-2-ketone
Intermediate 19(0.7 gram) is dissolved in the methylene dichloride (50 milliliters), and under vigorous stirring, add pyridinium chlorochromate (1.1 gram), after 2.5 hours, the filtration over celite filter, after methylene dichloride (150 milliliters) dilution with 5% cold spirit of salt (20 milliliters), solution washing is used sodium bicarbonate aqueous solution (20 milliliters) washing again.The dry also reduction vaporization of organic layer can get oily matter, and it can get title compound (0.48 gram) with flash chromatography purifying (eluent cyclohexane/ethyl acetate 30/70 Rf=0.3) again on silica gel solid is white in color.
IR ν Max(centimetre -1): 3456 and 3439(NH), 1759(CO), 1720 and 1718(CO), 1603(C=C);
NMR（d ppm）6.02（bs），5.98（m），5.23（m），5.12（bt），4.05（m），4.21（m），4.05（m），13.55（m），2.92（bs），2.68（m），2.58（m），2.1-1.55（m），1.32-1.2（m），1.04（d），0.87（s），0.06（s）。
Intermediate 21
(3S, 4R)-3-[(R)-and 1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-6 '-(2 '-isopropoxy-1 '-oxygen hexamethylene-2 '-thiazolinyl)) azetidine-2-ketone (21a) and (3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((S)-6 '-(2 '-isopropoxy-1 '-oxygen hexamethylene-2 '-thiazolinyl) azetidine-2-ketone (21b)
In two (TMS) acid amides lithium in the 1M of hexane solution (486 milliliters) and the mixture of anhydrous tetrahydro furan (300 milliliters), under inert atmosphere and be cooled to-78 ℃, dropwise be incorporated in anhydrous THF(100 milliliter) in 2-isopropoxy-2-cyclonene (30 gram) solution.Temperature remain on-78 ℃ following 30 minutes, dropwise add the solution of (3R, 4R)-4-acetoxy-3-((R)-tertiary butyl dimethylamino silane oxygen base) ethyl-azetidinone (46.59 gram) is in anhydrous THF(100 milliliter) again.The reaction remain on-78 ℃ following 10 minutes, pour into again (300 milliliters) in the cold saturated solution of ammonium chloride, extract with diethyl ether again.Organic layer is after the cold saturated solution washing of 1% cold hydrochloric acid solution (150 milliliters) and sodium bicarbonate, and drying is reduction vaporization again.The yellow oily residue is handled with sherwood oil.Can get the title compound 21a solid (8.4 gram) that is white in color after filtering; M.p.130 ℃ of decomposition; T.l.c. cyclohexane/ethyl acetate
4/6(Rf 0.21); IR(Nujol), ν Max(centimetre -1): 3233(NH), 1759(C=0 β-Nei vinegar amine), 1680(C=0); H 1-NMR(CDCl 3): 5.92(t), 575(bs), 4.29(m), 4.2(m), 2.99(dd), 2.59(m), 2.52(m), 2.09(m), 1.9(m), 1.27(d), 1.25(d), 1.23(d), 0.86(s), 0.06(s), ppm.
The mother liquor reduction vaporization is also accepted flash chromatography and can be got title compound 21b, is oily (9.2 grams; T.l.c. cyclohexane/ethyl acetate 4/6 Rf=0.21);
IR(Nujol), ν Max(centimetre -1) 3425(NH), 1755(C=0 β-Nei vinegar amine), 1684(C=0), 1624(C=C),
H 1-NMR（CDCl 3）：6.35（bs），5.95（m），4.2（m），3.6（dd），2.75（m），2.5（m），2.44（m），2.07（m），1.7（m），1.27（d），1.25（d），1.86（s），0.07（s），0.057（s），ppm。
Intermediate 22
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-6 '-(2 '-isopropoxy-1 '-hydroxyl hexamethylene-2 '-thiazolinyl) azetidine-2-ketone
To intermediate 21a(5.7 gram) in the ice-cold solution of methyl alcohol (100 milliliters) and water (30 milliliters), in 1.5 hours, divide 10 parts and add sodium borohydride (560 milligrams).In adding fashionable pH value protection, utilize the 5% spirit of salt aqueous solution at 5 and 7.5.Add methylene dichloride (200 milliliters) and water (100 milliliters) finally.Organic layer, after washing, drying can get title compound 22 behind the reduction vaporization again, the spumescence that is white in color (5.5 gram).
Intermediate 23
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((S)-6 '-isopropoxy-1 '-the oxygen cyclohexyl))] azetidine-2-ketone (23a)
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-((R)-6 '-isopropoxy-1 '-the oxygen cyclohexyl))] azetidine-2-ketone (23b)
Intermediate 22(5.5 gram) is dissolved in the ethanol (100 milliliters).Add 10% palladium/charcoal (0.5 gram) again, mixture hydrogenation 4 hours under 3atm again.The catalyzer elimination, the solution decompression evaporation.Oily residue (5 gram) is dissolved in anhydrous methylene chloride (150 milliliters), adds pyridinium chlorochromate (4.2 gram) again.Reaction mixture stirred 6 hours down in 20 ℃, added more pyridinium chlorochromate (2.8 gram) again.Reaction was stirred 4 hours, afterwards with diethyl ether (100 milliliters) dilution, and decant on the black jelly again, it washes secondary with diethyl ether.Mixed organic solvents, reduction vaporization; Oily residue chromatography utilizes ethyl acetate/hexanaphthene (9/1) molten from getting title compound 23a, the solid that is white in color (0.8 gram; T.l.c. ethyl acetate/hexanaphthene 1/1 Rf=0.5); IR(CDCl 3),
ν Max(centimetre -1): 3416(NH), 1755(C=0 β-Nei vinegar amine), 1705(C=0 ketone).
H 1-NMR（CDCl 3）：5.89（bs），4.17（m），3.97（m），3.78（m），3.53（m），3.15（m），2.86（dd），2.13（m），2.10（m），1.8-1.4（m），1.24（d），1.13（d），0.88（s），0.08（s），0.06（s），ppm。
Molten again from can get title compound 23b be white in color solid (1 the gram; M.p.121 ℃; T.l.c. ethyl acetate/hexanaphthene 1/1 Rf=0.28); IR
(CDCl 3) ν Max(centimetre -1) 3416(NH), 1759(C=0 β-Nei vinegar amine), 1722(C=0),
H 1-NMR（CDCl 3）：5.7（bs），4.18（m），4.09（m），3.97（dd），3.6（m），2.8（dd），2.55（m），2.3（m），2.1（m），1.98（m），1.8-1.6（m），1.22（d），1.14（d），0.8（s），0.07（s），0.06（s），ppm。
Intermediate 24
(3S, 4R)-3-[(R)-and 1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-6 '-(2 '-cyclopentyloxy-1 '-oxygen hexamethylene-2 '-thiazolinyl)) azetidine-2-ketone (24a) and (3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((S)-6 '-(2 '-cyclopentyloxy-1 '-oxygen hexamethylene-2 '-thiazolinyl)) azetidine-2-ketone (24b)
Two (TMS) acid amides lithium in the 1M solution of (140 milliliters) of hexane and the mixture of anhydrous tetrahydro furan (70 milliliters), is added 2-cyclopentyloxies-2-cyclonenes (8.5 gram) down in inert atmosphere and-78 ℃ and is dissolved in anhydrous THF(70 milliliter) solution.Temperature remain on-78 ℃ following 40 minutes, add anhydrous THF(70 milliliter afterwards) in (3R, 4R)-4-acetoxy-3-((R)-tertiary butyl dimethylamino silane oxygen base) ethyl-azetidinone (11.25 gram) cold soln.Reaction mixture-78 ℃ following 5 minutes, pour into afterwards in the cold mixing liquid of diethyl ether (225 milliliters), 10% spirit of salt (63 milliliters), water (180 milliliters) and ammonium sulfate saturated solution (180 milliliters).Organic layer is with 10% spirit of salt (2 * 70 milliliters) and salt solution (3 * 70 milliliters) washing, and drying is reduction vaporization again.Residue is chromatography on silica gel, utilizes the mixed solution of cyclohexane/ethyl acetate 9/1 to 8/2 can wait two the title chemical combination 24a and the 24b(6.82 gram of the ear concentration of rubbing).
Title compound 24a in THF/ sherwood oil 1/5 crystallization and get (2.1 the gram, m.p.111-113 ℃; T.l.c. cyclohexane/ethyl acetate 1/1(Rf=0.29); IR(CDCl 3), ν Max(CM -1): 3412(NH), 1757(C=0 β-Nei vinegar amine), 1688(C=0); 1626(C=C).
H 1-NMR（CDCl 3）：5.85（t），5.67（s），4.4（m），4.3（dd），4.2（m），2.98（dd），2.57（m），2.50（m），2.1（m），1.9（m），1.5（m），1.22（d），0.83（s），0.05（s）。
The mother liquor reduction vaporization can get title compound 24b, contains a small amount of compound 24a(2.45 gram; T.l.c. cyclohexane/ethyl acetate 1/1 Rf=0.29);
IR(CDCl 3) ν Max(centimetre -1) 3425(NH), 1755(C=0 β-Nei vinegar amine), 1684(C=0), 1624(C=C), H 1-NMR(CDCl 3): 6.38(sa), 5.87(m), 4.41(m), 4.17(m), 3.60(dd), 2.75(m), 2.49(m), 1.20(m), 1.7-1.6(m), 1.235(d), 0.86(s), 0.068(s), 0.054(s).
Intermediate 25
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[((2 ' R, 6 ' S) 6 '-(2 '-cyclopentyloxy-1 '-the oxygen basic ring oneself-6 '-yl)) azetidine-2-ketone
Intermediate 24b(3.2 gram) is dissolved in the ethyl acetate (290 milliliters), adds 10% palladium/carbon (1.35 gram), mixture hydrogenation 1 hour under 3atm again.Catalyzer filters through diatomaceous earth filter, the solution decompression evaporation.Residue is chromatography on silica gel, utilizes the mixed solution of ethyl acetate/hexanaphthene 9/1 to 7.3 can get title compound, the spumescence that is white in color (1.2 gram); T.l.c. cyclohexane/ethyl acetate 1/1 Rf=0.45).IR:(CDCl 3) ν Max(centimetre -1) 3418(NH), 1755(C=0, β-Nei vinegar amine), 1722(C=0).
H 1-NMR（CDCl 3）：6.097（sa），4.15（m），4.01（m），3.905（m），3.67（dd），2.69（m），2.43-2.22（m），2.10（m），2.00-1.90（m），1.83-1.50（m），1.33（m），1.22（d），0.86（s），0.075（s），0.049（s）。
Intermediate 26
2-(tertiary butyl dimethyl-silicon alcoxyl methyl) pimelinketone
With 2-methylol pimelinketone (8.8 gram), tertiary butyl dimethylsilyl chlorine (10 gram), and imidazoles (4.6 gram) is dissolved in (100 milliliters) among the DMF under the room temperature.The gained mixture stirred 2 hours, poured into (200 milliliters) in the sherwood oil again.Organic layer is washed secondary with 10% cold sodium hydrogen carbonate solution (60 milliliters), drying, and reduction vaporization can get title compound (13.6 gram) and be yellow oily again with flash chromatography purifying (eluent cyclohexane/ethyl acetate 95/5 Rf=0.7).
IR:(ν MaxCentimetre -1): 3670 and 1703;
NMR（d ppm）：3.96（dd），3.555（dd），2.47（m），2.4-2.2（m），2.04（m），1.89（m），1.65（m），1.40（m），0.87（s），0.048（s），0.044（s）。
Intermediate 27
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((2 " R, 6 " R)-2 "-(tertiary butyl dimethylamino silane oxygen ylmethyl) 1 " oxygen hexamethylene-6 "-yl] azetidine-2-ketone
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((2 " S, 6 " R)-2 "-(tertiary butyl dimethylamino silane oxygen ylmethyl) 1 " oxygen hexamethylene-6 "-yl] azetidine-2-ketone
Under nitrogen, with 2,2,6,6-tetramethyl piperidines (28.3 milliliters) dropwise adds butyllithium 1.6M in hexane (125 milliliters) and anhydrous THF(1.50 milliliter) stirred solution, and be cooled to-50 ℃.Gained mixture heating up to 5 ℃ is gone through 10 minutes, is cooled to-78 ℃ again, dropwise adds intermediate 26(23 gram under-70 ℃) in anhydrous THF(100 milliliter) solution.After 1 hour, add (3R, 4R)-the 2-acetoxy-3-((R)-(tertiary butyl dimethylamino silane oxygen base) ethyl-azetidinone (27.5 gram), the gained mixture stirred 40 fens down in-78 ℃ again.Reaction mixture is poured in saturated ammonium chloride (300 milliliters) solution, with ethyl acetate (250 milliliters) extracting twice, the dry again reduction vaporization of organic layer.Gained oily matter is yellow solid with the mixing that flash chromatography purifying (eluent cyclohexane/ethyl acetate 90/10 Rf=0.3) can get title compound (17 gram).
IR:(ν MaxCentimetre -1) 3582,1755(CO β-Nei vinegar amine), 1612.
NMR（d ppm）：6.1-5.7（bs+bs+bs），4.18（m），4.06（m），3.97（m），3.90（m），3.51（m），3.74（m），2.80（m），2.7-2.5（m），2.40（m），2.14（m），2.1-1.6（m），1.32（m），1.24（d），1.17（d），0.87（s+s+s），0.05（m）。
Intermediate 28
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((2 ' S)-((6 ' R, S)-6 '-iodo-1 '-oxygen hexamethylene-2 '-yl] azetidine-2-ketone
To two (TMS) acid amides lithium in the 1M solution of (48.7 milliliters) of hexane, add be dissolved in anhydrous THF(70 milliliter) and be cooled to the intermediate 1a(7.4 gram of-78 ℃ (under nitrogen)) in the THF(70 milliliter) solution.The gained mixture stirred 1.5 hours down at-70 ℃, was cooled to-78 ℃ and slowly added iodine (7.4 gram) again in anhydrous THF(20 milliliter) solution.Reaction restir 10 minutes adds salt solution (250 milliliters) down in-78 ℃ again.The gained mixture extracts secondary (150 milliliters) with ether; Organic layer is successively washed secondary with S-WAT saturated solution (100 milliliters) and water (100 milliliters).Dry organic layer, reduction vaporization, can directly use must repurity for crude material (9.5 gram).
Intermediate 29
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((2 ' S)-((6 ' S)-6 '-thiophenyl-1 '-oxygen hexamethylene-2 '-yl)) azetidine-2-ketone 29a
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((2 ' S)-2 '-((6 ' R)-6 '-thiophenyl-1 '-oxygen hexamethylene-2 '-yl)] azetidine-2-ketone 29b
Thiophenol (7.424 gram) adds potassium hydroxide (5.33 gram) down in the solution of water (740 milliliters) in stirring.Add Tetrabutyl amonium bromide (1.52 gram) to gained solution, add intermediate 28(15.2 gram again) in the solution of methylene dichloride (500 milliliters).The gained mixture stirred 16 hours.Organic layer is told, and water is with dichloromethane extraction.The organic layer drying is reduction vaporization again.Residue chromatography (eluent cyclohexane/ethyl acetate 7/3) can get thiophenol (4.9 gram), can get the mixture 2(5.34 gram of title compound 29a and 29b and intermediate 1A).The mixture chromatography utilizes sherwood oil 40-60/ diethyl ether 9/1 to be eluent, can get title compound 29a(0.1 gram) for for the second time molten from material, and compound 29a and 29b mixture 2(1.1 gram) be second molten from material.Second molten from material again with PHLC purifying (silicon-dioxide, n-hexane/ethyl acetate 8/2,10 milliliters/centimeter, UV must survey and be set in 275 millimicrons of wavelength), can get title compound 29a(0.7 gram) solid that is white in color (m.p.116-117 ℃ from hexanaphthene) and title compound 29b(0.12 gram) be light yellow solid, m.p.65-67 ℃.
Title compound 29A
1H-NMR（ppm）7.4-7.2（m），5.8（bs）;4.13（m）;3.9（m）;3.8（m）;3.46（m）;2.75（dd）;2.3（m）;2.2（m）;2.00（m）;1.8（m）;1.6（m）;1.18（d）;0.8（s）;0.019（s）。
Title compound 29B
1H-NMR（ppm）7.4-7.3（m），5.77（bs）;4.17（m）;4.11（m）;3.95（m）;2.8（dd）;2.6（m）;2.4（m）;2.2（m）;2.00（m）;1.7（m）;1.4（m）;1.23（m）;0.86（s）;0.06（s）;0.055（s）。
Intermediate 30
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((2 ' S, 6 ' R)-2 '-methoxyl group-1 '-hydroxyl hexamethylene-6 '-yl)) azetidine-2-ketone
To intermediate 14(0.1 gram) in the solution of methyl alcohol (10 milliliters), add contraposition toluenesulphonic acids-hydrate down in 0 ℃.The gained mixture stirred 2 hours down at 22 ℃, poured diethyl ether (30 milliliters) into, with salt washing (2 * 50 milliliters), can get rough title compound, (70 milligrams of the solids that is white in color after drying and the evaporation; T.l.c. diethyl ether Rf=0.20); IR:(CDCl 3) ν MaxCm -1) 3700,2690,3418,1753; 1H-NMR(300MHz, CDCl 3) 5.85(bs), 4.18(m), 3.88(bm), 3.64(dd), 3.34(s), 3.30(m), 2.95(m), 1.8(m), 1.8-1.4(m), 1.27(d), 0.88(s), 0.08(s).
Intermediate 31
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((2 ' S, 6 ' R)-2 '-methoxyl group-1 '-oxygen hexamethylene-6 '-yl)] azetidine-2-ketone
To intermediate 30(70 gram) in the solution of anhydrous methylene chloride (8 milliliters), add pyridinium chlorochromate (80 milliliters) in the mixture of anhydrous methylene chloride down in nitrogen.The gained mixture stirred 4 hours down at 22 ℃, and with diethyl ether dilution (30 milligrams), decant on the black jelly filters florisil more again.The organic solution reduction vaporization can get title compound, is (30 milligrams of buff powders; T.l.c. cyclohexane/ethyl acetate 4/6 Rf=0.43); IR(CDCl 3) ν Max(centimetre -1) 3418,1757,1718; 1H-NMR(300 MHz, CDCl 3) 5.84(sa), 4.18(m), 3.99(m), 3.57(m),
3.28（s），3.10（m），2.876（dd），2.24（m），2.08（m），1.98（m），1.68（m），1.56（m），1.248（d），0.87（s），0.075（s），0.063（s）。
Intermediate 32
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((1 ' S, 2 ' S, 6 ' R)-2 '-methylamino-1 '-hydroxyl hexamethylene-6 '-yl] azetidine-2-ketone
To intermediate 14(5 gram) in the solution of 96% ethanol (150 milliliters) and water (50 milliliters), (40 weight % solution are in water to add ammonium chloride (1.67 gram) and methylamine; 30 milliliters).The gained mixture refluxed 15 hours, poured in methylene dichloride (150 milliliters) and salt solution (400 milliliters) mixture again.Water extracts with methylene dichloride (2 * 120 milliliters), and organic layer can get title compound with salt solution (150 milliliters) washing after drying and the evaporation, the foam that is white in color (5.2 grams; T.l.c.CH 2Cl 2/ MeOH/NH 4OH 23/7/0.5 Rf=0.75);
IR:(CDCl 3) ν Max(centimetre -1) 3416,1753, 1H-NMR(300 MHz, CDCl 3) 6.26(bs), 4.20(m), 3.80(m), 3.72(dd), 3.13(s), 2.67(m), 2.49(s), 2.02(m), 1.7-1.2(m), 1.31(d), 0.91(s), 0.12(s).
Intermediate 33
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((1 ' S, 2 ' S, 6 ' R)-2 '-(N-allyloxycarbonyl-N-methylamino)-1 '-hydroxyl hexamethylene-6 '-yl] azetidine-2-ketone
To intermediate 32(5.2 gram) in the solution of anhydrous methylene chloride (120 milliliters), under nitrogen and 0 ℃, add chloroformic acid allyl ester (2.2 milliliters) and 2,2,6,6-tetramethyl piperidines (3.5 milliliters).Reaction mixture stirred 10 minutes down at 0 ℃, and with methylene dichloride (60 milliliters) dilution, again with ammonium chloride saturated aqueous solution (2 * 100 milliliters), sodium bicarbonate 5% solution (100 milliliters), salt solution (100 milliliters) washs respectively afterwards, and drying is vacuum-evaporation again.Residue grinds purifying (30 milliliters) in diethyl ether can get title compound, the powder that is white in color (4.54 grams; M.p.159-161 ℃; T.l.c. methylene chloride 9/1 Rf=0.64).
IR: ν Max(CDCl 3) 3414,1753,1688 centimeters -1; 1H-NMR(300MHz, CDCl 3) 6.2(bs), 5.9(m), 5.2(m), 4.6(m), 4.2(m), 4.04(m), 3.87(dd), 3.8(m), 3.17(dd), 2.86(s), 2.26(m), 1.8-01.2(m), 1.30(d), 0.89(s), 0.10(s), 0.09(s).
Intermediate 34
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((2 ' S, 6 ' R)-2 '-N-allyl group carbonyl-N-methylamino-1 '-oxygen hexamethylene-6 '-yl)] azetidine-2-ketone
The A method
To intermediate 33(1.8 gram) in the solution of methylene dichloride (50 milliliters), add pyridinium chlorochromate (2.2 gram) down in nitrogen.Reaction mixture stirred 5 hours down at 22 ℃, filtered florisil again, the evaporation of ethyl acetate washing (200 milliliters) gained solution decompression.Oily residue chromatography on silica gel utilizes cyclohexane/ethyl acetate 1/1 mixture to be eluent, can get title compound be white in color powder (1.0 the gram; M.p.140-142 ℃).
The B method
In the solution of anhydrous methylene chloride (15 milliliters), reach-70 ℃ to oxalyl chloride (3.35 milliliters), in 15 minutes, dropwise add methyl-sulphoxide (3.35 milliliters) in the solution of anhydrous methylene chloride (40 milliliters) in nitrogen.After 15 minutes, in 20 minutes, dropwise add intermediate 33(4.34 gram) in the solution of anhydrous methylene chloride (35 milliliters), solution stirred 2 hours down in-70 ℃, was heated to-40 ℃ and added triethylamine (14 milliliters) in 10 minutes afterwards.Solution is with saturated ammonium chloride solution (2 * 100 milliliters), salt solution (2 * 100 milliliters) washing, dry, revaporization.Raw product grinds with the mixed solution of sherwood oil (40 milliliters) and diethyl ether (10 milliliters), can get title compound powder (3.71 grams that are white in color; M.p.140-142 ℃ of t.l.c. diethyl ether Rf=0.3); IR: ν Max(CDCl 3) 3414,1763,1718,1691cm -1) 1H-NMR(300 MHz, CDCl 3) 6.08(bs), 5.92(m),
5.3-5.1（m），4.55（m），4.20（m），4.03（dd），2.99（m），2.85（s），2.66（m），2.08-1.8（m），1.06（dd），0.86（s），0.06（s）。
Intermediate 35
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(2 ' S, 6 ' R)-2 '-N-allyloxycarbonyl-N-methylamino)-1-carboxylic hexamethylene-6 '-yl]-1-allyl group oxalyl group]-azetidine-2-ketone
To intermediate 34(3.77 gram) in the solution of anhydrous methylene chloride (50 milliliters), add potash solid (0.15 gram), allyl group oxalyl chloride (3 milliliters) down in 22 ℃ nitrogen.In 5 minutes, dropwise add triethylamine (6 milliliters) afterwards.Reaction mixture stirred 45 minutes down at 22 ℃, used saturated ammonium chloride solution (2 * 90 milliliters), salt solution (2 * 90 milliliters) washing afterwards, dry again and evaporation.Residue is chromatography on silica gel, utilizes sherwood oil/diethyl ether 1/1 mixed solution to be eluent, can get title compound, is colorless oil (4.0 grams; T.l.c. diethyl ether R=0.76).
IR: ν Max(CDCl 3) 1809,1753,1703 centimeters -1; 1H-NMR(300MHz, CDCl 3) 5.97(m), 5.3(m), 5.25(m), 4.79(m), 4.65(m), 4.55(m), 4.54(m), 4.30(m), 3.24(m), 2.87(m), 2.87(s), 2.2-1.8(m), 1.1(d), 0.84(s), 0.06(s) ppm.
Intermediate 36
2-(2-benzyloxy oxyethyl group)-pimelinketone
The mixture of the 2-hydroxy-cyclohexanone of dimerization (13.7 gram), 2-BOE (20 gram) and contraposition toluenesulphonic acids (2 gram) is dissolved in the dimethylbenzene of round-bottomed flask (500 milliliters), this vessel assembly has Dean Stark device, makes it reflux 10 hours again.Gained solution cools off, washs (3 * 50 milliliters) with sodium bicarbonate, and drying reduces pressure and contracts.Rough oily matter utilizes cyclohexane/ethyl acetate 60/40 can get the title compound (Rf=0.5) of 20 grams for eluent with the flash chromatography purifying.
IR, CDCl 3(centimetre -1): 1722(C=0), 1603(C=C). 1H-NMR, 300 MHz, CDCl 3, chemical shift (ppm, TMS): 7.32(m), 4.55(dd), 3.92(m), 3.83(m), 3.64(m), 3.60(m), 2.48(m), 2.24(m), 1.93(m), -1.55(m).
Intermediate 37
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-[(S)-6 '-(2-benzyloxy oxyethyl group)-1 '-the oxygen cyclohexyl]] azetidine-2-ketone
With 2,2,6,6-tetramethyl piperidines (12.7 gram) under-70 ℃ nitrogen atmosphere, splashes into n-Butyl Lithium in hexane (33 milliliters) and tetrahydrofuran (THF) (150 milliliters) 2.5M solution.Reaction mixture is heated to 10 ℃, is cooled to-70 ℃ again, with intermediate 36(18.72 gram) slowly adding keep below-70 ℃ simultaneously.After adding fully, solution kept 15 fens under this temperature, added to be dissolved in the THF(200 milliliter in 30 minutes again) intermediate A(11.48 restrain), and remain under-70 ℃.After 5 minutes, utilize ammonium chloride (100 milliliters of saturated solutions) and spirit of salt (200 milliliter of 10% solution) mixed solution stopped reaction, again with ethyl acetate extraction.Organic layer utilizes cyclohexane/ethyl acetate 85/15 to 30/70 to be eluent with salt water washing, drying, concentrating under reduced pressure flash chromatography purifying again, can get title compound (2.2 grams, Rf=0.65).
IR(CDCl 3) centimetre -1: 3418(NH), vinegar amine in the 1757(C=0), 1718(C=0), 1603(C=0), 1H-NMR 300 MHz, CDCl 3, chemical shift (ppm TMS): 7.32(m), 5.71(s is wide), 4.56(s+m), 4.18(m), 3.99(m), 3.73(m), 3.6-3.5(m), 3.15(m), 2.87(dd), 2.30(m), 2.10(m), 1.80-1.50(m), 1.19(d), 0.86(s), 0.07(s+s).
Intermediate 38
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-[(S)-6 '-(2-azido-oxyethyl group)-1 '-the oxygen cyclohexyl]] azetidine-2-ketone
To intermediate 37(3.7 gram) replace in the stirred solution of methane amide in anhydrous dimethyl, add triphenyl phosphine (2.6 gram) and sodiumazide (1.8 gram).In 10 minutes, add carbon tetrabromide (3.4 gram) again.After 2 hours, the gained mixture is with diethyl ether (50 milliliters) dilution, with water give a baby a bath on the third day after its birth time (30 milliliters) again.The organic layer drying is evaporated under vacuum again.Stay thing chromatography on silica gel, utilize cyclohexane/ethyl acetate 7/3 mixed solution to be eluent, but title compound is colorless oil (2.6 grams, t.l.c. ethyl acetate/hexanaphthene 9/1 Rf=0
Figure 911014705_IMG25
).
IR(CDCl 3ν MaxCentimetre -1): 3161(N-H) vinegar amine in the 1759(), 1707(C=0), 1H-NMR(CDCl 3): 5.84(sa), 4.18(m), 4.00(m), 3.71(t), 3.60(m), 3.49(m), 3.35(m), 3.12(m), 2.88(dd), 2.25(m), 2.20-2.00(m), 1.6(m), 1.22(d), 0.86(s), 0.06(s), 0.05(s).
Intermediate 39
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-[S)-6 '-(2-azido-oxyethyl group)-(R/S)-1 '-hydroxy-cyclohexyl]] azetidine-2-ketone
To intermediate 38(2.6 gram) in the solution of methyl alcohol (70 milliliters), under-10 ℃, in 15 minutes, add sodium borohydride (0.4 gram), after 1 hour, reaction makes termination with saturated ammonium chloride solution (100 milliliters) and ethyl acetate (2 * 150 milliliters) afterwards.Organic layer drying and evaporation can get title compound (2.8 gram), are the mixing (t.l.c.Rf=0.6 ethyl acetate/hexanaphthene 95/5) of two stereoisomerses.
IR(CDCl 3ν MaxCentimetre -1): 3461(N-H, OH), 2108(N 3) the interior vinegar amine of 1753() 1H-NMR(CDCl 3): 6.32(sa), 6.08(sa), 6.04(sa), 5.96(sa), 4.14(m), 4.00-3.00(m), 3.21(dd), 2.10-1.0(m), 1.32(d), 1.26(s), 0.90(s), 0.12(s).
Intermediate 40
(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-((R)-2 '-[(S)-6 '-(2-allyloxy carbonyl amine oxyethyl group)-1 '-the oxygen cyclohexyl]] azetidine-2-ketone
To the solution of intermediate 39 in anhydrous tetrahydro furan (100 milliliters), add triphenyl phosphine (1.6 gram), mixture restir 36 hours adds water (0.09 milliliter) afterwards.After 12 hours, be cooled to-50 ℃.Add N-ethylpiperidine (0.92 milliliter) and chloroformic acid allyl ester (0.8 milliliter) again.After 3 hours, mixture is with ethyl acetate dilution (100 milliliters), again with cold 5% hydrochloric acid solution washing (2 * 30 milliliters).Organic layer drying, evaporation be purifying on silica gel again, utilizes ethyl acetate/hexanaphthene 6/4 mixed solution to be eluent.The material of gained is dissolved in the methylene dichloride (30 milliliters); With 40 minutes adding pyridinium chlorochromate (2.6 gram), mixture refluxed again.After 4 hours, mixture filtration over celite filter washs with 5% cold hydrochloric acid solution (2 * 20 milliliters).The organic layer drying is chromatography on silica gel again, utilizes ethyl acetate/hexanaphthene 2/8 for eluent can get title compound, is colourless liquid (0.75 gram), t.l.c. ethyl acetate/hexanaphthene 9/1 Rf=0.4.）
IR(CDCl 3) ν Max(cm -1) 3458 and 3418(N-H), vinegar amine in the 1757(), 1718(c=0) 1603(C=C).
1H-NMR（CDCl 3）：5.92（m），5.25（m），5.10（sa），4.56（m），4.18（m），3.98（m），3.80-3.20（m），3.05（m），2.88（m），2.40-1.10（m），1.22（d），0.87（s），0.07（m），0.06（s）。
Intermediate 41
2-[(3S, 4R)-3-[(R)-1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(2 ' S, 6 ' R)-2 '-methoxyl group-1 " oxygen basic ring own-6 "-yl] azetidine-2-ketone-1-yl]-2-hydroxacetic acid benzyl ester
To intermediate 2a(0.6 gram) in the solution of dry toluene (5 milliliters), add acetaldehyde acid benzyl ester (0.83 gram) and 3A molecular sieve.The gained mixture refluxed 3 hours, and mat Dean Stark device removes and anhydrates, afterwards concentrating under reduced pressure.The residual residue of oily chromatography on silica gel utilizes cyclopropane/ethyl acetate 8/2 mixed solution to be eluent, can get title compound, is mixing (0.67 gram of two stereoisomerses; T.l.c. cyclohexane/ethyl acetate 1/1 Rf=0.61 and 0.72).
IR(CDCl 3) ν Max(centimetre -1) 3490(O-H), 1753(C=0 β-Nei vinegar amine), the 1713(C=0 ester);
1H-NMR（300 MHz，CDCl 3）：7.4-7.30（m），5.54（d），5.46（d），5.34（d），5.16（d），4.80（d），4.21（m），4.05（m），4.05-3.90（m），3.55（d），3.53（m），3.48（m），3.24（s），3.23（s），3.2-3.0（m），2.94-2.86（dd），2.15-1.40（m），1.26（d）。
Intermediate 42
2-[(3S ', 4 ' R)-3-[(R)-1 " (tertiary butyl dimethylamino silane oxygen base) ethyl]-4 '-[(2 " S, 6 " R)-2 '-methoxyl group-1 ' "-oxygen hexamethylene-6 " '-yl] azetidine-2 '-ketone-1 '-yl]-2-hydroxacetic acid ethyl ester
To (3S, 4R)-3-[(R)-1 '-(tertiary butyl dimethylamino silane oxygen base) ethyl]-4-[(2S "; 6R ")-2 '-methoxyl group-1 "-oxygen hexamethylene-6 " yl] azetidine-2-ketone (0.1 gram) is in the solution of anhydrous tetrahydro furan (5 milliliters), add glyoxylic acid ethyl ester (0.5 gram), N, N, N-triethylamine (0.02 milliliter) and 3A molecular sieve.The mixture of gained stirred 17 hours down at 22 ℃, and with ethyl acetate dilution (30 milliliters), with salt water washing (3 * 70 milliliters), drying is vacuum concentration more afterwards.Raw product is chromatography on silica gel, is eluent with diethyl ether/sherwood oil 3/7, can get title compound and be colorless oil (0.1 gram) (isomer 1/1 mixing on 2 positions; T.l.c. diethyl ether: Rf=0.36 and 0.51).
IR(CDCl 3) ν MaxCentimetre -1: 3524(OH), 1747(C=0 β-Nei vinegar amine), the 1715(C=0 ester);
Example 1
Example 1a
(4S, 8S, 9R, 10S, 12R)-and 4-methylthio group-10-(1-(tertiary butyl dimethylamino silane oxygen) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To intermediate 6a(3.85 gram) in the ice-cold solution of 200 milliliters of methylene dichloride, add salt of wormwood (3 gram).Mixture stirred 10 minutes, successively added allyl group oxalyl group chlorine (5.57 gram) and pyridine (3.48 gram) again.Reaction mixture stirred 1.5 hours down at 25 ℃, with the methylene dichloride dilution, filtered afterwards, and is dry again with the frozen water washing.Except that after desolvating, can get rough careless inferior acid amides intermediate (5.37 gram), it is handled with phosphonous acid triethyl (9.97 gram) after being dissolved in anhydrous dimethyl benzene (150 milliliters) again.The vlil of gained 6 hours, the solvent vacuum is removed, residue is chromatography on silica gel again, utilizes EE/P(3/7) mixed solution is eluent, can get title compound (1.78 gram) and be yellow oily.IR：ν max
(CDCl 3) 1772 and 1717 centimeters -1; 1H-NMR(300 MHz, CDCl 3) 6.00(m), 5.43(d), 5.26(d), 4.75(m), 4.70(m), 4.17(m), 3.41(m), 3.20(dd), 2.02(s), 1.9-1.7(m), 1.23(d), 0.88(s) and 0.080(s) ppm.
Use general step can get following compound:
Example 1b
(8R, 9R, 10S, 12R)-and 10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1c
(4S, 8S, 10S, 12R)-and 4-oxyethyl group-10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1d
(8R, 9R, 10S, 12R)-and 10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-thiazolinyl-2-carboxylic acid allyl ester
Example 1e
(4S, 8R, 9R, 10S, 12R)-and 4-methyl isophthalic acid 0-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1f
(4R, 8R, 9R, 10S, 12R)-and 4-methylthio group-10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1g
(8R, 9R, 10S, 12R)-4, and 4-dimethoxy-10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1h
(4S, 8R, 9R, 10S, 12R)-and 4-methylthio group-10-(1-(tertiary butyl dimethylamino silane oxygen) ethyl)-11-oxygen-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1i
(4S, 8R, 9R, 10S, 12R)-and 4-methoxyl group-10-(1-(tertiary butyl dimethylamino silane oxygen) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1j
(4R, 8R, 9R, 10S, 12R)-and 4-methyl isophthalic acid 0-(1-(tertiary butyl dimethylamino silane oxygen) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1k
(4S, 8S, 9R, 10S, 12R)-and 4-methyl isophthalic acid 0-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1l
(4R, 8S, 9R, 10S, 12R)-and 4-methoxyl group-10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 1m
(8S, 9R, 10S, 12R)-and 4-methoxyl group-10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2,4-diene-2-carboxylic acid allyl ester
Example 1n
(8R, 9R, 10S, 12R)-and 4-methoxyl group-10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2,4-diene-2-carboxylic acid allyl ester
The physical property of above-claimed cpd adds that the modification of reaction conditions is shown in following table.
Figure 911014705_IMG26
Figure 911014705_IMG27
Example 2
(4S, 8S, 9R, 10S, 12R)-and 4-methoxyl group-10-(1-(tertiary butyl dimethylamino silane oxygen) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Intermediate 2a(0.5 gram) is dissolved in the methylene dichloride (20 milliliters).Add Anhydrous potassium carbonate (150 milligrams), and mixture stirs at (under the nitrogen) under 23 ℃.Successively add the stirring of allyl group oxalyl chloride (0.2 milliliter) and triethylamine (0.2 milliliter) reaction mixture refiltered in 40 minutes.Filtrate is washed respectively with water (50 milliliters), 5% sodium hydrogen carbonate solution (50 milliliters) and salt solution, and is dry again.Solution decompression concentrates, and the oily residue then is dissolved in (30 milliliters) in the anhydrous dimethyl benzene.Add triethyl-phosphite (2 milliliters), mixture was 140 ℃ of following heated and stirred 3 hours.Reaction mixture cooling, concentrating under reduced pressure, residue chromatography (eluent CH/EA; 8: 2) can get title compound, be colorless oil.
IR(CDCl 3) ν Max(centimetre -1): 1772(β-Nei vinegar amine), 1717(C=O), 1634(C=C), 1H-NMR δ (CDCl 3): 6.0(m), 5.45(m), 4.98(m), 4.74(m), 4.22(m), 4.15(dd), 3.28(s), 3.22(m), 3.21(m), 2.07(m), 1.84(m), 1.66(m), 1.6-2.1(m), 1.25(d), 0.9(s), 0.88(s) ppm
Example 3
(8R, 9R, 10S, 12R)-and 4-Oxy-1 0-(1-(tertiary butyl dimethylamino silane oxygen) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
With 10% oxalic acid aqueous solution, under continuous magnetic agitation, add as for (10 grams, silica gel 60 is for tubing string chromatography usefulness, 70-230 hole sizer) in the silica gel suspension in the methylene dichloride (20 milliliters).After 2-3 minute, example 1g(4.31 gram) add, mixture stirred under room temperature 2 hours.Solid phase is filtered, and solid washs with methylene dichloride (200 milliliters).The blended dichloromethane layer washs with 1% sodium carbonate solution, can get title compound (3.15 gram) after drying and the evaporation and be yellow oily.
IR ν Max(CDCl 3) 1786,1736 and 1696 centimeters -1
1H-NMR(300 MHz, CDCl 3) δ 5.94(m), 5.43-5.27(m), 4.75(m), 4.20(m), 3.95(dd), 3.34(m), 3.24(dd), 2.6(m), 2.37(m), 2.25-2.1(m), 1.8-1.6(m), 1.25(d), 0.89(s) and 0.08(s) ppm.
Example 4
(4S, 8S, 9R, 10S, 12R)-and 4-hydroxyl-10-(1-(tertiary butyl dimethylamino silane oxygen) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 3(1 gram) in the ice-cold solution of methyl alcohol (20 milliliters) and water (10 milliliters), in 10 minutes, divide 5 parts and add sodium borohydride (180 milligrams).Adding fashionable pH value remains between 4 and 7 with rare spirit of salt (1%).Add methylene dichloride (100 milliliters) and water (100 milliliters) afterwards, tell organic layer, with washing, can get title compound (980 milligrams) after drying and the evaporation, elaioleucite is white in color.IR: ν Max(CDCl 3) 1774 and 1693 centimeters -1; 1H-NMR(300 MHz, CDCl 3) δ 6.2(s), 5.94(m), 5.45(m), 5.28(m), 4.77(m), 4.41(m), 4.17(m), 3.70(dd), 2.93(m), 2.22(m), 2.09(m), 1.42(m), 1.22(dd), 0.88(s), 0.07(s), ppm.
Example 5
Example 5a
(4S, 8S, 9R, 10S, 12R)-4-methylthio group-10-(1-(hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 1a(1.75 gram) in the ice-cold solution of anhydrous tetrahydro furan (70 milliliters), add acetic acid 92.32 grams) and tetrabutyl ammonium fluoride (3.05 gram) (11.7 milliliters) in the 1.0M of THF solution.Mixture stirred 20 hours down at 25 ℃, afterwards with diethyl ether (250 milliliters) dilution, and more respectively with 2% sodium bicarbonate aqueous solution, frozen water and salt water washing.The organic layer drying can be evaporated under vacuum can get thick oily matter, its through silica gel column chromatography with EE/P(7/3) mixed solution is that eluent can get title compound, is yellow oily (0.52 gram).
(CDCl 3) 1772 and 1720 centimeters -1; 1H-NMR(300 MHz, CDCl 3) δ 5.96(m), 5.43(dq), 5.27(dq), 4.80(m), 4.67(m), 4.21(dd), 4.20(m), 3.48(m), 3.25(dd), 2.01(s), 2.10-1.60(m), 1.50-1.30(m), and 1.32(d) ppm.
Utilize the identical following compound of general step preparation.
Example 5b
(8R, 9R, 10S, 12R)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5c
(4S, 8S, 9R, 10S, 12R)-4-oxyethyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5d
(8S, 9R, 10S, 12R)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5e
(4S, 8R, 9R, 10S, 12R)-4-methyl isophthalic acid 0-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5f
(4R, 8R, 9R, 10S, 12R)-4-methylthio group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5g
(4S, 8R, 9R, 10S, 12R)-4-hydroxyl-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5h
(4S, 8R, 9R, 10S, 12R)-4-methylthio group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5i
(4S, 8R, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5k
(4S, 8S, 9R, 10S, 12R)-4-methyl isophthalic acid 0-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 5l
(4R, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 6
(4S, 8S, 9R, 10S, 12R)-and 4-methoxyl group-10-(1-hydroxyl) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 2(80 milligram) is dissolved in anhydrous tetrahydro furan (2 milliliters), successively adds acetic acid (0.09 milliliter) and tetrabutyl bromine fluoride again in the 1M solution of tetrahydrofuran (THF) (0.45 milliliter).Be reflected at 23 ℃ and stirred 48 hours down, again with ethyl acetate (50 milliliters) dilution, successively with 5% sodium hydrogen carbonate solution (2 * 50 milliliters) and salt solution (50 milliliters) extraction.Residue after evaporating can get 20 milligrams of title compounds with flash chromatography purifying (eluent CH/EA mixed solution), is oily.
IR(CDCl 3) ν Max(centimetre -1): 3609(O-H), 1772(β-Nei vinegar amine), 1717(C=0), 1642(C=C)
1H-NMR（CDCl 3）：5.96（m），5.43（m），5.27（m），4.96（m），4.82（m），4.68（m），4.237（m），4.19（dd），3.25（s），3.28（m），3.20（m），2.08（m），1.9-1.8（m），1.65（m），1.45（m），1.32（d）ppm。
Example 7
Example 7a
(4S, 8S, 9R, 10S, 12R)-4-methylsulfinyl-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 5a(0.15 gram) in the solution of anhydrous methylene chloride (30 milliliters), under-78 ℃, in 15 minutes, dropwise be incorporated in the 3-chloroperoxybenzoic acid (0.77 gram) in the methylene dichloride (10 milliliters).Mixture stirred 1 hour down at-78 ℃, more respectively with 3% sodium sulfite aqueous solution, and ice-cold 3% sodium bicarbonate aqueous solution and water washing.Can get title compound after organic layer drying and the evaporation, be clarification oily (0.10 gram).IR: ν Max(CDCl 3) 1778,1717 and 1040 centimeters -1 1H-NMR(300 MHz, CDCl 3) δ 5.96(m), 5.35(m), 4.77(m), 4.23(m), 3.29(m), 3.10(m), 2.68-2.55(m), 2.58(s), 2.2-1.6(m), 1.5-1.4(m), and 1.30(d) ppm.
Use above-mentioned general step, but with-40 ℃ temperature of reaction.Then (4S, 8S, 9R, 10S, 12R)-4-methylsulfinyl-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester (7B), 113 milligrams can derive from example 5h(190 milligram) and 3-chloroperoxybenzoic acid (96 milligrams).
Example 8
Example 8a
(4S, 8S, 9R, 10S, 12R)-4-methylthio group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
To example 5a(500 milligram) and the solution of triphenyl phosphine (78 milligrams) in anhydrous methylene chloride (3 milliliters) and ethyl acetate (3 milliliters) mixed solution, be incorporated in 2 ethyl hexanoic acid potassium (246 milligrams) and four (triphenyl phosphine) palladium (86 milligrams) solution in the methylene dichloride (4 milliliters).Mix to stir 30 minutes, and added diethyl ether (25 milliliters) again, the gained solid filtering, with after the diethyl ether washing again drying can get title compound (400 milligrams), be yellow solid.IR：ν max
(Nujol) 1749,1701 and 1589 centimeters -1 1H-NMR(300 MHz, D 2O-acetone) s4.53(m), 4.06(m), 4.02(m), 3.24(m), 3.18(m), 1.83(s), 1.85-1.50(m), 1.4-1.2(m) and 1.10(d) ppm.
Utilize above-mentioned general step, can prepare following compound, its special details are shown in the table.
Example 8b
(8R, 9R, 10S, 12R)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8c
(4S, 8S, 9R, 10S, 12R)-4-oxyethyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8d
(8S, 9R, 10S, 12R)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8e
(4S, 8R, 9R, 10S, 12R)-4-methyl isophthalic acid 0-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8f
(4R, 8R, 9R, 10S, 12R)-4-methylthio group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8g
(4S, 8R, 9R, 10S, 12R)-4-hydroxyl-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8h
(4S, 8R, 9R, 10S, 12R)-4-methylthio group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8i
(4S, 8R, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8j
(4R, 8R, 9R, 10S, 12R)-4-methyl isophthalic acid 0-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8k
(4S, 8S, 9R, 10S, 12R)-4-methyl isophthalic acid 0-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8l
(4R, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 8m
(4S, 8R, 9R, 10S, 12R)-4-methylsulfinyl-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Figure 911014705_IMG29
Example 9
(4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
With example 6(17 milligram) be dissolved in (2 milliliters) in the anhydrous tetrahydro furan, this is added the 0.5 volumetric molar concentration solution that forms in ethyl acetate (0.1 milliliter) by 2 ethyl hexanoic acid potassium again, reach four (triphenyl phosphine) palladium (5 milligrams) and triphenyl phosphine (3 milligrams) in tetrahydrofuran (THF) (1.5 milliliters) solution.Be reflected at 23 ℃ and stirred 20 fens down, again with 1/1 ether and the dilution of sherwood oil mixed solution.The solid filtering of gained with the washing of ethyl acetate/petroleum ether mixed solution, can get title compound (5 milligrams) after drying, and solid is white in color.
IR(CDCl 3) ν Max(centimetre -1): 1751(β-Nei vinegar amine), 1589(C=O)
1H-NMR δ（CDCl 3）4.76（m），4.70（m），4.03（m），3.26（dd），3.08（s），2.99（m），1.84（m），1.71（m），1.53（m），1.41（m），1.2（m），1.11（d）ppm。
Example 10
(4S, 8S, 9R, 10S, 12R)-4-methylsulfinyl-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
To example 7a(160 milligram) and the solution of triphenyl phosphine (9 milligrams) in 4 milliliter of 1/1 anhydrous methylene chloride and ethyl acetate mixed solution, be incorporated in 2 ethyl hexanoic acid potassium (80 milligrams) and four (triphenyl phosphine) palladium (20 milligrams).Mixture stirred 45 fens, added anhydrous diethyl ether (5 milliliters) again.The gained solid filtering can get title compound (25 milligrams) after diethyl ether washing and the drying, is yellow solid.
IR: ν Max(Nujol) 1751 centimeters -1: 1H-NMR δ (D 2O-acetone): 4.6(m), 4.07(m), 4.04(dd), 3.34(dd), 2.93(m), 2.50(s), 2.22-1.6(m), 1.27(m), and 1.09(d) ppm.
Example 11
(4S, 8S, 9R, 10S, 12R)-and 4-trimethyl silane Oxy-1 0-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To intermediate 11(2.7 gram) compound is in the ice-cold solution of methylene dichloride (50 milliliters), adds salt of wormwood (1.8 gram).Mixture stirred 10 minutes, added diethylamine (2.7 milliliters) again.In 15 minutes, dropwise add the allyl group oxalyl chloride that is dissolved in the methylene dichloride (5 milliliters), reaction mixture stirs and refiltered in 1 hour, to wash back (3 * 200 milliliters) and dry, can get rough careless inferior acid amides intermediate except that after desolvating, it is dissolved in the anhydrous dimethyl benzene (50 milliliters) and with triethyl-phosphite (6.7 milliliters) again handles.The solution reflux of gained 3.5 hours, solvent is removed under vacuum, and residue uses sherwood oil and diethyl ether (8/2) mixed solution to be eluent in the silica gel top plate, can get title compound (1.6 gram) and be yellow oil.
IR(CDCl 3) ν Max(centimetre -1): 1771 -(C=O), 1751(COO) -, 1634(C=C)
1H-NMR a（CDCl 3）：5.96（m），5.44（m），5.25（m），4.72（m），4.18（m），4.08（dd），3.28（m），3.145（dd），2.0-1.75（m），1.6（m），1.41（m），1.32（m），1.23（d），0.8（s），0.09-0.06（s），ppm。
Example 12
(4S, 8S, 9R, 10S, 12R)-and 4-hydroxyl-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
With example thing 11(1.4 gram) be dissolved in the tetrahydrofuran (THF) (20 milliliters), mixture stirs down in 0 ℃ again.Add acetic acid (0.5 milliliter), add the 1.1M solution of tetrabutyl ammonium fluoride again in tetrahydrofuran (THF) (2.8 milliliters).React on 0 ℃ and stirred 45 minutes down, add more acetic acid (0.5 milliliter) and tetrabutyl ammonium fluoride again in tetrafluoro furans (1 milliliter).Reaction was stirred 45 minutes, poured the mixing in the liquid of ice-cold diethyl ether (150 milliliters) and 2.5% sodium bicarbonate aqueous solution (100 milliliters) again into.Organic layer can get title compound (1.1 gram) with water (2 * 200 milliliters), salt water washing after drying and evaporation and be the clarification oily.
IR(CDCl 3) ν Max(centimetre -1): 1772(C=O), 1717(COO), 1634(C=C) 1H-NMR a (CDCl 3): 5.94(m), 5.48(m), 5.43(m), 5.25(m), 4.73(m), 4.20(m), 4.14(dd), 3.36(m), 3.19(dd), 2.3(m), 2.1-1.8(m), 1.65(m), 1.51(m), 1.4(m), 1.23(d), 0.88(s), 0.07(s), ppm.
Example 13
(4S, 8S, 9R, 10S, 12R)-and 4-methoxyl group-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Under nitrogen, example 12 compounds (1 gram) are dissolved in (100 milliliters) in the diethyl ether, and are cooled to-78 ℃.Add trifluoromethayl sulfonic acid methyl esters (0.54 milliliter), add two (TMS) acid amides potassium (7.8 milliliters) (the 0.5M solution in toluene) again and tie up to dropwise adding in 2 hours, add trifluoromethayl sulfonic acid methyl esters (0.3 milliliter) and several two (TMS) acid amides potassium (4 milliliters, 0.5M is in toluene) finally again.After 1 hour, reaction mixture is poured saturated ammonium chloride solution (300 milliliters) into and is separated.Organic layer is respectively with cold spirit of salt (2 * 200 milliliters), water and salt water washing, dry revaporization.Oily residue chromatography on silica gel, utilizing sherwood oil and diethyl ether (7/3) mixed solution is eluent, can get title compound (370 milligrams) and be colorless oil (Rf=0.45).
IR(CDCl 3) ν Max(centimetre -1): 1772(C=O), 1717(COO), 1634(C=C) 1H-NMR(CDCl 3): 6.0(m), 5.45(m), 4.98(m), 4.74(m), 4.22(m), 4.15(dd), 3.28(s), 3.22(m), 3.21(m), 2.07(m), 1.84(m), 1.66(m), 1.6-1.2(m), 1.22(d), 0.9(s), 0.8(s), ppm.
Example 14
(4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 13(370 milligram) compound is dissolved in (12 milliliters) in the anhydrous tetrahydro furan, adds acetic acid (0.5 milliliter) again, and tetrabutyl bromine fluoride is in the 1.1M solution of tetrahydrofuran (THF) (2.85 milliliters).Reaction was at room temperature stirred 30 hours, afterwards with ethyl acetate dilution (200 milliliters), wash respectively with 5% sodium hydrogen carbonate solution (2 * 200 milliliters) and salt solution, can get yellow oil after drying and the evaporation, it is that eluent (Rf=0.4) can get title compound (180 milligrams) oily is white in color with chromatography purification and with the diethyl ether.
IR(CDCl 3) ν Max(centimetre -1): 3609(OH), 1772(C=O), 1717(COO), 1642(C=C), 1H-NMR s(CDCl 3): 5.96(m), 5.43(m), 5.27(m), 4.96(m), 4.82(m), 4.68(m), 4.237(dd), 4.19(dd), 3.25(s), 3.28(m), 3.20(m), 2.08(m), 1.9-1.8(m), 1.65(m), 1.45(m), 1.32(d) ppm.
Example 15
(4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
To example 14(420 milligram) and diphenyl phosphine (15 milligrams) add four (triphenyl phosphine) palladium (30 milligrams) fast in the solution of tetrahydrofuran (THF) (2 milliliters) in the solution of anhydrous tetrahydro furan, and 0.5M2-thylhexoic acid potassium (3 milliliters) solution.Reaction mixture stirred 30 fens, the white solid of centrifugal gained again, with diethyl ether and tetrahydrofuran (THF) (8/2) mixed solution (3 * 10 milliliters) and diethyl ether (2 * 10 milliliters) washing, again vacuum-drying with title compound (400 milligrams).
IR(Nujol) ν Max(centimetre -1): 3609(OH), 1772(C=O), 1717(COO), 1642(C=C), 1H-NMR s(D 2O-acetone): 4.6(m), 4.07(m), 4.04(dd), 3.34(dd), 2.39(m), 2.50(s), 2.22-1.6(m), 1.27(m), 1.09(d), ppm.
Example 16
(4S, 8S, 9R, 10S, 12R)-and 4-allyloxycarbonyl amido-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To intermediate 17(2 gram) in the ice-cold solution of anhydrous methylene chloride (100 milliliters), add solid carbonic acid potassium (0.680 gram).Mixture stirred 30 fens, successively added allyl group oxalyl chloride (0.88 gram) and triethylamine (0.59 gram) again.Reaction mixture at room temperature stirred 1 hour, added allyl group oxalyl chloride (0.88 gram) and triethylamine (0.59 gram) again.After 15 minutes, reaction mixture dilutes with methylene dichloride, filter, and more respectively with 5% hydrochloric acid solution, 5% sodium hydrogen carbonate solution and salt water washing.Can get rough careless inferior acid amides intermediate except that after desolvating, it is handled with triethyl-phosphite (7.4 milliliters) after being dissolved in anhydrous dimethyl benzene (130 milliliters) again.The solution reflux of gained 2 hours half, solvent is removed under vacuum, and residue is chromatography on silica gel, and is that eluent can get title compound with diethyl ether/sherwood oil (9/1), is yellow oily (1.7 gram);
IR ν Max(CDCl 3) 3425,1769,1742,1649 centimeters -1;
H 1-NMR（300 MHz，CDCl 3）6.05-5.8（m），5.45（t），5.5-5.18（m），4.96（d），4.78（m），4.55（m），4.19（m），4.12（dd），3.16（dd），3.06（m），1.97（m），1.9-1.5（m），1.4-1.2（m），1.23（d），0.88（s），0.07（s）。
Example 17
(4S, 8S, 9R, 10S, 12R)-4-allyloxycarbonyl amido-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 16(0.98 gram) in the ice-cold solution of tetrahydrofuran (THF) (60 milliliters), add acetic acid (0.93 gram) and solid 4-butyl ammonium fluoride trihydrate (1.83 gram).Mixture at room temperature stirred 30 hours, poured in the water to extract with ethyl acetate (3 * 180 milliliters) again.Organic layer is with 5% sodium hydrogen carbonate solution and salt water washing, drying and reduction vaporization again.Residue is chromatography on silica gel, is that eluent can get title compound with methylene chloride (9/1) mixed solution, the spumescence that is white in color (0.4 gram).IR: ν Max(CDCl 3) 3447,1772,1718 centimeters -1; 1H-NMR(300 MHz, CDCl 3) 6.05-5.8(m), 5.45-5.39(bt), 5.4-5.5(m), 4.94(m), 4.9-4.6(m), 4.54(m), 4.21(m), 4.16(dd), 3.19(dd), 3.12(m), 2.05-1.5(m), 1.4(m), 1.31(d).
Example 18
(4S, 8S, 9R, 10S, 12R)-4-amido-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid
Example 17(0.4 gram) and acetic acid (0.24 gram) in the solution of anhydrous tetrahydro furan (10 milliliters), under nitrogen, stirred 15 fens.Add four (triphenyl phosphine) palladium (0.650 gram) that is dissolved in the anhydrous tetrahydro furan (25 milliliters) again, mixture stirred 1 hour.The elimination of gained solid with diethyl ether washing after drying, can get title compound, is pale yellow solid (0.230 gram).
IR: ν Max(Nyjol) 3364-2669,1767,1872 centimeters -1; 1H-NMR(300 MHz, D 2O-acetone) 5.0(m), 4.12-4.0(m), 3.32(m), 3.09(m), 2.0-1.5(m), 1.25(m), 1.12(d).
Example 19
(4S, 8S, 9R, 10S, 12R)-4-(allyloxycarbonyl amine methyl)-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Intermediate 20(0.48 gram) is dissolved in (20 milliliters) in the anhydrous methylene chloride under the room temperature, successively adds salt of wormwood (1 gram), allyl group oxalyl chloride (0.18 milliliter) and triethylamine (0.18 gram) again.5 hours after-filtration mixtures are released with methylene dichloride (80 milliliters) alkene, again with 5% sodium hydrogen carbonate solution and salt solution (30 milliliters) washing.The organic layer drying is reduction vaporization again.Residue is dissolved in (100 milliliters) in the anhydrous dimethyl benzene, adds triethyl-phosphite (0.8 milliliter) and quinhydrones (0.05 gram), and mixture then refluxed 3.5 hours.Can get oily matter after the solvent removed under reduced pressure, its again on silica gel flash chromatography purifying (eluent ether and hexanaphthene 80/20 Rf=0.7) can get title compound (0.30 gram) and be yellow oily.
The IR(centimetre -1): 3450(NH), 1769(*CO), 1744(CO), 1715(CO);
NMR（ppm）5.92（m），5.5-5.1（m），4.9（m），4.8-4.5（m），4.18（m），4.11（dd），3.72（m），3.55-3.0（m），2.0-1.2（m），1.36（t），1.19（d），0.86（s），0.05（s）。
Example 20
(4S, 8S, 9R, 10S, 12R)-4-(allyloxycarbonyl amine methyl)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 19(0.30 gram) is dissolved in the anhydrous tetrahydro furan, adds acetic acid (0.3 milliliter) and tetrabutyl ammonium fluoride (2.5 milliliters in the solution of THF), mixture restir 30 hours.Mixture is washed secondary with salt solution (100 milliliters) and 5% sodium bicarbonate aqueous solution again with ethyl acetate dilution (150 milliliters).Can get residue behind organic layer drying and the reduction vaporization, it can get title compound (0.06 gram) with flash chromatography on silica gel purifying (eluent hexanaphthene and ethyl acetate 50/50 Rf=0.1) again, is colorless oil.
IR(ν MaxCentimetre -1): 3650(OH), 3447(NH), 1771(CO), 1717(CO), 1620(C=C); NMR(CDCl 3Ppm); 6.0-5.8(m), 5.5-5.1(m), 4.93(bm), 4.8-4.6(m), 4.48(m), 4.3-4.1(m), 3.73(m), 3.58(m), 3.3-3.1(m), 1.75-1.2(m), 1.27(d).
Example 21
(4S, 8S, 9R, 10S, 12R)-4-(amine methyl)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid
Example 20(0.06 gram) is dissolved in anhydrous tetrahydro furan (1 milliliter), adds acetic acid (0.036 milliliter) and four (triphenyl phosphine) palladium (0.09 gram) again.Mixture stirred 1 hour, again with ether (8 milliliters) and the dilution of sherwood oil (4 milliliters) mixed solution.The solid of gained is washed secondary with ether (8 milliliters) and sherwood oil (4 milliliters) mixed solution.Solid (5 milliliters) soluble in water is a water in silica gel C-18(eluent again) go up reverse-phase chromatography, and solution can get title compound (0.04 gram) and is white solid after lyophilize.
IR(Nujol, centimetre -1): 3300-2650(NH 3+, OH, NH 2), 1751(CO), 1582(C=C, CO), NMR(D 2O, ppm): 7.62(m), 4.78(m), 4.07(m), 4.00(dd), 3.9-3.65(m), 3.24(m), 3.3-2.9(m), 2.1-1.95(m), 1.8-1.4(m), 1.3-1.0(m), 1.11(d), 1.02(d), UV(ν MaxNm): 268.5
Example 22
(a) (4S, 8S, 9R, 10S, 12R)-and 4-sec.-propyl-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To intermediate 23a(1.13 gram) in the ice-cold solution of anhydrous methylene chloride (150 milliliters), add solid K 2CO 3Mixture stirred 30 fens under nitrogen, under 25 ℃ in 40 hours mark criticize and add allyl group oxalyl chloride (4.43 milliliters) and triethylamine (5 milliliters), transform fully up to initiator.Organic layer after filtering, with salt water washing, drying reduction vaporization again.Oily residue (1.05 gram) is equivalent to rough careless inferior acid amides intermediate, is dissolved in that (40 milliliters) add triethyl-phosphite (1.445 milliliters) again in the anhydrous dimethyl benzene, and mixture was in 140 ℃ of following reflux 3 hours.Reaction mixture cooling again, reduction vaporization and chromatography are eluent with 1/1 mixture liquid of cyclohexane/ethyl acetate.Can get title compound and be yellow oily (0.33 gram; T.l.c. cyclohexane/ethyl acetate 1/1 Rf 0.68); IR(CDCl 3) ν Max(cm -1): 1772(C=O β-Nei vinegar amine), the 1717(C=0 allyl ester), H 1-NMR(CDCl 3): 6(m), 5.43(m), 5.26(m), 5.18(m), 4.86-4.6(m), 4.21(m), 4.125(dd), 3.55(m), 3.18(dd), 3.20(m), 2.05-1.5(m), 1.5-1.2(m), 1.23(d), 1.14(dd), 0.88(s), 0.08(s), ppm.
(b) in a similar manner
(4S, 8S, 9R, 10S, 12R)-and 4-isopropoxy-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester (0.2 gram; T.l.c. Ring hexane/ethyl acetate 7/3 Rf 0.67); IR(CDCl 3) ν Max(centimetre -1): 1765(C=O β-Nei vinegar amine), the 1744(C=0 allyl ester), 1612(C=C), 1H-NMR(CDCl 3): 5.94(m), 5.33(m), 4.73(m), 4.17(dd), 3.67(m), 3.23(dd), 2.78(m), 2.4-1.2(m), 1.22(d), 1.10(m), 0.88(s), 0.018(s), ppm can derive from intermediate 23b(1.64 gram) 7/3 cyclohexane/ethyl acetate mixed solution except chromatography is molten from thing.
Example 23
(a) (4S, 8S, 9R, 10S, 12R)-4-isopropoxy-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
With example 22a(0.330 gram) be dissolved in tetrahydrofuran (THF) (30 milliliters) and add ester acid (0.325 milliliter) and 4-butyl ammonium fluoride trihydrate (0.674 gram) more respectively.Mixture stirred 20 hours down at 20 ℃, again with ethyl acetate (50 milliliters) dilution, and with 2% sodium hydrogen carbonate solution and salt solution (50 milliliters) washing.After evaporation, residue utilizes cyclohexane/ethyl acetate 1/1 mixed solution to be eluent with the flash chromatography purifying, can get title compound, is oily (0.12 gram; T.l.c. cyclohexane/ethyl acetate 1/1 Rf 0.15); IR ν MaxCentimetre -1, 3614(OH); 1772(C=O β-Nei vinegar amine), the 1717(C=0 ester), 1632(C=O); H 1-NMR(CDCl 3) (CDCl 3): 5.96(m), 5.45(m), 5.27(m), 5.18(m), 4.82(m), 4.69(m), 4.25(m), 4.18(dd), 3.53(m), 3.3(m), 3.23(dd), 2.0(m), 1.88(m), 1.77(m), 1.7-1.2(m), 1.33(d), 1.13(dd), ppm.
(b) (4S, 8S, 9R, 10S, 12R)-4-isopropoxy-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Example 23b(0.03 gram) is dissolved in anhydrous methylene chloride (10 milliliters), successively adds triphenyl phosphine (0.0022 gram) again, four (triphenyl phosphine) palladium (0.0033 gram) and 2-ethyl acid potassium 0.005M solution (0.16 milliliter).Reaction mixture stirred 2 hours under nitrogen, and solvent evaporation afterwards is to reduce volume, and the gained mixed solution with ether dilution (5 milliliters) gained solid filtering, with ether/petroleum ether, can get title compound more after drying, the solid that is white in color (0.22 gram); IR(CDCl 3) ν Max(centimetre -1): 1751(C=O β-Nei vinegar amine), 1959(C=0, C=C), H 1-NMR D 2O; 4.02(m), 4.1-4(m), 3.6(q), 3.44(dd), 2.07(m), 2.05(m), 1.79(m), 1.6(m), 1.1(d), 0.9(s), 1.4(m), ppm.
Example 25
(4S, 8S, 9R, 10S, 12R)-and 4-cyclopentyloxy-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
In intermediate 25(1.2 gram) be dissolved in the ice-cold solution of anhydrous methylene chloride (60 milliliters), add solid K 2CO 3(300 milligrams) and 4A molecular sieve.To this stirred solution, add allyl group oxalyl chloride (0.48 milligram) and triethylamine (0.33 milliliter), gained solution is in nitrogen-20 ℃ following the stirring 3 hours.The solid elimination, solution is with 10%NaHCO 3Solution, salt water washing, put on the sodium sulfate drying reduction vaporization again.The inferior acid amides intermediate of rough grass is dissolved in (50 milliliters) in the anhydrous dimethyl benzene, adds triethyl-phosphite (4.6 milliliters) again.Gained solution is 80 ℃ of following stirring heating 1 hour, afterwards in 140 ℃ 3 hours.Reaction mixture cooling and reduction vaporization.Residue chromatography and be eluent with the hexanaphthene on silica gel can get title compound and be yellow oily.(0.75 gram t.l.c., cyclohexane/ethyl acetate 1/1 Rf=0.6).IR(CDCl 3) ν Max(centimetre -1): vinegar amine in the 1771(C=O β), 1738(C=O), 1601(C=C), H 1-NMR(CDCl 3): 5.38(m), 5.23(m), 4.70(m), 4.11(m),
Example 26
(4S, 8S, 9R, 10S, 12R)-4-cyclopentyloxy-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 25 in anhydrous THF(40 milliliter) stirred solution in, add acetic acid (0.75 milligram) and 4-butyl ammonium fluoride trihydrate (1.80 gram), mixture stirred 24 hours down at 20 ℃.Pour into again in the water and with ethyl acetate extraction; Organic layer is with 10%NaHCO 3Solution washing is washed rearmounted MgSO with salt again 4Last dry and reduction vaporization.Residue utilizes cyclohexane/ethyl acetate 8/2 mixed solution to be eluent with the flash chromatography purifying, can get title compound 4b, is oily.(0.19 gram t.l.c. cyclohexane/ethyl acetate, 3/7 Rf=0.3) IR
(CDCl 3) ν Max(centimetre -1): 3600(OH) vinegar amine in the M 1771(C=0 β), 1738(C=O), 1603(C=C),
H 1-NMR（CDCl 3）：5.95（m），5.39（m），5.26（m），4.71（m），4.16（m），4.09（m），4.00（m），3.79（dd），3.18（dd），2.90（m），1.90（m），1.8-1.2（m），1.31（d）。
Example 27
(4S, 8S, 9R, 10S, 12R)-4-cyclopentyloxy-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
To example 26(0.17 gram) in the stirred solution of anhydrous ethyl acetate (9 milliliters) and anhydrous methylene chloride (9 milliliters), add the thylhexoic acid potassium solution (0.85 milliliter) of triphenyl phosphine (18 milligrams), four (triphenyl phosphine) palladium (23.6 milligrams) and 0.5M.Mixture stirred 4 hours down for 120 ℃ at nitrogen.Add diethyl ether/petroleum ether solution (15 milliliters) of 1/1 again, the elimination of gained solid with 1/1 diethyl ether/sherwood oil (3 * 15 milliliters) washing, can get title compound (0.10 gram again after the drying; T.l.c., methylene dichloride/acetic acid 9/1 Rf=0.2).IR(Nujol), ν Max(centimetre -1): 1072-1680(C=O); 1640,
1585（C＝C）
H 1-NMR（D 2O）：4.05（m），3.89（m），3.26（dd），3.22（dd），2.83（m），1.9-1.0（m），1.1（d）。
Example 28
(4S, 8S, 9R, 10S, 12R)-4-(tertiary butyl dimethylamino silane oxygen ylmethyl)-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Intermediate 27(5.2 gram) is dissolved in the anhydrous methylene chloride (100 milliliters), adds Anhydrous potassium carbonate (1 gram) again.Under room temperature, with allyl group oxalyl chloride (1.9 milliliters), and triethylamine (1.9 milliliters) adds in the stirred solution gained mixture stirring 2.5 hours.Filter, wash secondary with saturated sodium bicarbonate aqueous solution (80 milliliters) again.The organic layer drying, the oily residue evaporation of gained is with flash chromatography partial purification (eluent cyclohexane/ethyl acetate 98/2 Rf=0.7) in the polarity impurity.Eluent evaporation is shifted out, and residue is dissolved in the anhydrous dimethyl benzene (150 milliliters) again and adds diethyl phosphite (8.3 milliliters).Solution reflux 4 hours, solvent shift out under decompression again.Oily residue chromatography on silica, (eluent cyclohexane/ethyl acetate 98/2 Rf=0.7) can get title compound (1.8 gram) and be yellow oily.
IR: ν Max(centimetre -1) 1769,1715 and 1647;
NMR：（d ppm）5.96（m），5.33（m），4.72（m），4.18（m），4.18（m），4.07（dd），3.75（m），3.16（dd），3.0（m），1.95（m），1.9-1.7（m），1.3（m），1.23（m），0.87（s），0.07（s），0.03（s）。
Example 29
(4S, 8S, 9R, 10S, 12R)-the 4-(methylol)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 28(90 milligram) be dissolved in anhydrous THF(15 milliliter) stirred solution, add (0.82 milliliter of acetic acid (0.1 milliliter) and tetrabutyl ammonium fluoride, in the 1M of THF solution), the gained mixture stirred 30 hours, again with ethyl acetate (100 milliliters) dilution, and respectively with 2% sodium bicarbonate aqueous solution, frozen water and salt water washing.Organic layer drying reduction vaporization again can get oily matter, and its chromatography (eluent cyclohexane/ethyl acetate 50/50 Rf=0) on silica gel can get title compound, is colorless oil (25 milligrams).
IR: ν Max(centimetre -1): 3605,3497,1771,1713 and 1620; NMR:(d ppm), 5.98(m), 5.35(m), 4.74(m), 4.23-4.18(m+dd), 3.78(m), 3.24(dd), 3.08(dd), 2.1-1.2(m), 1.31(d).
Example 30
(4S, 8S, 9R, 10S, 12R)-the 4-(methylol)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
Example 29(25 milliliter) be dissolved in anhydrous THF(1.5 milliliter) in, add four (triphenyl phosphine) palladium (10 milligrams), triphenyl phosphine (10 milligrams) and 2-ethyl acetic acid potassium (0.14 milliliter in ethyl acetate 0.5M solution) more respectively, be dissolved in 0.5 milliliter of anhydrous THF, mixture stirred 1 hour, again with anhydrous diethyl ether (15 milliliters) and sherwood oil (10 milliliters) dilution.Solid is washed secondary with anhydrous diethyl ether (15 milliliters) and sherwood oil (10 milliliters).Solid (0.2 milliliter) soluble in water again, and in the last reverse-phase chromatography (eluent is a water) of silica gel C-18, solution can get title compound (10 milligrams) after lyophilize solid is white in color.
IR(Nujol, centimetre -1) 1751 and 1583;
NMR（d ppm D 2O）4.06（m），3.57（m），3.178（dd），3.51（m），2.92（m），1.50（m）。
Example 31
(4S, 8S, 9R, 10S, 12R)-and 4-thiophenyl-10-[1-(tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To intermediate 29a(0.75 gram) in the solution of anhydrous methylene chloride (25 milliliters), add Anhydrous potassium carbonate (0.24 gram), mixture stirred 15 fens down at 23 ℃.Mixture adds triethylamine (0.36 milliliter) again 0 ℃ of cooling down, with syringe adding allyl group oxalyl chloride (0.385 gram).Be reflected at 23 ℃ and stirred 0.5 hour down, the solid elimination is with washed with dichloromethane (20 milliliters).Solvent evaporation, and the mixture of gained added ether (40 milliliters) and salt solution (20 milliliters).Extract two layers and separation, organic phase extracts with salt solution (20 milliliters), 5% sodium bicarbonate (6 * 20 milliliters), water (20 milliliters), cold 1% hydrochloric acid solution (3 * 20 milliliters) and water (20 milliliters) respectively.Get organic layer, can get yellow oil (0.85 gram) after evaporation, gained solution under agitation heated 16 hours.Reactive evaporation, oily residue are accepted flash chromatography (CH/EA 8/2).The wax shape is white in color can to get title compound (0.29 gram, 32.6%(Rf=0.7 CH/EA7/3).
The IR(centimetre -1) 1774(β-Nei vinegar amine); The 1717(carboxyl); 1651(Twin key); 1626(Twin key); 1583(Twin key).
1H-NMR（ppm）7.37（m），7.20（m），5.81（m），5.25（m），5.17（m），4.54（m），4.13（m），4.06（dd），3.39（m），3.14（dd），2.04（m），2.0-1.8（m），1.8-1.65（m），1.37（m），1.19（d），0.85（s）。
Example 32
(4S, 8S, 9R, 10S, 12R)-4-thiophenyl-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 31(0.13 gram) in the stirred solution of anhydrous THF, under nitrogen, add acetic acid (0.116 milliliter) with syringe earlier, be added on the THF(6 milliliter again) in tetrabutyl ammonium fluoride dihydrate (0.239 gram) solution.The gained mixture stirred 20 hours, again with salt solution (10 milliliters) dilution, with ethyl acetate extraction 3 times (30 milliliters).Organic layer washs respectively with 5% sodium hydrogen carbonate solution (30 milliliters) and salt solution (30 milliliters).Residue after evaporating can get the 5(0.08 gram with flash chromatography purifying (CH/EA gradient molten from from 7/3 to 1/1)) be earlier molten from the person of going out, title compound (0.03 gram, 3%) is molten again from going out afterwards, is colorless oil (Rf=0.3, CH/EA 1/1).
The IR(centimetre -1) the 3612(hydroxyl); 1772(β-Nei vinegar amine); The 1717(carboxyl); 1649(Twin key); 1626(Twin key); 1583(Twin key).
1H-NMR（ppm）7.38（m），7.26（m），5.83（m），5.22（m），4.58（m），4.20（m），4.15（dd），3.51（m），3.22（dd），2.2-1.5（m），1.4（m），1.3（d）。
Example 33
(4S, 8S, 9R, 10S, 12R)-and 4-(1-thiophenyl-10-((1-hydroxyl) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
To example 32(30 milligram) methylene dichloride and ethyl acetate (2 milliliters) mixed solution in 1/1, under nitrogen, be incorporated in triphenyl phosphine solution (2 milligrams) in the methylene dichloride (0.5 milliliter), again add four (triphenyl phosphine) palladium in methylene dichloride (0.5 milliliter) and 2 ethyl hexanoic acid potassium in the 0.5M solution of ethyl acetate (0.125 milliliter).Solution stirring 1 hour.Tell the precipitation that is formed after centrifugal, give a baby a bath on the third day after its birth time, can get the title compound solid (6 milligrams, 20%) that is white in color with diethyl ether.
IR(Nujol, centimetre -1) 3344(Hydroxyalkyl yl); 1765(β-Nei vinegar amine); 1645(Twin key); 1591(Twin key).
1H-NMR（D 2O ppm）7.20（m），5.17（bs），4.01（m），3.87（dd），3.18（m+dd），1.9-1.5（m），1.25（m），1.08（d）。
Example 34
(4S, 8S, 9R, 10S, 12R)-4-(N-allyloxycarbonyl-N-methylamino)-10-[1-tertiary butyl dimethylamino silane oxygen base) ethyl]-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
Intermediate 35 is in the solution of anhydrous dimethyl benzene (120 milliliters), in the presence of the 4A molecular sieve, stirs 1 hour under nitrogen and 22 ℃, adds triethyl-phosphite (25 milliliters) again, solution reflux 7 hours, and solvent is removed under vacuum afterwards.Residue is in the silica gel top plate, and utilizing diethyl ether/sherwood oil (7/3) is eluent, can get title compound, is yellow oily (3 grams, t.l.c. diethyl ether Rf=0.76); IR: ν Max(CDCl 3) 1767,1744,1693,1649 centimeters -1; 1H-NMR(300 MHz, CDCl 3)
5.96（m），5.5-5.1（m），5.36（m），4.8-4.5（m），4.21（m），4.16（dd），3.20（m），3.0（s），2.25-2.1（m），1.92-1.8（m），1.75-1.4（m），1.38（t），1.23（d），0.88（s），0.078（s）。
Example 35
(4S, 8S, 9R, 10S, 12R)-4-(N-allyloxycarbonyl-N-methylamino)-10-(1 '-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 34(3.0 gram) in the solution of anhydrous tetrahydro furan (50 milliliters), add acetic acid (2.6 milliliters) and the 4-butyl ammonium fluoride trihydrate solution in anhydrous tetrahydro furan (30 milliliters) (5.5 gram).Mixture stirred 15 hours down at 22 ℃, poured in the water again, extracted with ethyl acetate (2 * 80 milliliters).Organic layer is respectively with the washing of 5% sodium hydrogen carbonate solution (2 * 80 milliliters) and salt solution (100 milliliters), drying reduction vaporization again on anhydrous sodium sulphate.Residue is chromatography on silica gel, and utilizing methylene chloride (9/1) mixed solution is eluent, can get title compound, is colorless oil (0.77 gram); IR: ν Max
(CDCl 3) 3612,1776,1720,1713,1700 centimeters -1; 1H-NMR(300MHz, CDCl 3) 5.94(m), 5.5-5.15(m), 5.35(t), 4.73(m), 4.56(m), 4.23(m), 4.21(dd), 3.24(dd), 3.23(m), 2.99(s), 2.20(m), 1.91(m), 1.8-1.5(m), 1.4(m), 1.32(d).
Example 36
(4S, 8S, 9R, 10S, 12R)-4-methylamino-10-(1-hydroxyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid
To example 35(1.2 gram) in the solution of anhydrous tetrahydro furan (50 milliliters), under 22 ℃ nitrogen, add methone (1.67 gram).Solution stirring 15 minutes dropwise was incorporated in four (triphenyl phosphine) palladium (1.7 gram) solution in the anhydrous tetrahydro furan (70 milliliters) again in 10 minutes.Mixture also stirred 1 hour.In 5 minutes, dropwise add diethyl ether (200 milliliters), leach the gained solid, with diethyl ether washing back (3 * 15 milliliters) drying with alr mode.Solid (19 milliliters) soluble in water afterwards, after ethyl acetate (5 * 15 milliliters) and frozen water washing, drying can get title compound, is light yellow solid (0.6 gram); IR: ν Max
(Nujol) 3370-1700,1767,1597, centimetre -1: 1H-NMR(300MHz, D 2O-acetone) 4.81(m), 4.15-4.02(m), 3.36(dd), 3.03(m), 2.47(s), 2.01-1.9(m), 1.33(m), 1.10(d).
Example 37
(4S, 8S, 9R, 10S, 12R)-4-(2-allyloxycarbonyl amido oxyethyl group)-10-[1-(tertiary butyl dimethylamino silane oxygen base)-ethyl-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To the solution of intermediate 40, under room temperature, add potash solid (0.5 gram), allyl group oxalyl chloride (0.4 milliliter), and triethylamine (0.4 milliliter) in anhydrous methylene chloride (40 milliliters).After 3 hours, mixture is with methylene dichloride dilution (100 milliliters).Filter again with cold 5% sodium hydrogen carbonate solution washing (2 * 40 milliliters).Dry and the evaporation of organic layer.Residue is dissolved in (100 milliliters) adding quinhydrones (0.02 gram) and triethyl-phosphite (1.6 milliliters) in the anhydrous dimethyl benzene, and mixture removes under vacuum after 110 ℃ are heated 3 hours down and desolvates.Residue is chromatography on silica gel, is that eluent can get title compound (0.52 gram, t.l.c. with the mixed solution of ethyl acetate/hexanaphthene 3/7; Ethyl acetate/hexanaphthene 1/1, Rf=0.8).
IR(CDCl 3) ν MaxCentimetre -1) 3454(N-H), 1774(β-Nei vinegar amine), 1718(C=O), 1651(C=O), 1H-NMR(CDCl 3): 6.20-5.85(2m), 5.48-5.19(2m), 5.085(m), 5.04(bs), 4.82-4.64(m), 4.58(d), 4.216(m), 4.15(dd), 3.50-3.30(m), 3.195(dd), 3.15(m), 3.05(m), 1.88-1.55(m), 1.52-1.20(m), 1.22(d), 0.0887(s), 0.082(s), 0.077(s).
Example 38
(4S, 8S, 9R, 10S, 12R)-4-(2-allyloxycarbonyl amido oxyethyl group)-the 10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid allyl ester
To example 37(0.52 gram) in the solution of anhydrous tetrahydro furan (50 milliliters), add acetic acid (0.4 milliliter) and the tetrabutyl ammonium fluoride (5.5 milliliters) in anhydrous tetrahydro furan.Mixture at room temperature stirred 36 hours, dilute with ethyl acetate (100 milliliters), again with saturated hydrogenation ammonium solution (1 * 40 milliliter) and 5% sodium hydrogen carbonate solution, again with saturated ammonium chloride solution (1 * 40 milliliter) and 5% sodium hydrogen carbonate solution (2 * 40 milliliters) washing.The organic layer evaporation drying, chromatography on silica gel utilizes ethyl acetate/hexanaphthene 6/4 mixture to be eluent again, can get title compound (0.2 gram, t.l.c.; Ethyl acetate/hexanaphthene 6/4, Rf=0.1).
IR(CDCl 3) ν MaxCentimetre -13609 reach
3499(N-H, OH), vinegar amine in the 1722(), 1718(C=O). 1H-NMR（CDCl 3）：6.20-5.84（m），5.5-5.18（m），5.08（t），5.02（sa），4.88-4.64（m），4.57（m），4.124（m），4.18（m），3.44-3.3（m），3.25-3.14（m），M2.05（m），1.92-1.25（m），1.32（d）。
Example 39
(4S, 8S, 9R, 10S, 12R)-4-(2-amido oxyethyl group)-the 10-[1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid
To example 38(0.04 gram) in the solution of tetrahydrofuran (THF) (2 milliliters), add acetic acid (0.05 milliliter) and four (triphenyl phosphine) palladium (0.05 gram) in tetrahydrofuran (THF) (0.5 milliliter).After 4 hours, add diethyl ether (10 milliliters) and sherwood oil (5 milliliters).The solid of gained is centrifugal, and is dry again with diethyl ether washing back (3 * 10 milliliters).Solid is gone up purifying (Cartridge SEP-PAK Water Associates) in C-18, is eluent with water, and sample is soluble in water afterwards can get title compound (1 milligram) solid is white in color after lyophilize.
IR(CDCl 3) ν MaxCentimetre -13558-3100(NH 2), vinegar amine in the 1763(), 1595(C=O, C=C), 1H-NMR(D 2O): 4.91(m), 4.08(m), 4.04(dd), 3.58-3.40(m), 3.28(dd), 3.12-2.93(m), 1.9(m), 1.80-1.30(m), 1.25(m), 1.11(d).
Example 40
4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-benzyl carboxylate
To intermediate 41(0.54 gram) in the solution of anhydrous tetrahydro furan (5 milliliters), at nitrogen and 0 ℃ of following thionyl chloride (0.15 milliliter) and 2,6-lutidine (0.27 milliliter) of adding.Reaction mixture stirred 3 hours down at 22 ℃, after ethyl acetate (2 milliliters) dilution, washed respectively with saturated aqueous ammonium chloride solution (2 * 25 milliliters), evaporated under drying and the vacuum again.Oily residue (0.56 gram) is dissolved in 1, in the 4-dioxane (10 milliliters), adds 2,6-lutidine (0.18 milliliter), Sodium Bromide (0.21 gram) and triphenyl phosphine (0.54 gram).Reaction mixture stirred 15 hours down at 22 ℃, and reflux is 2 hours afterwards.Reaction mixture is with ethyl acetate dilution (50 milliliters), and with saturated ammonium chloride (2 * 50 milliliters), salt solution (2 * 50 milliliters) washing, drying is vacuum concentration again.Oily residue chromatography on silica gel is that eluent can get colorless oil (0.16 gram) with sherwood oil/diethyl ether 9/1 mixed solution.This is dissolved in (5 milliliters) in the anhydrous tetrahydro furan, adds acetic acid (0.14 milliliter) again, and N, N, and the N-tetrabutyl ammonium fluoride is in the 1.1M solution of anhydrous tetrahydro furan (0.84 milliliter).Reaction mixture stirred 15 hours down at 22 ℃, with ethyl acetate (25 milliliters) dilution, washed respectively with 5% sodium bicarbonate aqueous solution (3 * 25 milliliters), salt solution (2 * 25 milliliters) again, and drying concentrates under the vacuum again.Residue is chromatography on silica gel, utilizes ethyl acetate/hexanaphthene 3/7 mixed solution to be eluent, can get title compound, is (35 milligrams of colorless oil; T.l.c. cyclohexane/ethyl acetate 1/1;
Rf＝0.3）。IR(CDCl 3) ν Max(centimetre -1): 3600(O-H), 1772(C=O β-Nei vinegar amine), the 1718(C=0 ester), 1632(C=C); H 1-NMR(300MHz CDCl 3): 7.47-7.30(m), 5.29(dd), 4.94(t), 4.24(m), 4.19(dd), 3.3-3.32(m), 3.20(s), 2.05(m), 1.9-2.1(m), 1.61(d), 1.32(d).
Example 41
(4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid potassium
To example 40(30 milligram) in the solution of ethyl acetate (1 milliliter), add ethanol (1 milliliter) and palladium black (11 milligrams), mixture and under 25 ℃ hydrogen (1atm) stirred 25 fens.Elimination catalyzer afterwards, solution also extracts with 0.4% saleratus (2.5 milliliters).Water layer is dope under vacuum, afterwards the reverse-phase chromatography purifying.Aqueous solution lyophilize can get title compound, the solid that is white in color (20 gram).
Example 42
4-methoxyl group-10-[(1-hydroxyethyl-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-benzyl carboxylate
To intermediate 41(1 gram) in the solution of anhydrous tetrahydro furan (10 milliliters), at nitrogen and 0 ℃ of following thionyl chloride (0.27 milliliter) and 2,6-lutidine (0.48 milliliter) of adding.Reaction mixture stirred 3 hours down at 22 ℃, dilute through ethyl acetate (50 milliliters), after saturated ammonium chloride (2 * 50 milliliters), 5% sodium bicarbonate aqueous solution (2 * 50 milliliters), salt solution (2 * 50 milliliters) wash respectively, dry and concentrated under vacuum.Oily residue (1.1 gram) is dissolved in 1, in the 4-diox (20 milliliters), adds 2,6-lutidine (0.33 milliliter), Sodium Bromide (0.39 gram) and triphenyl phosphine (0.98 gram).Reaction mixture stirred 15 hours down at 22 ℃, poured saturated aqueous ammonium chloride solution (50 milliliters) afterwards into and extracted with ethyl acetate (50 milliliters).After organic layer washs with saturated aqueous ammonium chloride solution (50 milliliters) and salt solution (2 * 25 milliliters), dry and concentrating under reduced pressure.Oily residue chromatography on silica gel utilizes ethyl acetate/hexanaphthene 3/7 mixed solution to be eluent, can get oily matter (1.0 grams, t.l.c. ethyl acetate/hexanaphthene 1/1 Rf=0.6).Oil is dissolved in (15 milliliters) in the acetonitrile, and in ice-cooled adding acetic acid (1.3 milliliters) and concentrated hydrochloric acid (1 milliliter).Reaction mixture stirred 1 hour down at 0 ℃, poured into (50 milliliters) in the 5% ice-cold sodium bicarbonate aqueous solution again, and extracted with ethyl acetate (50 milliliters).Organic layer is with salt water washing, drying, and concentrating under reduced pressure can get white foam shape thing (0.9 gram, t.l.c. ethyl acetate/hexanaphthene again; 25/5Rf=0.36).This is dissolved in 1 again, in the 4-diox (20 milliliters), and reflux 5 hours, solvent is removed under vacuum again.Oily residue chromatography on silica gel utilizes ethyl acetate/hexanaphthene 1/1 mixed solution to be eluent, can get title compound, is colorless oil (0.26 gram; T.l.c. ethyl acetate/hexanaphthene 1/1 Rf=0.3).
Example 43
(4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid sodium
To example 42(0.195 gram) in the solution of ethyl acetate (8 milliliters), add ethanol (8 milliliters) and palladium black (75.3 milligrams).Reaction mixture stirred 25 fens under 25 ℃ hydrogen.The 2 ethyl hexanoic acid sodium (87 milligrams) of elimination catalyzer, and adding afterwards.The organic solution concentrating under reduced pressure, the sodium salt residue is with water dilution another mistake phase chromatography purification.Aqueous solution lyophilize can get title compound, the solid that is white in color (90 milligrams).
IR(CDCl 3) ν Max(centimetre -1): 3375(O-H), 1749(C=O β-Nei vinegar amine), 1595(C=0; C=C); H 1-NMR(300 MHz CDCl 3): 4.77(m), 4.16-4.06(m), 4.08(dd), 3.31(dd), 3.11(s), 3.03(m), 1.89(dd), 1.75(m), 1.6-1.2(m), 1.14(d).
Example 44
(4S, 8S, 9R, 10S, 12R)-and 4-methoxyl group-10-(1-(tertiary butyl dimethylamino silane oxygen base) ethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid, ethyl ester
To intermediate 42(0.7 gram) in the solution of anhydrous tetrahydro furan (15 milliliters), under-10 ℃ nitrogen, add thionyl chloride (0.24 milliliter) and 2,6-lutidine (0.41 milliliter).Reaction mixture stirred 30 fens down at-10 ℃, and afterwards with ethyl acetate (100 milliliters) dilution, with saturated aqueous ammonium chloride solution (2 * 80 milliliters) and salt solution (2 * 70 milliliters) washing, drying is evaporated under the vacuum more again.Oily residue (0.72 gram) is dissolved in 1, and 4-diox (10 milliliters) and 2 in the 6-lutidine (0.28 milliliter), adds Sodium Bromide (0.33 gram) again, and triphenyl phosphine (0.85 gram).Reaction mixture stirred 24 hours down at 22 ℃, and after ethyl acetate (2 * 50 milliliters) dilution, with saturated ammonium chloride (2 * 50 milliliters), and salt solution (2 * 50 milliliters) washing, drying concentrates under vacuum again.Oily residue chromatography on silica gel utilizes cyclohexane/ethyl acetate 8/2 mixed solution can get colorless oil (0.66 gram) (t.l.c. cyclohexane/ethyl acetate 1/1 for eluent; Rf=0.3).
Raw oil (0.66 gram) is in 1, the solution of 4-diox (10 milliliters), and reflux 4 hours is with ethyl acetate (30 milliliters) dilution, again through salt solution (2 * 50 milliliters) washing, drying and vacuum concentration.Oily residue chromatography on silica gel utilizes cyclohexane/ethyl acetate 9/1 mixed solution to be eluent, can get colorless oil (0.13 gram; T.l.c. cyclohexane/ethyl acetate 1/1Rf=0.66).
IR(CDCl 3) ν Max(centimetre -1): 1774(C=O β-Nei vinegar amine), the 1715(C=0 ester), 1632(C=C);
Example 45
(4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid, ethyl ester
To example 45(0.1 gram) in the solution of tetrahydrofuran (THF) (4 milliliters), add acetic acid (0.1 milliliter) and N, N, N, the 1.1M solution of N-4-butyl ammonium fluoride trihydrate (0.22 gram).Reaction mixture stirred 17 hours down at 22 ℃, concentrated under vacuum with diethyl ether dilution (20 milliliters) and with 5% sodium bicarbonate aqueous solution (30 milliliters) and salt solution (30 milliliters) washing, drying afterwards again.Residue is chromatography on silica gel, is eluent with diethyl ether/sherwood oil 1/1, can get title compound, is (40 milligrams of colorless oil; T.l.c. diethyl ether; Rf=0.32).
The pharmacy example
Injection dry powder
Every bottle
(4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyl second
Base)-11-Oxy-1-a word used for translation three ring [7.2.0.0 3,8] 538 milligrams in 11 carbon
-2-alkene-2-carboxylic acid sodium
Sodium salt is riddled sterile vials.Be full of the bottle headspace with aseptic nitrogen; With soft rubber ball and buckle envelope bottle (finishing) with wrinkle shape.Before dispensing, product can water for injection (10 milliliters) or other suitable aseptic injections make reorganization with solvent.

Claims (8)

1, the method for non-persistent ester class and solvate in a kind of preparation formula (I) compound and its esters (comprising suitable inner salt), the metabolism
Wherein
R 1Represent hydrogen atom or hydroxyl protecting group;
R 2Represent hydrogen atom or carboxyl-protecting group;
R 3Represent hydrogen atom, hydroxyl, methylol, C 1-3Alkyl or XR 4Group, X represention oxygen atom or S (O) n group wherein, wherein n is 0 or integer 1 or 2, and R 4Represent C 1-5Alkyl, C 3-7Cycloalkyl or phenyl, or when X be then R of oxygen or sulphur atom 4Can represent AlKNR 5R 6Group, wherein Alk represents C 2-6The alkylidene chain of straight or branched, and R 5And R 6Represent hydrogen atom or C independently of one another 1-4Alkyl or R 5Can represent formyl radical, ethanoyl or formimino, and R 6Represent hydrogen atom, or R 5And R 6Add that the nitrogen-atoms that joins with it forms N-pyrrolidine ring or N-hexahydropyridine ring, or R 3Representative (CH 2) mNR 7R 8Group, wherein m is 0 or 1, and R 7And R 8Represent hydrogen atom or C independently of one another 1-4Alkyl, or R 7Represent formyl radical, ethanoyl or formimino, and R 8Represent hydrogen atom, or R 3And the carbon that joins with it is represented ketone group or its ketal derivatives;
This method comprises following arbitrary step:
(i) cyclisation of formula II compound
Figure 911014705_IMG3
R wherein 1aBe hydroxyl protecting group, R 2aBe carboxyl-protecting group, R 3aAs R 3Definition, or one Y is oxygen or phosphino-by its group that is transformed,
(ii) R 2Be carboxyl-protecting group, R 3Be SR 4The oxidation of the formula I compound of base produces R 3Be SOR 4The formula I compound,
(iii) R 2Be carboxyl-protecting group, R 3Represent the hydrolysis of the formula I compound of a ketal group together with coupled carbon atom, produce R 3Represent the formula I compound of a ketone group together with coupled carbon atom,
(iv) R 2Be carboxyl-protecting group, R 3Represent the reduction of the formula I compound of a ketone group together with coupled carbon atom, produce R 3Be the formula I compound of hydroxyl,
(V) R 1Be hydroxyl protecting group, R 2Be carboxyl-protecting group, R 3Be the formula I compound of hydroxyl) the 0-alkylation, produce R 3Be the formula I compound of alkoxyl group,
If desired, in the compound separation that will obtain for its three-dimensional chemical isomer before or after, it be subjected to following one or more operations thereafter:
A) with R 3aBase is converted into required R 3Base,
B) remove one or several protecting group,
C) with R 2The compound that is hydrogen or hydroxyl protecting group is converted into non-persistent ester class or solvate in corresponding salt, the metabolism.
2, according to the process of claim 1 wherein that Y is that the cyclisation of compound of the formula II of Sauerstoffatom is carried out through heating in the presence of organophosphite.
3, according to the method for claim 1 or 2, the product that wherein makes is R 1And R 2Represent on the compound (I) of hydrogen atom or its physiology non-persistent ester class or solvate in acceptable salt (comprising inner salt), the metabolism.
4, according to arbitrary method of claim 1-3, the compound that wherein makes (I) is R 3Represent hydrogen, amino, aminomethyl, methylamino-, hydroxyl, methylol, methyl, methoxyl group, oxyethyl group, isopropoxy, cyclopentyloxy, ammonia oxyethyl group, methylthio group, thiophenyl, methylsulfinyl or and coupled carbon atom form the compound of ketone group or dimethyl ketal base together.
5, according to arbitrary method of claim 1-4, the compound that wherein makes (I) is that the carbon atom on its 8 is in beta configuration.
6, according to the method for claim 1 or 2, the compound that wherein makes is non-persistent ester or a solvate in the compound of general formula (I b) or its physiologically acceptable salt, the metabolism,
Figure 911014705_IMG4
R in the formula 3Represent amino, aminomethyl, methylamino-, hydroxyl, methylol, methoxyl group, oxyethyl group, isopropoxy, ammonia oxyethyl group, methylthio group, methylsulfinyl or thiophenyl.
7, according to arbitrary method of claim 1-3, the compound that wherein makes be selected from (4S, 8S, 9R, 10S, 12R)-4-methoxyl group-10-(1-hydroxyethyl)-11-oxo-1-aza-tricycle [7.2.0.0 3,8] non-persistent ester and solvate in acceptable salt, the metabolism on 11 carbon-2-alkene-2-carboxylic acid and its physiology.
8, according to arbitrary method of claim 1-3, the compound that wherein makes is to be selected from:
(4S, 8S, 9R, 10S, 12R)-4-methylthio group-10-(1-hydroxyethyl)-11-oxo-1-aza-tricycle [7.2.0.0 3,8] 11 carbon-2-alkene-2-carboxylic acid,
(4S, 8S, 9R, 10S, 12R)-4-methylsulfinyl-10-(1-hydroxyethyl)-1-oxo-1-aza-tricycle [7.2.0.0 3,8]-11 carbon-2-alkene-carboxylic acid,
(4S, 8S, 9R, 10S, 12R)-4-amino-10-(1-hydroxyethyl)-11-oxo-1-aza-tricycle [7.2.0.0 3,8] 11 carbon-2-alkene-carboxylic acid,
With non-persistent ester and solvate in its physiologically acceptable salt, the metabolism.
CN91101470A 1989-09-08 1991-03-07 Heterocyclic compounds Expired - Fee Related CN1030604C (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB898920337A GB8920337D0 (en) 1989-09-08 1989-09-08 Heterocyclic compounds
MX2227590A MX22275A (en) 1989-09-08 1990-09-07 PROCEDURE FOR THE PREPARATION OF HETERO CYCLIC COMPOUNDS.
ZA907137A ZA907137B (en) 1989-09-08 1990-09-07 Heterocyclic compounds
CN91101470A CN1030604C (en) 1989-09-08 1991-03-07 Heterocyclic compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB898920337A GB8920337D0 (en) 1989-09-08 1989-09-08 Heterocyclic compounds
CN91101470A CN1030604C (en) 1989-09-08 1991-03-07 Heterocyclic compounds

Publications (2)

Publication Number Publication Date
CN1064682A true CN1064682A (en) 1992-09-23
CN1030604C CN1030604C (en) 1996-01-03

Family

ID=36764664

Family Applications (1)

Application Number Title Priority Date Filing Date
CN91101470A Expired - Fee Related CN1030604C (en) 1989-09-08 1991-03-07 Heterocyclic compounds

Country Status (4)

Country Link
CN (1) CN1030604C (en)
GB (1) GB8920337D0 (en)
MX (1) MX22275A (en)
ZA (1) ZA907137B (en)

Also Published As

Publication number Publication date
ZA907137B (en) 1991-11-27
CN1030604C (en) 1996-01-03
GB8920337D0 (en) 1989-10-25
MX22275A (en) 1993-11-01

Similar Documents

Publication Publication Date Title
CN1032257C (en) Pyrroliaylthiocarbapenem derivatives
CN1036006C (en) Antibiotic compounds
CN1107502C (en) Preparation method for medicinal composition containing hydrogenated pyridine derivative as active components
CN1086386C (en) Novel multi-drug resistance modifier
CN86105664A (en) Diamide and congener prostaglandin analogue thereof that 7-oxabicyclo heptane replaces
CN1110969A (en) Fused phenol derivatives
CN1681801A (en) Quinolylpropylpiperidine derivatives and their use as anti-microorgans agent
CN87107938A (en) 3-pyrrolidyl sulfo--1-azabicyclo [3,2,0] hept-2-ene"-2-formic acid cpds and preparation method thereof
CN1037149A (en) The preparation method of 3-alkenyl-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid cpd
CN1432015A (en) Indazoles substituted with 1,1-dioxoisothiazolidine useful as inhibitors of cell proliferation
CN1950358A (en) Novel gamma secretase inhibitors
CN1043501A (en) Prepare the method that replaces 2-pyridone and pyridine-2-thioketones
CN1077954A (en) New 1-benzopyran derivatives
CN1852715A (en) Cephem compounds
CN1056612C (en) Process for epoxidising prochiral olefins and catalyst therefor and intermediates for making the catalyst
CN1063284A (en) Antiseptic-germicide
CN1066657A (en) Antimicrobial compounds
CN1079396C (en) Aromatic amidine derivatives useful as selective thrombin inhibitors
CN1106390A (en) Azole compounds, their production and use
CN1159303C (en) Preparation of intermediate for monocyclic beta-lactams derivatives
CN1026786C (en) Anti-fungal triazole derivatives, their preparation and uses
CN1653071A (en) 10-(3-cyclopropylaminomethyl-1-pyrrolidinyl)pyridobenzoxazinecarboxylic acid derivative effective against resistant bacterium
CN1034329C (en) Novel 2-substituted alkyl-3-carboxy carbapenems as antibiotics and a method of producing them
CN1222508C (en) Process for preparation of condensed sulfamide
CN1030604C (en) Heterocyclic compounds

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C15 Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993)
OR01 Other related matters
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee