CN109824696A - A kind of preparation method of the alpha-brominated penam sulfoxide acid benzhydryl ester of Tazobactam Sodium key intermediate 6 - Google Patents
A kind of preparation method of the alpha-brominated penam sulfoxide acid benzhydryl ester of Tazobactam Sodium key intermediate 6 Download PDFInfo
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- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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- C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, 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
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Abstract
The present invention relates to a kind of new preparation methods of the alpha-brominated penam sulfoxide acid benzhydryl ester of key intermediate 6 in Tazobactam Sodium synthesis.It is the following steps are included: 6 alpha-brominated penam sulfoxide acid are dissolved in organic solvent, diphenyl diazomethane is added, decompression boils off solvent after complete reaction, is extracted with organic solvent, after organic layer is washed through saturated common salt, anhydrous sodium sulfate is dry, depressurize after boiling off solvent up to crude product.6 alpha-brominated penam sulfoxide acid benzhydryl esters can be obtained after organic solvent recrystallizes or mashing is washed in crude product.This method compared to it is traditional using condensing agents such as DCC at the method for ester, avoid byproduct of reaction and be difficult to the problem of removing；It is esterified compared to using Benzophenonehydrazones/KI/ Peracetic acid system, simplifies operation, reduced by-product generation, improve the purity of final product, be more advantageous to industrialized production.
Description
Technical field
The invention belongs to organic and technical field of medicine synthesis, and in particular to a kind of 6 α of Tazobactam Sodium key intermediate-bromine
For the preparation method of penam sulfoxide acid benzhydryl ester.
Background technique
The structural formula of 6 alpha-brominated penam sulfoxide acid benzhydryl esters is
6 alpha-brominated penam sulfoxide acid benzhydryl esters are synthesizing new beta-lactamase inhibitor Tazobactam Sodiums (tazobactam)
Important intermediate, Tazobactam Sodium is a kind of beta-lactamase inhibitor of broad-spectrum high efficacy, by Japanese roc drug company develop,
Because of its excellent application performance, the characteristics such as toxic side effect is small, and Inhibiting enzyme activity is strong and stability is high, in the 30th international chemotherapy meeting
Most promising beta-lactamase inhibitor is cited as in view.
Tazobactam Sodium (tazobactam), chemical name: 3- methyl -7- oxo -3- (1H-1,2,3- triazole -1- methylenes
Base) -4- thia -1- azabicyclo [3.2.0] heptane -2- carboxylic acid -4,4- dioxide, structural formula is as follows.Its knot
Structure is one triazole ring of increase on the basis of Sulbactam, and to improve suppression enzyme effect, it is the optimal β-of current clinical effectiveness
Lactamase restrainer has the characteristics that stability is high, activity is low, toxicity is low, Inhibiting enzyme activity is strong.1992, Tazobactam Sodium
Compound medicine Tazobactam Sodium/Piperacillin (1:8) is listed in France for the first time, for treating various bacteria infection.
Tazobactam structural formula is as follows
According to the literature, by 6 alpha-brominated penam sulfoxide acid prepare 6 alpha-brominated penam sulfoxide acid benzhydryl esters substantially have with
Lower two kinds of routes:
Packet Jian Hua, Liu Yulin, Ma Jun et al. prepare 6 α-bromine with DCC/DMAP/ benzhydrol method in patent CN 101935324
For penam sulfoxide acid benzhydryl ester, synthetic route such as following formula:
2 β of document Micetich R G, Maiti S N, Spevak P, et al. Synthesis of-
azidomethylpenicillin-1, 1-dioxides and 3β-azido-3α-methylcepham-1, 1-
Dioxides [J] Synthesis, 1986,1986 (04): 292-296. is used in the presence of Peracetic acid and KI, with two
Benzophenone hydrazone reaction prepares 6 alpha-brominated penam sulfoxide acid benzhydryl esters, and report synthetic route is as follows:
6 alpha-brominated penam sulfoxide acid and benzhydrol are condensed under carbonyl dimidazoles (DCC) effect in the above route methods one
Prepare benzhydrol ester, the by-product of generationN,N'-dicyclohexylurea (DCU) is not easy to remove, and influences product quality；In method two,
6 alpha-brominated penam sulfoxide acid are esterified with diphenylmethanone hydrazone reaction in the presence of 40% Peracetic acid and KI, required 40% mistake
Fluoroacetic acid is unstable and use is dangerous, and reaction generates a large amount of acetic acid, and excessive Benzophenonehydrazones are not easy to remove, and influences product
Quality.
Summary of the invention
To overcome the above such as raw material to be not easy to buy, the defects of by-product is difficult to remove, product quality is not easy to control, this hair
Bright to provide a kind of preparation method of 6 alpha-brominated penam sulfoxide acid benzhydryl esters, synthetic route is as follows:
Should the following steps are included:
6 alpha-brominated penam sulfoxide acid are dissolved in solvent, diphenyl diazomethane, insulation reaction is added.After reaction, it steams
Dry reaction solvent is extracted with ethyl acetate or methylene chloride, and organic phase is dry, filters, is evaporated to obtain 6 alpha-brominated penam sulfoxides
Acid benzhydryl ester crude product；The mashing of crude product organic solvent is washed, is filtered, filter cake is dried to obtain 6 alpha-brominated penam sulfoxides
Acid benzhydryl ester；
Further, the organic solvent for dissolving 6 alpha-brominated penam sulfoxide acid can be selected from methylene chloride, ethyl acetate, acetone, first
Base isobutyl ketone, ethyl alcohol, methanol, acetonitrile, one of n,N-Dimethylformamide, dimethyl sulfoxide or a variety of, preferably acetone,
Acetonitrile, methylene chloride/acetone mixed solution；Methylene chloride/acetone volume ratio is preferably methylene chloride: acetone=1:2.
Further, the molar ratio of diphenyl diazomethane and 6 alpha-brominated penam sulfoxide acid is 1:0.9 ~ 1:5, preferably
For 1:0.9 ~ 1:1.5.
Further, extraction solvent for use is ethyl acetate, methylene chloride, chloroform, preferably ethyl acetate.
Further, it is different for methylene chloride, ethyl acetate, petroleum ether, n-hexane, acetone, methyl to recrystallize solvent for use
One of butyl ketone, acetonitrile, methanol, ethyl alcohol, isopropanol, water are a variety of, preferably ethyl acetate/petroleum ether mixed solvent.
Further, mashing solvent for use is methylene chloride, ethyl acetate, petroleum ether, n-hexane, acetone, methyl tert-butyl
One of base ketone, acetonitrile, methanol, ethyl alcohol, isopropanol, water are a variety of, preferably ethyl acetate/petroleum ether mixed solvent.
The advantages of method provided by the present invention, is:
(1) the 6 alpha-brominated penam sulfoxide acid benzhydryl esters prepared with the method for the present invention, effective solution acid system is at ester
When, react the problem of progress is incomplete, and excess benzophenone hydrazone influences product purity；
(2) effectively with DCC/ benzhydrol system at ester when, by-product N, the N'- dicyclohexylurea (DCU) of generation is not easy to remove, shadow
The problem of ringing product quality.
(3) the 6 alpha-brominated penam sulfoxide acid benzhydryl esters prepared with the method for the present invention, yield reach 93.5%, efficient liquid
Phase purity reaches 99.578%.
Detailed description of the invention
Fig. 1 is the 6 alpha-brominated penam sulfoxide acid benzhydryl ester efficient liquid phase figures that the operation preparation as described in example 1 obtains
Spectrum；
Fig. 2 is the 6 alpha-brominated penam sulfoxide acid benzhydryl ester HPLC-UV detections that the operation preparation as described in example 2 obtains；
Fig. 3 is the 1H-NMR spectrogram of 6 alpha-brominated penam sulfoxide acid benzhydryl esters；
Fig. 4 is by example 3(referenced patent CN 101935324) the obtained 6 alpha-brominated penam sulfoxide acid two of the operation preparation
Benzene methyl HPLC-UV detection；
Fig. 5 is by example 4(bibliography Synthesis, 1986,1986 (04): 292-296) operation preparation obtains
6 alpha-brominated penam sulfoxide acid benzhydryl ester HPLC-UV detections.
Specific embodiment
The present invention is described below by specific embodiment.Unless stated otherwise, technological means used in the present invention
It is method known in those skilled in the art.In addition, embodiment is interpreted as illustrative, it is not intended to limit the present invention
Range, the spirit and scope of the invention are limited only by the claims that follow.To those skilled in the art, without departing substantially from this
Under the premise of invention spirit and scope, to the various changes or change of material component and dosage progress in these embodiments
It belongs to the scope of protection of the present invention.The raw materials used in the present invention and reagent are commercially available.Wherein diphenyl diazomethane is purchased in upper
Hai Zhixin Chemical Co., Ltd.；
6 alpha-brominated penam sulfoxide acid are provided for oneself by our company, the method is as follows:
Water, hydrobromic acid 400g are successively added into reaction kettle, ethyl alcohol puts into 6-amino-penicillanic acid 400g.Temperature control less than 20 DEG C,
Sodium nitrite solution 200g and hydrobromic acid solution 666g is added dropwise, drop finishes, less than 20 DEG C insulation reaction 2 hours, heat preservation terminates, and takes out true
It is 30 ~ 60 minutes empty, methylene chloride extraction is added three times, organic layer merges.It is washed with water three times, extraction and washing process require temperature
Degree is less than 20 DEG C.Organic layer is cooled to subzero, sodium tungstate is added, less than 0 DEG C dropwises addition hydrogen peroxide of temperature control, drop is complete, less than 10 DEG C
It insulation reaction 5 hours, is washed twice with cold water, the alpha-brominated penam sulfoxide acid of sample 6 is distilled to recover to obtain after mother liquor layering.
Embodiment 1
The preparation of 6 alpha-brominated penam sulfoxide acid benzhydryl esters
The alpha-brominated penam sulfoxide acid of 300 g 6 is added in 1.8 L acetonitriles, and the acetonitrile of diphenyl diazomethane is added dropwise at room temperature
Solution (256 g diphenyl diazomethanes are dissolved in 600 mL acetonitriles), the reaction was continued 0.5 ~ 3h after being added dropwise, steams after the reaction was completed
Dry reaction solvent is added the extraction of 2L methylene chloride and is concentrated to get 6 after organic phase is washed through saturated common salt, anhydrous sodium sulfate is dry
Alpha-brominated penam sulfoxide acid benzhydryl ester crude product is washed through the mashing of ethyl acetate/n-hexane (1:5) mixed solvent, gets rid of drum after material
Wind is dried to obtain 6 alpha-brominated 438 g of penam sulfoxide acid benzhydryl ester, and 150 ~ 154 DEG C of fusing point, yield 93.5%, HPLC purity
99.578%(is shown in attached drawing 1)；
Embodiment 2
The preparation of 6 alpha-brominated penam sulfoxide acid benzhydryl esters
By the alpha-brominated penam sulfoxide acid of 300 g 6 be added to 1.8 L methylene chloride and acetone mixed solution (methylene chloride:
Acetone=1:2, volume ratio) in, dichloromethane solution (the 256 g diphenyl diazomethanes of diphenyl diazomethane are added dropwise at room temperature
It is dissolved in 600 mL methylene chloride), the reaction was continued 0.5 ~ 3h after being added dropwise is evaporated reaction dissolvent after the reaction was completed, and 2L bis- is added
Chloromethanes extraction after organic phase is washed through saturated common salt, anhydrous sodium sulfate is dry, is concentrated to get 6 alpha-brominated penam sulfoxide acid
Benzhydryl ester crude product, through ethyl acetate/n-hexane=1:5(volume ratio) mixed solvent mashing wash, get rid of material after be dried to obtain 6 α-
446 g of bromo penam sulfoxide acid benzhydryl ester, 149 ~ 154 DEG C of fusing point, yield 95.3%, HPLC purity 98.735%(is shown in attached drawing
2)；.1H-NMR(600MHz, CDCl3): δ( ppm): 7. 40~7. 29( m, 10H, Ar-H); 6. 99( s, 1H,
( C6H5)2C-H) ; 5. 09( d, 1H, 5-H) ; 5.01 ( d, 1H, 6-H) ; 4. 65( s, 1H, 2-H) ;
1. 68 ( s, 3H, -CH3 ) ; 0. 94( s, 3H, -CH3 )。1H-NMR spectrum is shown in attached drawing 3.
Embodiment 3.
500 ml methylene chloride and 6 30 g of alpha-brominated penam sulfoxide acid are added at 0 ~ 5 DEG C into 1 L flask, stir dissolved clarification,
0 ~ 5 DEG C of addition benzhydrol 1.0 g of 20.0 g and DMAP of temperature control continues stirring to reaction system dissolved clarification.Maintain the temperature at 0 ~
23.0 g of DCC and 80 ml of methylene chloride is added at 5 DEG C, about 5.0 h drops finish, and keep the temperature 1.0 h.It filters after completion of the reaction, filtrate
It is washed at 0 ~ 5 DEG C with 50ml, 20 min is stood after stirring 10min and wait for that solution is layered, organic phase is taken, 8% is added thereto
20 min, which are stood, after 80 ml of sodium bicarbonate, stirring 10min waits for that solution is layered, methylene chloride is recycled in organic phase air-distillation,
Evaporated under reduced pressure obtains white solid again.80 g toluene are added into gained white solid, it is cooling in 40 ~ 50 DEG C of 1.0 h of heat preservation
To -5 DEG C of 4.0 h of crystallization, filtering is eluted with toluene, and suction filtration is dried to obtain 6 alpha-brominated penam sulfoxide acid benzhydryl esters 42.
5g, molar yield 90.7%, 151 ~ 154 DEG C of fusing point, HPLC purity 96.772%(is shown in attached drawing 4),
Embodiment 4
Be added into 500 mL round-bottomed bottles by 6 alpha-brominated penam sulfoxide acid 19.56g(0.0698mol), 138 mL of chloroform and water
69 mL are cooled to 0 DEG C under stirring.40% Peracetic acid, 13.94 g(0.0733 is added dropwise into mixture in 30 minutes
Mol), maintain 0 DEG C to continue stirring 30 minutes, Benzophenonehydrazones 14.81g(0.0755mol be added) and 1% potassium iodide aqueous solution 4.6
mL.Then 40% Peracetic acid 15.93g(0.0838mol is added in about 30 min at 0 DEG C), 10% sulfuric acid 5.5 is then added dropwise
mL.Mixture is stirred 1 hour at 0 DEG C, 1 h is then stirred at room temperature.Separate chloroform layer, water layer with chloroform (2 ×
50ml) extract.Merge organic layer to be washed with cold water (200mL), and stirs 30 points with saturated sodium bicarbonate (150mL) at 10 DEG C
Clock.Chloroform layer is dry with anhydrous sodium sulfate after saturated brine washs.Filter, concentration gained filtrate, through ethyl acetate/just oneself
Alkane=1:5(volume ratio) mixed solvent mashing wash, filter it is dry after obtain yellowish product 28.2g, yield 92.4%, fusing point 149 ~
153 DEG C of HPLC purity 98.648%(are shown in attached drawing 5).
Conclusion:
The present invention relates to a kind of new systems of the alpha-brominated penam sulfoxide acid benzhydryl ester of key intermediate 6 in Tazobactam Sodium synthesis
Preparation Method.Diphenyl diazomethane is added the following steps are included: 6 alpha-brominated penam sulfoxide acid are dissolved in organic solvent in it,
Decompression boils off solvent after complete reaction, is extracted with organic solvent, and organic layer is washed through saturated common salt, anhydrous sodium sulfate is dry
Afterwards, it depressurizes after boiling off solvent up to crude product.It is alpha-brominated to can be obtained 6 after organic solvent recrystallizes or mashing is washed for crude product
Penam sulfoxide acid benzhydryl ester.This method compared to it is traditional using condensing agents such as DCC at the method for ester, it is secondary to avoid reaction
Product is difficult to the problem of removing；It is esterified compared to using Benzophenonehydrazones/KI/ Peracetic acid system, simplifies operation, subtract
By-product generation is lacked, has improved the purity of final product, be more advantageous to industrialized production.
Embodiment 5
Using prepared by the present invention 6 alpha-brominated penam sulfoxide acid benzhydryl ester intermediates, reacts by 6 steps, be finally prepared into
To beta-lactamase inhibitor Tazobactam Sodium (preparation method is detailed in US2009012287A1；EP1813619A1；
CN101048417B patent document), physicochemical property is consistent with what above patent document was reported, it was demonstrated that: prepared by the present invention 6
Alpha-brominated penam sulfoxide acid benzhydryl ester can be completely used for the preparation of Tazobactam Sodium (tazobactam).
Claims (7)
1. a kind of preparation method of the alpha-brominated penam sulfoxide acid benzhydryl ester of Tazobactam Sodium key intermediate 6, which is characterized in that
It is carried out by following step:
(1) 6 alpha-brominated penam sulfoxide acid are dissolved in organic solvent, add diphenyl diazomethane in batches at -20 DEG C -50 DEG C
Enter into reaction system, react 0.5 ~ 48 h under magnetic stirring, decompression steams solvent, residue dichloromethane after the reaction was completed
Alkane or ethyl acetate extraction, after organic layer is washed through saturated common salt, anhydrous sodium sulfate is dry, decompression is produced after boiling off solvent up to thick
Product；The molar ratio of the 6 alpha-brominated penam sulfoxide acid and diphenyl diazomethane is 1:0.9 ~ 1:5；
(2) 6 alpha-brominated penam sulfoxide acid benzhydryl esters can be obtained after organic solvent recrystallizes or mashing is washed in crude product；
The organic solvent is protonic solvents or petroleum ether, n-hexane, methylene chloride, acetonitrile, the tetrahydro furans such as ethyl alcohol, methanol
Mutter,N,NOne of non-protonic solvents such as dimethylformamide, dimethyl sulfoxide, acetone, methyl iso-butyl ketone (MIBK) are a variety of；
The recrystallization solvent or mashing solvent are ethyl acetate, n-hexane, hexamethylene, petroleum ether, ethyl alcohol, methanol, acetonitrile, third
Ketone, tetrahydrofuran,N,NOne or more of dimethylformamide, dimethyl sulfoxide, water.
2. preparation method described in claim 1, it is characterised in that the 6 alpha-brominated penam sulfoxide acid and diphenyl diazonium first
The molar ratio of alkane is 1:0.9 ~ 1:1.5.
3. preparation method described in claim 1, it is characterised in that the organic solvent of 6 alpha-brominated penam sulfoxide acid of the dissolution
For ethyl acetate, methylene chloride, chloroform, ethyl acetate or methylene chloride/acetone mixed solvent.
4. preparation method as claimed in claim 3, it is characterised in that the recrystallization solvent is beaten solvent as methylene chloride/the third
The volume ratio of ketone is methylene chloride: acetone=1:2 mixed solvent.
5. preparation method described in claim 1, it is characterised in that the recrystallization solvent or mashing solvent are ethyl acetate/just
Hexane, methylene chloride/acetone, ethyl acetate/n-hexane or ethyl acetate/petroleum ether mixed solvent.
6. preparation method described in claim 5, it is characterised in that the recrystallization solvent or mashing solvent are ethyl acetate/just
The mixed solvent that hexane volume ratio is 1:5 mixed solvent or ethyl acetate/petroleum ether volume ratio is 1:4.
7. using claim 1 the method preparation 6 alpha-brominated penam sulfoxide acid benzhydryl esters be used to prepare treatment it is more
Application in the tazobactam drug of kind bacterium infection.
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| CN201711179934.6A CN109824696A (en) | 2017-11-23 | 2017-11-23 | A kind of preparation method of the alpha-brominated penam sulfoxide acid benzhydryl ester of Tazobactam Sodium key intermediate 6 |
| PCT/CN2018/000379 WO2019100544A1 (en) | 2017-11-23 | 2018-11-05 | METHOD FOR PREPARING TAZOBACTAM KEY INTERMEDIATE, 6α-BROMOPENICILLANIC SULFOXIDE ACID DIPHENYLMETHYL ESTER |
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| CN201711179934.6A CN109824696A (en) | 2017-11-23 | 2017-11-23 | A kind of preparation method of the alpha-brominated penam sulfoxide acid benzhydryl ester of Tazobactam Sodium key intermediate 6 |
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