CN110483498A - A kind of preparation method of Tazobactam Sodium intermediate - Google Patents
A kind of preparation method of Tazobactam Sodium intermediate Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of Tazobactam Sodium intermediate, the following steps are included: using benzhydryl s-oxopenicillanate and 2-mercaptobenzothiazole as reaction raw materials, using the mixed solvent of solvent A and solvent B as reaction dissolvent, in 70-90 DEG C, midbody compound shown in formula (II) is prepared in hot cracked ring-opening reaction;Wherein, the solvent A is ethyl acetate or normal heptane, and solvent B is dehydrated alcohol or isopropanol.Preparation method provided by the invention, not needing decompression can effectively reduce reaction temperature, and eliminate subsequent reduced pressure drying steps, the purity of midbody compound shown in formula (II) obtained is up to 92%, yield simplifies production technology up to 95.8%, greatly improves production efficiency, without increasing equipment investment, and solvent for use is cheap and easy to get, reduces production cost, meets Green Chemistry production requirement, it is suitble to large-scale industrial production, has broad application prospects.
Description
Technical field
The present invention relates to medication chemistry production technical field more particularly to a kind of preparation methods of Tazobactam Sodium intermediate.
Background technique
Tazobactam Sodium is a kind of novel penicillanic acid sulfones beta-lactamase inhibitor, is developed by Japanese roc drugmaker,
For treating various bacteria infection, have the characteristics that stability is high, toxicity is low, Inhibiting enzyme activity is strong.[(α R, 2R) -1- azetidin
Alkane acetic acid -2- (2-[4-morpholinodithio two is thio)-α-(1- methyl ethylene) -4- oxo-benzhydryl ester], it is synthesis Tazobactam Sodium
Key intermediate, No. CAS is 87579-79-1, shown in structural formula such as formula (II).Intermediate shown in formula (II) is by original
Expect that mould alkanoic acid benzhydryl ester sulfoxide and the hot cracked ring-opening reaction of 2-mercaptobenzothiazole obtain, therefore is generally also referred to as hot tearing
Solve ring-opening product.The reaction of midbody compound shown in preparation formula (II) in prior art, reaction temperature is high, generally requires 110
DEG C or more temperature, side reaction is more, causes a large amount of hexatomic ring by-product to generate, these hexatomic ring by-products and formula (II) institute
The property of the midbody compound shown is similar, it is difficult to separate, therefore, end reaction yield is only capable of reaching 89% or so, and purity is only
70% or so can be reached, be affected to subsequent reactions.Midbody compound shown in preparation formula (II) is anti-in prior art
It answers, there is also the moisture that reduced pressure or rectifying are needed after open loop cracking reaction to generate except dereaction, could be carried out
The problem of reacting in next step, cumbersome, the reaction time is long, does not meet the requirement of green chemistry process, is unfavorable for realizing industry
Metaplasia produces.
Summary of the invention
For midbody compound shown in existing preparation formula (II) reaction process there are reaction temperature height, step is more,
Product yield and the lower problem of purity, the present invention provide a kind of preparation method of Tazobactam Sodium intermediate.
In order to solve the above technical problems, present invention provide the technical scheme that
A kind of preparation method of Tazobactam Sodium intermediate, comprising the following steps:
Using benzhydryl s-oxopenicillanate and 2-mercaptobenzothiazole as reaction raw materials, with the mixing of solvent A and solvent B
Solvent is as reaction dissolvent, and in 70-90 DEG C, midbody compound shown in formula (II) is prepared in hot cracked ring-opening reaction;
Wherein, the solvent A is ethyl acetate or normal heptane, and solvent B is dehydrated alcohol or isopropanol.
In above-mentioned thermal cracking ring-opening reaction, raw material benzhydryl s-oxopenicillanate is heated at a certain temperature, point
Son can temporarily generate shakiness and center, and promote σ-H to obtain energy and migrate, obtain intermediates aza cyclo-butanone sulfenic acids
Intermediate, this transition state is highly unstable, can quickly react with 2-mercaptobenzothiazole, generate thermal cracking ring-opening product.
Thermal cracking ring-opening reaction is the endothermic reaction, therefore, in order to improve reaction efficiency and conversion ratio, generally requires higher reaction temperature
Degree.The prior art generally uses 100 DEG C or more of reaction temperature, but reaction temperature is higher, also easier production by-product, produces
Raw a large amount of hexatomic ring impurity.Skilled person realizes by the way of reduced-pressure backflow to reduce the generation of by-product
The reaction of mould alkanoic acid benzhydryl ester sulfoxide and 2-mercaptobenzothiazole under lower temperature (70-80 DEG C), but it is subsequent also
Need to be concentrated under reduced pressure drying, cumbersome, the high requirements on the equipment, increase equipment investment, and obtained thermal cracking ring-opening product
Purity is about 70% or so, although reducing reaction temperature, does not significantly improve the purity of product.
Compared with the existing technology, the preparation method of Tazobactam Sodium intermediate provided by the invention, with penicillanic acid hexichol first
Ester sulfoxide and 2-mercaptobenzothiazole are reaction raw materials, and selection is by a kind of and ethyl alcohol or isopropanol in ethyl acetate or normal heptane
One of, composition mixed solvent cracks to obtain midbody compound shown in formula (II) through open loop as reaction dissolvent.This
The mixed solvent of invention selection can not only increase the uniformity coefficient of reaction system, effectively eliminate hinder reactant between contact because
Element increases reactant collision probability, improves conversion ratio;The transition state aza cyclo-butanone sulfenic acids intermediate generated can also be made more to hold
Solvolytic reaction easily occurs, reduces the position energy of transition state aza cyclo-butanone sulfenic acids intermediate, reduces the two reaction difficulty, adds
The fast reaction rate of transition state and 2-mercaptobenzothiazole, therefore, reaction temperature is lower, and the reaction time is shorter;It is prior
It is that the mixed solvent that the present invention selects can also continue transition state aza cyclo-butanone sulfenic acids and 2- sulfydryl benzene during the reaction
And the water removing that thiazole condensation reaction obtains, promote the two reaction forward to carry out, effectively improves conversion ratio.Since the present invention provides
Tazobactam Sodium intermediate preparation method, can react at a lower temperature, therefore, also effectively reduce the life of by-product
At the purity for the thermal cracking ring-opening product being prepared is higher.
Preferably, the Tazobactam Sodium intermediate preparation method the following steps are included:
Step 1: solvent A and solvent B are uniformly mixed, mixed solvent is obtained, the mixed solvent is heated to 70-90 DEG C,
Benzhydryl s-oxopenicillanate is added, is stirred to react 5-30min, obtains among the aza cyclo-butanone sulfenic acids as shown in formula (I)
Body;
Step 2: 2-mercaptobenzothiazole is added into the aza cyclo-butanone sulfenic acids intermediate, reacted in 70-90 DEG C
1-6h is concentrated by evaporation, give light yellow oil;
Step 3: ether is added into the light yellow oil, it is uniformly mixed, is cooled to 0-10 DEG C, growing the grain obtains formula
(II) midbody compound shown in, reaction equation are as follows.
The preparation method of Tazobactam Sodium intermediate provided by the invention, not needing decompression can effectively reduce reaction temperature,
And eliminate subsequent reduced pressure drying steps, the purity of midbody compound shown in formula (II) obtained up to 92%,
Yield simplifies production technology up to 95.8%, greatly improves production efficiency, without increasing equipment investment, and solvent for use
It is cheap and easy to get, production cost is reduced, Green Chemistry production requirement is met, is suitble to large-scale industrial production, there is wide answer
Use prospect.
Preferably, the molar ratio of the solvent A and solvent B are 1:1-5.
It is furthermore preferred that the molar ratio of the solvent A and solvent B are 1:1.5-2.5.
Preferably, the mass ratio of the benzhydryl s-oxopenicillanate and the mixed solvent is 1:10-25.
It is furthermore preferred that the mass ratio of the benzhydryl s-oxopenicillanate and the mixed solvent is 1:12-15.
Preferably, the solvent A is normal heptane, and the solvent B is dehydrated alcohol.
The ratio of preferred mixed solvent composition and benzhydryl s-oxopenicillanate and mixed solvent, can be such that raw material fills
Divide and be dissolved in solvent, increases the collision probability between reactant, and be effectively reduced among transition state aza cyclo-butanone sulfenic acids
The position energy of body, reduces the reaction energy barrier of transition state and 2-mercaptobenzothiazole, to reduce reaction temperature, improves reaction rate;
And preferably solvent promotes reaction forward to carry out than the water that as much as possible can also be removed condensation reaction and generate, raising, which is reacted, to be turned
Rate.
Preferably, the molar ratio of the benzhydryl s-oxopenicillanate and the 2-mercaptobenzothiazole is 1:0.5-
2.5。
It is furthermore preferred that the molar ratio of the benzhydryl s-oxopenicillanate and the 2-mercaptobenzothiazole is 1:1-2.
The ratio of preferred benzhydryl s-oxopenicillanate and 2-mercaptobenzothiazole can promote reaction forward progress,
The generation for reducing by-product, improves the purity and yield of product.
Preferably, in step 1, reaction time 13-17min.
It is furthermore preferred that the reaction time is 15min in step 1.
Preferably, in step 2, reaction time 1.5-2.5h.
It is furthermore preferred that the reaction time is 2h in step 2.
Preferably, in step 3, rearing crystal time 20-25h.
Preferably, in step 1 and step 2, reaction temperature is 75 DEG C.
Preferred reaction temperature and reaction time can be improved reaction speed, and reduces the generation of side reaction.
Preferably, in step 2, the temperature of evaporation and concentration is 35-45 DEG C, and the time of evaporation and concentration is 20-30min.
The temperature and time being preferably concentrated by evaporation can quickly remove the solvent in product, while also be avoided that evaporation is dense
Influence of the contracting processing to product quality, avoids generation of the impurity in evaporating concentration process, further ensures the purity of product.
Preferably, in step 3, the mass ratio of the additional amount of the ether and the light yellow oil is 5-15:1.
Preferred ether additional amount can make after being cooled to crystallization temperature, and the degree of supersaturation in system is easier to control one
It is a to be conducive in the range of crystal well grows, and do not allow to be also easy to produce impurity inclusion, be conducive to the raising of product purity.
Detailed description of the invention
Fig. 1 be embodiment 1 prepare thermal cracking ring-opening product hydrogen nuclear magnetic resonance spectrogram (1HNMR);
Fig. 2 is the high-efficient liquid phase chromatogram of the thermal cracking ring-opening product prepared in embodiment 1;
Fig. 3 is the high-efficient liquid phase chromatogram of thermal cracking ring-opening product prepared by comparative example 3.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1
A kind of preparation method of Tazobactam Sodium intermediate:
Step 1: 51mL normal heptane and 51mL dehydrated alcohol are added in 100mL reaction flask, it is uniformly mixed, must mixes molten
The mixed solvent oil bath is heated to 75 DEG C, 5g benzhydryl s-oxopenicillanate is added, is stirred to react 15min by agent, obtain as
Aza cyclo-butanone sulfenic acids intermediate shown in formula (I);
Step 2: 4.37g2- mercaptobenzothiazoler is added into the aza cyclo-butanone sulfenic acids intermediate, kept for 75 DEG C
2h is reacted, reaction solution is concentrated by evaporation 23min, give light yellow oil at 40 DEG C;
Step 3: the ether of 10 times of its quality is added into the light yellow oil, ultrasonic dissolution is cooled to 5 DEG C, supports
For 24 hours, white crystal 6.65g, yield 95.8%, purity 92.8% is precipitated in crystalline substance.
Thermal cracking ring-opening product shown in formula (II) prepared by embodiment 1 is passed through1HNMR carries out Structural Identification, such as Fig. 1 institute
Show, as a result as follows:
1H NMR(500MHz,CDCl3) δ 7.88 (d, J=8.1Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.45 (t, J
=7.7Hz, 1H), 7.40-7.27 (m, 11H), 6.91 (s, 1H), 5.38 (s, 1H), 5.14 (s, 1H), 5.00 (s, 1H), 4.91
(s, 1H), 3.44 (dd, J=15.4,4.7Hz, 1H), 3.21 (d, J=15.4Hz, 1H), 1.91 (s, 3H).
The high-efficient liquid phase chromatogram of thermal cracking ring-opening product shown in formula (II) manufactured in the present embodiment is as shown in Figure 2.
Embodiment 2
A kind of preparation method of Tazobactam Sodium intermediate:
Step 1: 35mL normal heptane and 37mL isopropanol are added in 100mL reaction flask, it is uniformly mixed, obtains mixed solvent,
The mixed solvent oil bath is heated to 70 DEG C, 4g benzhydryl s-oxopenicillanate is added, is stirred to react 30min, obtains such as formula
(I) aza cyclo-butanone sulfenic acids intermediate shown in;
Step 2: 2.62g2- mercaptobenzothiazoler is added into the aza cyclo-butanone sulfenic acids intermediate, kept for 70 DEG C
6h is reacted, reaction solution is concentrated by evaporation 25min, give light yellow oil at 35 DEG C;
Step 3: the ether of 5 times of its quality is added into the light yellow oil, ultrasonic dissolution is cooled to 0 DEG C, supports
White crystal 2.79g, yield 95.8%, purity 89.2% is precipitated in brilliant 25h.
Thermal cracking ring-opening product shown in formula (II) prepared by embodiment 2 is passed through1HNMR carries out Structural Identification, as a result such as
Under:
1H NMR(500MHz,CDCl3) δ 7.88 (d, J=8.1Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.45 (t, J
=7.7Hz, 1H), 7.40-7.27 (m, 11H), 6.91 (s, 1H), 5.38 (s, 1H), 5.14 (s, 1H), 5.00 (s, 1H), 4.91
(s, 1H), 3.44 (dd, J=15.4,4.7Hz, 1H), 3.21 (d, J=15.4Hz, 1H), 1.91 (s, 3H).
Embodiment 3
A kind of preparation method of Tazobactam Sodium intermediate:
Step 1: 20mL ethyl acetate and 23mL isopropanol are added in 100mL reaction flask, it is uniformly mixed, must mixes molten
The mixed solvent oil bath is heated to 85 DEG C, 1.4g benzhydryl s-oxopenicillanate is added, is stirred to react 8min, obtains by agent
The aza cyclo-butanone sulfenic acids intermediate as shown in formula (I);
Step 2: 1.31g2- mercaptobenzothiazoler is added into the aza cyclo-butanone sulfenic acids intermediate, kept for 85 DEG C
3h is reacted, reaction solution is concentrated by evaporation 20min, give light yellow oil at 45 DEG C;
Step 3: the ether of 8 times of its quality is added into the light yellow oil, ultrasonic dissolution is cooled to 10 DEG C, supports
White crystal 1.82g, yield 93.3%, purity 91.2% is precipitated in brilliant 20h.
Thermal cracking ring-opening product shown in formula (II) prepared by embodiment 3 is passed through1HNMR carries out Structural Identification, as a result such as
Under:
1H NMR(500MHz,CDCl3) δ 7.88 (d, J=8.1Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.45 (t, J
=7.7Hz, 1H), 7.40-7.27 (m, 11H), 6.91 (s, 1H), 5.38 (s, 1H), 5.14 (s, 1H), 5.00 (s, 1H), 4.91
(s, 1H), 3.44 (dd, J=15.4,4.7Hz, 1H), 3.21 (d, J=15.4Hz, 1H), 1.91 (s, 3H).
Embodiment 4
A kind of preparation method of Tazobactam Sodium intermediate:
Step 1: 10mL ethyl acetate and 6mL dehydrated alcohol are added in 100mL reaction flask, it is uniformly mixed, must mixes molten
The mixed solvent oil bath is heated to 90 DEG C, 1g benzhydryl s-oxopenicillanate is added, is stirred to react 5min by agent, obtain as
Aza cyclo-butanone sulfenic acids intermediate shown in formula (I);
Step 2: 0.22g2- mercaptobenzothiazoler is added into the aza cyclo-butanone sulfenic acids intermediate, kept for 90 DEG C
1h is reacted, reaction solution is concentrated by evaporation 30min, give light yellow oil at 38 DEG C;
Step 3: the ether of 15 times of its quality is added into the light yellow oil, ultrasonic dissolution is cooled to 5 DEG C, supports
For 24 hours, white crystal 0.89g, yield 92.4%, purity 88.6% is precipitated in crystalline substance.
Thermal cracking ring-opening product shown in formula (II) prepared by embodiment 4 is passed through1HNMR carries out Structural Identification, as a result such as
Under:
1H NMR(500MHz,CDCl3) δ 7.88 (d, J=8.1Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.45 (t, J
=7.7Hz, 1H), 7.40-7.27 (m, 11H), 6.91 (s, 1H), 5.38 (s, 1H), 5.14 (s, 1H), 5.00 (s, 1H), 4.91
(s, 1H), 3.44 (dd, J=15.4,4.7Hz, 1H), 3.21 (d, J=15.4Hz, 1H), 1.91 (s, 3H).
Comparative example 1
A kind of preparation method of Tazobactam Sodium intermediate:
Step 1: 51mL n-butyl acetate and 51mL dehydrated alcohol are added in 100mL reaction flask, it is uniformly mixed, obtains mixed
The mixed solvent oil bath is heated to 90 DEG C, 5g benzhydryl s-oxopenicillanate is added, is stirred to react 15min by bonding solvent,
Obtain the aza cyclo-butanone sulfenic acids intermediate as shown in formula (I);
Step 2: 4.37g2- mercaptobenzothiazoler is added into the aza cyclo-butanone sulfenic acids intermediate, kept for 90 DEG C
2h is reacted, reaction solution is concentrated by evaporation 25min, give light yellow oil at 40 DEG C;
Step 3: 35mL ether is added into the light yellow oil, ultrasonic dissolution is cooled to 5 DEG C, and growing the grain for 24 hours, is analysed
White crystal 5.41g out, yield 78%, purity 46%.
Water has been not observed in water segregator during the experiment to separate, has illustrated n-butyl acetate and dehydrated alcohol not
The water that dehydrating condensation in experimentation generates can be separated.And if temperature is lower than 90 DEG C, benzhydryl s-oxopenicillanate
It cannot react between 2-mercaptobenzothiazole.
Comparative example 2
A kind of preparation method of Tazobactam Sodium intermediate:
Step 1: 51mL toluene and 51mL hexamethylene are added in 100mL reaction flask, it is uniformly mixed, obtains mixed solvent, it will
The mixed solvent oil bath is heated to 80 DEG C, and 5g benzhydryl s-oxopenicillanate is added, is stirred to react 15min, obtains such as formula (I)
Shown in aza cyclo-butanone sulfenic acids intermediate;
Step 2: 4.37g2- mercaptobenzothiazoler is added into the aza cyclo-butanone sulfenic acids intermediate, kept for 80 DEG C
2h is reacted, reaction solution is concentrated by evaporation 25min, give light yellow oil at 40 DEG C;
Step 3: 35mL ether is added into the light yellow oil, ultrasonic dissolution is cooled to 5 DEG C, and growing the grain for 24 hours, is analysed
White crystal 5.41g out, yield 86.5%, purity 69.4%.
If this reaction temperature is lower than 80 DEG C, cannot be sent out between benzhydryl s-oxopenicillanate and 2-mercaptobenzothiazole
Raw reaction.
Comparative example 3
Water segregator is installed on 500mL four-hole bottle, has serpentine condenser on water segregator, is installed on serpentine condenser top
The vacuum tube of vacuum pump and the valve for adjusting sucking rate are accessed, 200mL toluene, 38.35g are put into four-hole bottle
(0.10mol) benzhydryl s-oxopenicillanate, 16.73g (0.10mol) 2-mercaptobenzothiazole, by adjusting sucking rate, control
Temperature is 70-80 DEG C, reduced-pressure backflow 3h in system, when HPLC detection benzhydryl s-oxopenicillanate residual is less than 1%, is terminated anti-
It answers, is concentrated to dryness, 200mL tetrahydrofuran stirring and dissolving is added, filter off insoluble matter, filtrate decompression is concentrated to dryness, obtains white
Color solid, yield 86.7%, product purity 71.6%.
The high-efficient liquid phase chromatogram that this comparative example prepares product is as shown in Figure 3, wherein 6.7min or so corresponding is formula
(II) thermal cracking ring-opening product shown in, 4.2min or so is corresponding be major impurity diphenyl disulfide produced during the preparation process simultaneously
Thiazole.The preparation method that comparison diagram 2 and Fig. 3 can be seen that open loop lysate provided by the invention can significantly reduce containing for impurity
Amount.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modification, equivalent replacement or improvement etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. a kind of preparation method of Tazobactam Sodium intermediate, which comprises the following steps:
Using benzhydryl s-oxopenicillanate and 2-mercaptobenzothiazole as reaction raw materials, with the mixed solvent of solvent A and solvent B
As reaction dissolvent, in 70-90 DEG C, midbody compound shown in formula (II) is prepared in hot cracked ring-opening reaction;
Wherein, the solvent A is ethyl acetate or normal heptane, and solvent B is dehydrated alcohol or isopropanol.
2. the preparation method of Tazobactam Sodium intermediate as described in claim 1, which comprises the following steps:
Step 1: solvent A and solvent B are uniformly mixed, mixed solvent is obtained, the mixed solvent is heated to 70-90 DEG C, is added
Benzhydryl s-oxopenicillanate is stirred to react 5-30min, obtains the aza cyclo-butanone sulfenic acids intermediate as shown in formula (I);
Step 2: 2-mercaptobenzothiazole is added into the aza cyclo-butanone sulfenic acids intermediate, in 70-90 DEG C of reaction 1-
6h is concentrated by evaporation, give light yellow oil;
Step 3: ether is added into the light yellow oil, it is uniformly mixed, is cooled to 0-10 DEG C, growing the grain obtains formula (II) institute
The midbody compound shown.
3. the preparation method of Tazobactam Sodium intermediate as claimed in claim 1 or 2, which is characterized in that the solvent A and solvent
The molar ratio of B is 1:1-5;And/or
The mass ratio of the benzhydryl s-oxopenicillanate and the mixed solvent is 1:10-25;And/or
The molar ratio of the benzhydryl s-oxopenicillanate and the 2-mercaptobenzothiazole is 1:0.5-2.5.
4. the preparation method of Tazobactam Sodium intermediate as claimed in claim 3, which is characterized in that the solvent A and solvent B's
Molar ratio is 1:1.5-2.5;And/or
The mass ratio of the benzhydryl s-oxopenicillanate and the mixed solvent is 1:12-15;And/or
The molar ratio of the benzhydryl s-oxopenicillanate and the 2-mercaptobenzothiazole is 1:1-2.
5. the preparation method of Tazobactam Sodium intermediate as claimed in claim 1 or 2, which is characterized in that the solvent A is positive heptan
Alkane, the solvent B are dehydrated alcohol.
6. the preparation method of Tazobactam Sodium intermediate as claimed in claim 2, which is characterized in that in step 1, the reaction time
For 13-17min;And/or
In step 2, reaction time 1.5-2.5h.
7. the preparation method of Tazobactam Sodium intermediate as claimed in claim 2, which is characterized in that in step 2, be concentrated by evaporation
Temperature be 35-45 DEG C, time of evaporation and concentration is 20-30min.
8. the preparation method of Tazobactam Sodium intermediate as claimed in claim 2, which is characterized in that in step 3, the ether
Additional amount and the light yellow oil mass ratio be 5-15:1.
9. the preparation method of Tazobactam Sodium intermediate as claimed in claim 2, which is characterized in that in step 3, rearing crystal time
For 20-25h.
10. the preparation method of Tazobactam Sodium intermediate as claimed in claim 2, which is characterized in that in step 1 and step 2,
Reaction temperature is 75 DEG C;And/or
The reaction time is 15min in step 1;And/or
The reaction time is 2h in step 2.
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CN111004231A (en) * | 2019-12-18 | 2020-04-14 | 凯莱英医药集团(天津)股份有限公司 | Continuous synthesis method of tazobactam intermediate |
CN113073348A (en) * | 2021-03-29 | 2021-07-06 | 吉林凯莱英制药有限公司 | Method for electrochemically synthesizing tazobactam key intermediate |
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