CN109651372A - A kind of preparation method of tebipenem acid - Google Patents
A kind of preparation method of tebipenem acid Download PDFInfo
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- CN109651372A CN109651372A CN201811605847.7A CN201811605847A CN109651372A CN 109651372 A CN109651372 A CN 109651372A CN 201811605847 A CN201811605847 A CN 201811605847A CN 109651372 A CN109651372 A CN 109651372A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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Abstract
As shown in Equation 1 L-084 intermediate --- the preparation method of tebipenem acid belongs to medicinal chemistry arts the invention discloses a kind of.This method is using compound I as starting material, with SiO2Or montmorillonite KSF load perfluorinated sulfonic resin pyridines salt is that catalyst is reacted with compound II in the presence of an organic base using dichloroethanes/acetonitrile as solvent, one pot directly prepares tebipenem acid.Compared with prior art, the synthesis technology of tebipenem acid of the present invention, synthesis step is few, easy to operate, and post-processing is simple, and strong operability, product cost is low, is suitable for industrialized production.The solid acid reagent used is cheap and easy to get, pollution-free non-corrosive, and can recycle.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of to prepare L-084 intermediate-tebipenem acid
Method.
Background technique
L-084 is researched and developed by Pfizer Inc., particle earliest as first oral carbapenem antibiotic
Agent is developed by Japanese Mingzhi company, in April, 2009 in Japanese Initial Public Offering.
L-084 is the prodrug of tebipenem, and tebipenem is a kind of spectrum antibacterial medicine, to gram-positive bacteria and
Gram-negative bacteria is effective, in terms of improving pneumonia, tympanitis and nasosinusitis symptom and reducing adverse reaction, has apparent
Advantage, while being used for the treatment of pediatric patients ear nose larynx and the infection of the upper respiratory tract.L-084 is to Penicillin-resistant type pneumonia
The antimicrbial power of coccus, macrolides drug-resistant type pneumococcus is all stronger than the antimicrbial power of previous oral type antimicrobial.For than training
Southern ester belongs to the oral carbapenem antibiotic class antibacterial that market needs and has wide clinical application and market prospects
Medicine.
Patent US5783703, CN106083858, CN103664948, CN103059026, CN102775409, document
J.Antibiotics 2006,59 (4), 241-247, Chinese journal of Medicinal Chemistry 2011,21 (5), 383-385, Chinese antibiosis
Plain magazine 2013,38 (1), the method for the synthesis L-084 of the disclosed report such as 41-43 use compound (I) for starting
Raw material is esterified to obtain compound III through esterification and enol phosphate, and main ring (compound III) is butted into branched chain compound convergence
Compound (IV), then benzyl synthesis tebipenem acid (compound V) is taken off through Pd/C catalytic hydrogenolysis.Then compound (V) and pivalic acid
Chloromethyl ester or iodometyl pivalate condensation prepare L-084.
Therefore, compound (I) or its ester are the critical materials for synthesizing L-084, and compound V (tebipenem acid) is
Synthesize the key intermediate of L-084.Synthesis according to literature method from compound (I) to compound V need to be by 4 passes
Key reaction step.Although the process route is comparatively mature, (hydrogen is catalyzed including Pd/C because its reaction step is more
Solution), and the diphenyl phosphate chloride of chemically unstable is used, troublesome in poeration in industrial production, risk is big, and quantity of three wastes is big, former
Subeconomy is low, high production cost.For to meet actual production demand, be badly in need of improving its technique at present, especially its
The preparation of intermediate.
Summary of the invention
The object of the present invention is to provide a kind of proper methods for preparing tebipenem acid.
The technical problem to be solved by the present invention is in order to overcome it is existing prepare tebipenem acid method, synthetic route is long,
High production cost, provides a kind of simple preparation method of tebipenem acid at troublesome in poeration, the defects of quantity of three wastes is high, and risk is big.
Purpose to realize the present invention, for the present invention from compound I, one pot prepares tebipenem acid.Including following three
Experimental procedure: using compound I as starting material, with SiO2It loads perfluorinated sulfonic resin pyridiniujm or montmorillonite KSF loads perfluor
Sulfonate resin pyridiniujm passes through enol sulfonic acid esterification-sulfydryl nucleophilic of carbonyl using dichloroethanes/acetonitrile as solvent for catalyst
Tebipenem acid is directly prepared in the reaction of substitution-ester hydrolysis three phases.
Perfluorinated sulfonic resin is a kind of stronger organic solid acid of acidity, compared with liquid acid catalyst, perfluorinated sulfonic acid tree
Rouge have many advantages, such as it is non-corrosive, do not generate that acid pickle, product are easily separated, selectivity is high and can multiple Reusability, be one
The solid acid catalyst of the ideal environmental sound of kind.
Perfluorinated sulfonic resin is by tetrafluoroethene and side chain terminal band-SO2The perfluoroalkene ethers of F group are anti-under certain condition
The copolymer that should be obtained.It, can shape due to the features such as perfluorinated sulfonic resin C-F key has very high bond energy, and fluorine atom radius is larger
The protective layer of pairs of polymer C-C main chain, thus there is good thermal stability.Perfluorinated sulfonic resin is usually in dense non-porous
State, specific surface is lower, and the acid centre being buried in fluorocarbon radical body is not easy to be approached by reactant, and internal acid centre is not
It can be utilized by chemical reaction, as catalyst, weight specific activity is low.Therefore, acid can be utilized by increasing its specific surface and improving
The ratio at center is to improve an important measures of perfluorinated sulfonic resin catalysis potentiality.Perfluorinated sulfonic resin pyrrole prepared by the present invention
Pyridine salt (Rf-SO3HPy the catalytic activity of the solid acid catalyst) is effectively increased.
The present invention passes through the perfluorinated sulfonic resin pyridiniujm (Rf-SO that will be prepared3HPy SiO) is loaded to2On, obtain SiO2
Load perfluorinated sulfonic resin pyridiniujm (Rf-SO3H·Py/SiO2), to substantially increase the specific surface of the solid acid catalyst
Product.
The present invention passes through the perfluorinated sulfonic resin pyridiniujm (Rf-SO that will be prepared3HPy it) loads on montmorillonite KSF, obtains
Perfluorinated sulfonic resin pyridiniujm (Rf-SO is loaded to KSF3HPy/KSF), to increase urging for perfluorinated sulfonic resin pyridiniujm
Change activity, is conducive to the catalysis reaction diversity of the solid acid catalyst.
The reaction process of compound (I) and 3- sulfydryl -1- (1,3- thiazoline -2- base) azetidine (compound II) point
For three phases.First stage is the ketone carbonyl of compound I and perfluorinated sulfonic acid tree in organic solvent and under certain reaction temperature
The sulfonic group of rouge forms corresponding enol sulphonic acid ester；Second stage is to exist in organic solvent in alkaline reagent and centainly react
At a temperature of, intermolecular nucleophilic occurs for the enol sulphonic acid ester and 3- sulfydryl -1- (1,3-thiazoles quinoline -2- base) azetidine of generation
Substitution reaction generates enol thioether；The sulfonic acid pyridinium group left away, which repeats, participates in next reaction cycle；Third reacts rank
Section is in the presence of acidic catalyst used, and carboxylate methyl ester occurs acidic hydrolysis and generates corresponding tebipenem acid.Synthetic reaction
Equation is as follows:
The perfluorinated sulfonic resin is commercial product (Rf-SO3350 DEG C of H, initial decomposition temperature >, resin density: 1.9 ±
0.10g/cm3, exchange capacity 0.8-1.30.
The pyridines reactant includes: pyridine, 2- picoline, 3- picoline, 4- picoline, 2,4- dimethyl
Pyridine, 2,6- lutidines, 2-aminopyridine, 4-aminopyridine, N, N- dimethyl -4-aminopyridine, quinoline, isoquinolin
Deng being commercially available analysis net product.
The preparation of the perfluorinated sulfonic resin pyridiniujm is to stir perfluorinated sulfonic resin and pyridine compounds and their being equipped with
Heating stirring in the reaction vessel of device, reflux condenser is mixed, certain time is swollen, it is cooling, it adds water and stirs, filters, washing, vacuum
It dries to translucent powder obtained from constant weight.
The SiO2Load perfluorinated sulfonic resin pyridiniujm (Rf-SO3H·Py/SiO2) preparation, be by it is a certain amount of just
Tetraethyl orthosilicate acidic aqueous solution pours into a certain amount of above-mentioned perfluorinated sulfonic resin pyridine salt solution, and solution quickly becomes gel.
It stands overnight, it is 48 hours dry in 95 DEG C, it is dried in vacuum overnight then at 95 DEG C.Glassy product is pulverized into sieving, it is dry, to obtain the final product
SiO2Load perfluorinated sulfonic resin pyridiniujm (Rf-SO3H·Py/SiO2) catalyst, perfluorinated sulfonic resin pyridine salt quality percentage
Content is 3~5%.
The montmorillonite KSF loads perfluorinated sulfonic resin pyridiniujm (Rf-SO3HPy/KSF preparation) is by perfluor sulphur
The aqueous solution of alcohol is made in acid resin pyridiniujm under certain temperature, pressure, with a certain proportion of montmorillonite KSF
(Montmorillonite KSF, specific surface area: 20-40m2/ g) mixing, it stands overnight.Solvent is boiled off on a rotary evaporator,
It is 10 hours dry in 110 DEG C, it is dried in vacuum overnight then at 95 DEG C.Product is pulverized and sieved, loads perfluor sulphur up to montmorillonite KSF
Acid resin pyridiniujm (Rf-SO3HPy/KSF) catalyst, perfluorinated sulfonic resin pyridiniujm mass percentage are 1~3%.
The SiO prepared by the above method2Load perfluorinated sulfonic resin pyridiniujm (Rf-SO3H·Py/SiO2) and montmorillonite
KSF loads perfluorinated sulfonic resin pyridiniujm (Rf-SO3HPy/KSF) average ion exchange capacity is not less than 0.90mmol/g.
The molar ratio of two kinds of key reaction substrates are as follows: the molar ratio of compound I and compound II are 1:2-2:1,
Preferred molar ratio is 1:1.2-1.2:1；The dosage of catalyst and the weight ratio of compound I are 1:20-1:5, and preferred weight ratio is
1:12–1:8。
The organic solvent of the described first stage reaction includes methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, THF,
DMF, DMAC, DMSO, HMAP, NMP, AcOH, the mixture of one or more of dioxane composition.Preferably, described to have
Solvent selects dichloroethanes, MeCN, THF, AcOH or DMF.
The reaction temperature of the first stage reaction is -20 DEG C -50 DEG C, and preferable temperature is -10 DEG C -10 DEG C
The reaction time of the first stage is 2-5 hours, and preferred reaction time is 3-4 hours.
The organic solvent of the second stage reaction includes MeCN, THF, DMF, DMAC, DMSO, HMAP, NMP, pyridine
With the mixture of one or more of triethylamine composition.Preferably, the organic solvent selects MeCN, THF, DMF, NMP or pyrrole
Pyridine.
It include common inorganic base and organic base used in the second stage reaction.Inorganic base includes NaH, NaOH,
KOH,NaCO3,KCO3, KF etc., preferably NaH；Organic base includes NaOMe, NaOEt, NaOBut,KOBut, DIEA, DMAP and
DIPEA etc., preferably DMAP (4-dimethylaminopyridine), DIPEA (n,N-diisopropylethylamine) and KOBut。
The reaction temperature of the second stage reaction is -10 DEG C -20 DEG C, and preferable temperature is 0-10 DEG C
The reaction time of the second stage is 1-5 hours, and preferred reaction time is 2-4 hours.
The reaction temperature of the phase III is 0 DEG C -50 DEG C, and preferable temperature is 10-30 DEG C.
The reaction time of the phase III is 10-30 hours, and preferred reaction time is 20-25 hours.
The reaction condition is preferred: using compound I as starting material, to load perfluorinated sulfonic resin pyridiniujm as catalysis
Agent is stirred 3-4 hours at 0 DEG C ± 10 DEG C using dichloroethanes as solvent.Decompression boils off most of solvent, and acetonitrile, cooling is added
To 0 DEG C hereinafter, the acetonitrile solution of compound II and organic base is slowly added dropwise under stirring, time for adding 3 hours or more.After dripping off
0-5 DEG C is stirred 3 hours, then is stirred at room temperature 24 hours, and TLC is detected to fully reacting.Catalyst is filtered out, water quenching is added to go out instead
It answers, adds acetone crystallization.It filters, filter cake acetonitrile and water washing, obtains solid tebipenem acid.
Compared with prior art, tebipenem acid preparation method of the present invention, synthesis step is few, high income, up to 45% or more.
Easy to operate, post-processing is simple, strong operability, is suitable for industrialized production.The support type perfluorinated sulfonic resin pyridiniujm used
Catalyst, raw material are cheap and easy to get, and preparation is easy, and can be recycled.The SiO prepared by the above method2Load perfluor sulphur
Acid resin pyridiniujm (Rf-SO3H·Py/SiO2) and montmorillonite KSF load perfluorinated sulfonic resin pyridiniujm (Rf-SO3H·Py/
KSF) average ion exchange capacity is not less than 0.90mmol/g.Good, chemical stability and mechanical strength height etc. with heat resistance
Feature.When as catalyst, it is easily isolated, it can Reusability.And corrosivity is small, is easy for industrialized production.
Specific embodiment
It is to be illustrated by embodiment to the method for the present invention, but the present invention is not limited thereto below.
Experimental method described in the following example is unless otherwise specified conventional method；Agents useful for same and material, such as
Without specified otherwise, commercially obtain.
Embodiment 1, the preparation of perfluorinated sulfonic resin pyridiniujm
In three mouthfuls of glass reaction containers equipped with blender, reflux condenser and thermometer, 1.0kg perfluor sulphur is added
Acid resin (NR 50, Lanca ster chemical company, average grain diameter about 0.9mm, acid amount are 0.89mmol/g) and 2.0kg pyridine
Or substituted pyridines, oil bath heating, stirred 8 hours at 100 DEG C or more, until resin is no longer obviously swollen.It is cooled to room temperature, adds
4.0Kg water stirs 1 hour, filters, is washed to neutrality, is dried under vacuum to constant weight, obtain translucent powdery end solid.With TG, DSC
Detect perfluorinated sulfonic resin pyridiniujm Rf-SO3Decomposition temperature >=250 DEG C of HPy.
Embodiment 2, SiO2Load perfluorinated sulfonic resin pyridiniujm (Rf-SO3H·Py/SiO2) preparation.
(1) prepared by perfluorinated sulfonic resin pyridine salt solution
Perfluorinated sulfonic resin pyridiniujm (20g) prepared by embodiment 1 is placed in 1000mL autoclave, it is mixed that 600mL is added
Bonding solvent (45% water: 45% normal propyl alcohol: 10% methanol) is heated to 200 DEG C, stirs, at this temperature holding 4 hours, then
Stop heating and stirring, at room temperature natural cooling.Insoluble sludge is filtered out, perfluorinated sulfonic resin pyridine salt quality percentage is obtained
The resin solution that content is 2.0~3.0%.
(2)SiO2Load the preparation of perfluorinated sulfonic resin pyridine salt catalyst
In 700mL tetraethyl orthosilicate, 1000mL deionized water is added, adds 100mL dilute hydrochloric acid, stirs to clear
Clearly.The perfluor sulfoacid resin solution and 600mL c (N aOH)=0.1mol/ that 1000mL step (1) obtains are poured under stirring
In the mixed solution of L, pH value of solution=7.0, solution quickly become gel at this time.It stands overnight, it is 48 hours dry in 95 DEG C, then at
95 DEG C are dried in vacuum overnight.Glassy product is pulverized into sieving, it is dry, up to SiO2Load perfluorinated sulfonic resin pyridiniujm (Rf-
SO3H·Py/SiO2) catalyst, perfluorinated sulfonic resin pyridiniujm mass percentage is 3~5%.
Embodiment 3, montmorillonite KSF load perfluorinated sulfonic resin pyridiniujm (Rf-SO3HPy/KSF) the preparation of catalyst.
By the perfluorinated sulfonic resin pyridine salt solution of above-mentioned preparation and a certain proportion of montmorillonite KSF
(Montmorillonite KSF, specific surface area: 20-40m2/ g) mixing, it stands overnight.Solvent is boiled off on a rotary evaporator,
It is 10 hours dry in 110 DEG C, it is dried in vacuum overnight then at 95 DEG C.Product is pulverized and sieved, loads perfluor sulphur up to montmorillonite KSF
Acid resin pyridiniujm (Rf-SO3HPy/KSF) catalyst, perfluorinated sulfonic resin pyridiniujm mass percentage are 1~3%.
Embodiment 4 (1R, 5S, 6S) -1- methyl -6- [(R) -1- ethoxy] -2- [1- (1,3- thiazoline)-azacyclo-
Butyl -3-] thio-carbon mould -2- alkene -3- formic acid (tebipenem acid V) preparation.(SiO2Load perfluorinated sulfonic resin pyridine
Salt catalysis)
By 50g (0.207mol) compound I (5R, 6S) -6- [(R) -1- ethoxy] -4- (R)-methyl -3,7- dioxo -
1- azabicyclo [3,2,0] heptane] -2- carboxylate methyl ester is dissolved in 350mL dichloroethanes, it is added with stirring 5g SiO2Load is complete
Perfluorosulfonic acid resin pyridiniujm is cooled to -10 DEG C, stirs 3 hours at this temperature.Decompression boils off most of solvent, and 300mL is added
Acetonitrile, be cooled to 0 DEG C hereinafter, stirring under be slowly added dropwise compound II acetonitrile aqueous slkali (36g compound II, 0.207mol,
50mL n,N-diisopropylethylamine, 100mL acetonitrile), time for adding 3 hours.Continue stirring 3 hours, TLC after dripping off at 0-5 DEG C
It detects to fully reacting.Room temperature is warmed naturally to, continues stirring 24 hours under room temperature.Catalyst is filtered out, water quenching reaction is added,
HPLC detects tebipenem acid yield 46.8%.Add acetone crystallization, filter, filter cake acetonitrile and water washing obtain off-white color and replace
Solid sourer than training south.
Structural identification data is as follows:
1H NMR (400MHz, DMSO-d6, ppm): δ 6.25-5.01 (b, 2H), 4.40-4.30 (m, 2H), 4.25-4.22
(m,1H),4.13-4.10(m,1H),3.10-3.88(t,1H),3.80-3.77(m,2H),3.76-3.73(m,2H),3.37-
3.35 (t, 2H), 3.19-3.17 (m, 2H), 1.15-1.13 (d, 3H, J=8.0Hz), 1.08-1.06 (d, 3H, J=8.0Hz)
.13C 173.99,163.62 NMR (100MHz, DMSO-d6, ppm): δ, 162.61,147.36,126.37,64.83,60.56,
59.73,58.36,55.98,42.50,36.11,32.81,22.24,17.11。
Embodiment 5 (1R, 5S, 6S) -1- methyl -6- [(R) -1- ethoxy] -2- [1- (1,3- thiazoline)-azacyclo-
Butyl -3-] thio-carbon mould -2- alkene -3- formic acid (tebipenem acid V) preparation.(montmorillonite KSF loads perfluorinated sulfonic resin
Pyridiniujm catalysis)
The present embodiment is in addition to by SiO2Load perfluorinated sulfonic resin pyridiniujm changes montmorillonite KSF load perfluorinated sulfonic resin into
Pyridiniujm as catalyst outside, other conditions are identical with embodiment 4.HPLC detects tebipenem acid yield 58.5%.
Embodiment 6, for the present embodiment other than changing diisopropylethylamine into NaH as alkali, other conditions and embodiment 5 are complete
It is exactly the same.Catalyst: montmorillonite KSF loads perfluorinated sulfonic resin pyridiniujm, and HPLC detects tebipenem acid yield 45.5%.
Embodiment 7, the present embodiment is other than changing NaH into t-BuOK as alkali, other conditions and the complete phase of embodiment 6
Together.Catalyst: montmorillonite KSF loads perfluorinated sulfonic resin pyridiniujm, and HPLC detects tebipenem acid yield 45.8%.
Embodiment 8, the present embodiment is other than changing t-BuOK into DMAP as alkali, other conditions and the complete phase of embodiment 7
Together.Catalyst: montmorillonite KSF loads perfluorinated sulfonic resin pyridiniujm, and HPLC detects tebipenem acid yield 55.9%.
Embodiment 9, montmorillonite KSF that the present embodiment uses embodiment 8 to recycle load perfluorinated sulfonic resin pyridiniujm as
Catalyst, other conditions are identical with embodiment 8.The yield 55.1% of HPLC detection tebipenem acid.
Embodiment 10, montmorillonite KSF that the present embodiment uses embodiment 9 to recycle load perfluorinated sulfonic resin pyridiniujm as
Catalyst, other conditions are identical with embodiment 9.HPLC detects tebipenem acid yield 52.8%.
Embodiment 11, the montmorillonite KSF load perfluorinated sulfonic resin pyridiniujm that the present embodiment is recycled using embodiment 10 are made
For catalyst, other conditions are identical with embodiment 10.HPLC detects tebipenem acid yield 45.6%.
Embodiment 12, the SiO that the present embodiment is recycled using embodiment 42Perfluorinated sulfonic resin pyridiniujm is loaded as catalysis
Agent, other conditions are identical with embodiment 4.HPLC detects tebipenem acid yield 45.7%.
Claims (5)
1. a kind of preparation method of tebipenem acid, which is characterized in that realize by the following method: being that starting is former with compound I
Material, with SiO2Loading perfluorinated sulfonic resin pyridines salt or montmorillonite KSF load perfluorinated sulfonic resin pyridines salt is catalyst,
Organic solvent A is added, is stirred to react at -20 DEG C -50 DEG C, boils off organic solvent；In -10 DEG C -20 DEG C, in inorganic base or have
In the presence of machine alkali, organic solvent B and 3- sulfydryl -1-(1,3- thiazoline -2- base is added) azetidine (compound II) stirring,
0 DEG C -50 DEG C are reacted, and tebipenem acid is prepared；
The organic solvent A selects methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, THF, DMF, DMAC, DMSO, HMAP,
NMP, AcOH, the mixture of one or more of dioxane composition；
The organic solvent B selects MeCN, THF, DMF, DMAC, DMSO, HMAP, NMP, pyridine, one or more of triethylamine
The mixture of composition；
The inorganic base selects NaH, NaOH, KOH, NaCO3, KCO3, KF；Organic base selects NaOMe, NaOEt, NaOBu t ,
KOBu t , DIEA, DMAP, DIPEA；
。
2. according to the preparation method of the acid of tebipenem described in claim 1, which is characterized in that catalyst SiO2Load perfluorinated sulfonic acid
Perfluorinated sulfonic resin pyridines salt described in resin pyridines salt or montmorillonite KSF load perfluorinated sulfonic resin pyridines salt is complete
Perfluorosulfonic acid resin with following compound: pyridine, 2- picoline, 2,4- lutidines, 2,6- lutidines, 3- methyl
Pyridine, 4- picoline, 2-aminopyridine, 4-aminopyridine, N, N- dimethyl -4-aminopyridine, quinoline, isoquinolin react institute
The compound of formation.
3. according to the preparation method of tebipenem acid as claimed in claim 1 or 2, which is characterized in that
The organic solvent A selects dichloroethanes, MeCN, THF, AcOH or DMF；Organic solvent B selects MeCN, THF, DMF, NMP or
Pyridine.
4. according to the preparation method of tebipenem acid as claimed in claim 1 or 2, which is characterized in that the inorganic base selects NaH；Have
Machine alkali selects DMAP(4- dimethylamino naphthyridine), DIPEA(N, N- diisopropylethylamine) or KOBu t 。
5. according to the preparation method of tebipenem acid as claimed in claim 1 or 2, which is characterized in that the montmorillonite KSF load is complete
Perfluorosulfonic acid resin pyridiniujm, perfluorinated sulfonic resin pyridiniujm mass percentage are 1 ~ 3%；The SiO2Load perfluorinated sulfonic acid tree
Rouge pyridiniujm, perfluorinated sulfonic resin pyridiniujm mass percentage are 3 ~ 5%.
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| US10889587B2 (en) | 2017-02-06 | 2021-01-12 | Spero Therapeutics, Inc. | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10889587B2 (en) | 2017-02-06 | 2021-01-12 | Spero Therapeutics, Inc. | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use |
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