CN109096283A - A kind of preparation method of high-purity tebipenem crystalline esters - Google Patents
A kind of preparation method of high-purity tebipenem crystalline esters Download PDFInfo
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- CN109096283A CN109096283A CN201811019995.0A CN201811019995A CN109096283A CN 109096283 A CN109096283 A CN 109096283A CN 201811019995 A CN201811019995 A CN 201811019995A CN 109096283 A CN109096283 A CN 109096283A
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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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- 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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Abstract
The invention discloses a kind of preparation methods of high-purity tebipenem crystalline esters comprising following steps: the first solvent being added into L-084 crude product, stirs, obtains just molten product；At the reaction temperatures, the second solvent is added dropwise into first molten product, thereafter stirring and crystallizing；First solvent includes water, and second solvent is acetonitrile, and the reaction temperature is 0~60 DEG C.The tebipenem crystalline esters of high-purity, low-residual quantity of solvent can be prepared in the present invention.
Description
Technical field
The present invention relates to the technical fields of the preparation of high-purity L-084.
Summary of the invention
(+)-methylol (4R, 5S, 6S) -6- [(1R) -1- ethoxy] -4- methyl -7- oxygen -3- { [1- (2- thiazoline -2-
Base) -3- azetidin -1- azabicyclo [3.2.0] hept-2-ene" -2- -2- volt esters of carboxylate, i.e. L-084 are a kind of
The oral new broad-spectrum antibiotic of Carbapenems, grinds exploitation by Hui Shi Rieter Perfojet original, transfers Japanese Mingzhi drugmaker later,
And ratify in the Japan of acquisition in 2 months 2009, listing in April in the same year.The drug is to except small parts bacterium such as enterococcus faecium and Pseudomonas aeruginosas
Most of bacterial strains being clinically separated outside kind show antibiotic property more stronger than penicillin series and cephalo series and first
It is a to be infected for streptococcus pneumonia drug resistance strain, the penem-like pharmaceutical including duration tympanitis, bacterial pneumonia etc..It is to large intestine
The white bacterium of bacillus, kerekou pneumonia, Hemophilus influenzae, Legionella pneumonia inhibitory activity be better than comparison medicine such as Imipenem, cephalo
Buddhist nun, Amoxicillin and levofloxacin magnitude.Meanwhile compared with the carbapenem antibiotic of other injections, L-084
Also the antibacterial effect for showing identical or stronger degree, especially for the resistance to mould for causing childhood infection main cause in recent years
Plain streptococcus pneumonia (PRSP), resistance to erythromycin streptococcus pneumonia (MRSP) and haemophilus influenzae
(HaemophilusInfluenzae) extremely strong antibacterial effect is shown.Clinical research shows L-084 to children's lung
Inflammation, tympanitis, paranasal sinus inflammation have significant curative effect, the favor by numerous drugmakers.
More research is carried out to the synthesis of L-084 in the prior art, wherein a kind of relatively universal and effective conjunction
At method such as document J.Antibiot.59 (4): as described in 241-247, including following synthetic route:
It is crude product by the L-084 that the above method synthesizes, purity is lower, can not directly carry out medicinal, need
It further to purify.
The purification process taken in the prior art be mainly included in L-084 crude product be added ethyl acetate stirring or
Grinding dissolution is added thereafter other solvents or changes the step of carrying out crystallization by temperature, wherein common other solvents include
Alcohols, alkanes, ethers, esters etc..But researcher investigates these purification process repeatedly, it has been found that it exists
Excessive cycle when crystallization slow (the usual crystallization time was up to for more than 20 a hours), industrial production, crystallization yield is low, product melting range
Long, particle disperses the defects of uneven, and especially it is generally also provided with the Q3C that residual solvent is unable to satisfy in ICH guideline
Residual solvent bound requirements this serious problems.
Summary of the invention
It is an object of the invention to propose a kind of system of the tebipenem crystalline esters of available high-purity, low-residual solvent
Preparation Method.
The present invention also aims to propose that residual solvent meets Q3C in ICH in a kind of gained tebipenem crystalline esters
The preparation method of the guideline of residual solvent.
The present invention also aims to propose that a kind of industrial production campaign is short, crystallization yield is high, and product melting range is short, crystal shape
The preparation method of the tebipenem crystalline esters of shape rule, uniform particle diameter.
Technical scheme is as follows:
A kind of preparation method of high-purity tebipenem crystalline esters comprising following steps:
(1) the first solvent is added into L-084 crude product, stirs, obtains just molten product；
(2) at the reaction temperatures, the second solvent is added dropwise into the just molten product, stirring and crystallizing, crystal is filtered thereafter, is done
It is dry；
First solvent includes water, and second solvent is acetonitrile, and the reaction temperature is 0~60 DEG C；
Shown in the structural formula of the L-084 such as formula (I):
In above scheme:
In the step (1) L-084 crude product can not washed sufficiently after the completion of just preparation, it is dry for than training
Southern ester can also be the L-084 having been subjected to after washing, drying, for self-control or can also buy pure through other extractions, crystallization
The L-084 coarse crystal of residual solvent bound requirements is unable to satisfy after change method.
Further, the L-084 crude product can be washed, dry to be prepared by following synthetic route
Or the product without sufficiently washing, being dried to obtain:
Further, the bound requirements of the residual solvent, referring to the residual solvent limit of the Q3C in ICH guideline
It is required that the bound requirements such as partial solvent are as shown in the table:
| Solvent | Solvent classes | ICH limit |
| Methanol | Two classes | 0.3% |
| Ethyl acetate | Three classes | 0.5% |
| Acetone | Three classes | 0.5% |
| Normal heptane | Three classes | 0.5% |
| The tertiary ether of first | Three classes | 0.5% |
| Acetonitrile | Two classes | 0.041% |
First solvent is preferably only water.
Inventors have found that because in tebipenem ester molecular structure contain multiple oxygen atoms, by common recrystallisation solvent (such as
Esters, alcohols, ketone equal solvent) purified during, can with solvent generate intramolecular hydrogen bond, formed solvent chemical combination
Object, so that solvent be caused to wrap up, this solvent package, subsequent to handle anyway once being formed, is all difficult to further decrease molten
Agent residual quantity, so that solvent residual amount is unable to satisfy bound requirements.
Inventor also found that the structure of L-084 is unstable at high temperature, molten to reduce by conventional raising drying
The remaining method of agent can make L-084 degrade in the drying process, increase in relation to dopant species in substance, content
It increases, causes product unqualified, therefore should not all make product exposure during purifying or when finishing up at too high a temperature.
For the present invention by the first solvent, height is can be obtained under the action of particular step, temperature in such as water and the second solvent acetonitrile
The tebipenem crystalline esters of purity, low-residual solvent.
In a preferred embodiment the volume ratio of the L-084 crude product and first solvent be 1:1~
1:10, preferably 1:5~1:8；The volume ratio of second solvent and first solvent is 0.5:1~5:1, preferably 2:1
~3:1.
After the preferred embodiment may make the second solvent of addition, product is prevented from caking, and crystallization is uniform, and height finally can be obtained
Spend uniform, regular crystal.
It is 1:1~1:10, described the in the volume ratio of preferred embodiment L-084 crude product and first solvent
The volume ratio of two solvents and first solvent is obtained product L-084 crystal yield > in 0.5:1~5:1
85%, purity > 99.2%, residual solvent ethane nitrile content < 0.04%.
The volume ratio of the second solvent described in further preferred embodiment and first solvent is to obtain in 2:1~3:1
Product L-084 crystal yield > 95%, purity > 99.8%, residual solvent ethane nitrile content≤0.025%.
Another preferred embodiment of the invention is that the reaction temperature is 40~60 DEG C, preferably 50 DEG C.
Under two kinds of preferred embodiments, the present invention can complete crystal preparation within the crystallization time of 1~5h.
Another preferred embodiment of the invention is that the stirring rate in the step (2) is 200~400rpm.
Its further be preferably the step (2) in stirring rate be 300~350rpm.
Another preferred embodiment of the invention is that the temperature of drying described in the step (2) is 50~60 DEG C.
The tebipenem crystalline esters that chemical stability is high, impurity content is low can be obtained in the preferred embodiment.
It is 0.5~5h that another preferred embodiment of the invention, which is the crystallization time described in the step (2),.Further
Preferably 2~3h.
The present invention is also equipped with following some preferred embodiments:
The volume ratio of the L-084 crude product and first solvent is 1:1~1:10, and second solvent with
The volume ratio of first solvent is 2:1~3:1, and the reaction temperature is 40~50 DEG C, and the stirring in the step (2)
Rate is 300~350rpm.
Under the preferred embodiment, high-purity, high yield, short melting range, low molten can be obtained under the crystallization time of 1~3h
The uniform tebipenem crystalline esters of the shape of agent residual quantity.
Or the volume ratio of the L-084 crude product and first solvent is 1:1~1:10, and second solvent
Volume ratio with first solvent is 2:1, and the reaction temperature is 50 DEG C, and the stirring rate in the step (2) is
300rpm, and the time of the crystallization is 2h.Under the preferred embodiment, remained in obtained high-purity tebipenem crystalline esters
The content < 0.02% of solvent.
In a kind of specific embodiment of the invention, the L-084 crude product includes following preparation step:
S1: four hydrate of raw material tebipenem, dimethylformamide (DMF), N, N- diisopropylethylamine is added
(DIPEA), benzyltriethylammoinium chloride reacts at room temperature；
S2: chloromethyl pivalate being added into the mixed liquor of reaction, is warming up to 45 DEG C of reactions thereafter；
S3: it after the reaction was completed to S2, by mixed liquor cooling, adds water and stirs, organic solvent is added thereafter and carries out one or more times
The organic phase being obtained by extraction is adjusted with acid liquid separation after pH to 4.0 ± 0.1 by extraction, and the water phase that liquid separation is obtained uses organic molten
Water phase remaining after extraction alkali is adjusted pH to 7.5 ± 0.1, reuses organic solvent extraction thereafter, will extract by agent extraction
Obtained organic phase washing one or more times, thereafter dries, filters organic phase, is concentrated to get L-084 crude product is arrived.
Organic solvent described in the step S3 described in a kind of more specific embodiment is ethyl acetate.
Or/and the time of reaction described in the step S1 is 50~70min.
Or/and the time of reaction described in the step S2 is 4.5~5.5h.
The present invention have it is following the utility model has the advantages that
(1) the present invention can obtain high-purities, the tebipenem crystalline esters of low-residual solvent；
(2) the present invention can obtain residual solvent levels lower than in ICH the residual solvent bound requirements of Q3C it is medicinal for than
Train southern crystalline esters；
(3) industrial production campaign of the invention is short, and crystallization yield is high, and product melting range is short, and obtained crystal shape is regular, equal
One, solvent-free package；
(4) the present invention can obtain crystal yield > 85%, purity > 99.2%, residual solvent ethane nitrile content < 0.04%
Medicinal tebipenem crystalline esters；
(5) present invention can also obtain crystal yield > 95%, purity > 99.8%, and residual solvent ethane nitrile content≤
0.025% medicinal tebipenem crystalline esters；
(6) present invention can also obtain crystal yield > 95%, purity > 99.8%, residual solvent ethane nitrile content <
0.02% medicinal tebipenem crystalline esters.
Detailed description of the invention
Fig. 1 is the polarization microscope picture of 2 gained high-purity tebipenem crystal of embodiment；
Fig. 2 is the HPLC purity detecting result of 2 gained high-purity tebipenem crystal of embodiment；
Fig. 3 is the polarization microscope picture of contrast sample 1 obtained in embodiment 3；
Fig. 4 is the polarization microscope picture of contrast sample 2 obtained in embodiment 4；
Fig. 5 is the polarization microscope picture of contrast sample 3 obtained in embodiment 5；
Fig. 6 is the polarization microscope picture of contrast sample 4 obtained in embodiment 6.
Specific embodiment
Below by way of some specific embodiments, the present invention is described in further detail, but this should not be interpreted as this hair
Bright range is only limitted to embodiment below.Without departing from the idea of the above method of the present invention, common according to this field
The various replacements or change that technological know-how and customary means are made, should be included in the scope of the present invention.
The preparation of 1 L-084 crude product of embodiment
Four hydrate 1.0kg of tebipenem, dimethylformamide (DMF) 3L, N, N- bis- are added into the reaction flask of 5L
Wopropyl ethyl amine (DIPEA) 0.7kg, benzyltriethylammoinium chloride (TBAB) 500g, react 60min at 25 DEG C, thereafter this temperature
Degree is lower to be added dropwise chloromethyl pivalate 500g, and drop, which finishes, is warming up to 45 DEG C of reaction 5h, after completion of the reaction, is cooled to room temperature, water 3L is added to stir
After mixing 10min, ethyl acetate 3L is added and extracts, and remaining water phase ethyl acetate 3L is extracted once, merges acetic acid second thereafter
Ester phase adjusts pH to 4.0 ± 0.1 with 1N citric acid solution, and the ethyl acetate 3L of the water phase after liquid separation is extracted three by liquid separation thereafter
It is secondary, organic phase is discarded, water phase unsaturated carbonate potassium solution is adjusted into pH to 7.5 ± 0.1, is extracted again with 3L ethyl acetate thereafter
Three times, and merge organic phase and washed five times with saturated sodium chloride solution 3L, collect organic phase, be dried overnight with anhydrous sodium sulfate,
Filtering, filtrate are concentrated to dryness, and obtain off-white color formula solid 1.05kg, are L-084 crude product shown in formula (I), and HPLC is pure
Degree is 98.5%.
The preparation of 2 high-purity tebipenem crystalline esters of embodiment
Acetonitrile is added dropwise thereafter in water in the stirring of crude product 100g made from Example 1, slightly rising temperature for dissolving, stirs when being added dropwise
It mixes, and continues stirring a period of time after being added dropwise, constantly carry out crystallization in solution, white solid persistently occur, thereafter mistake
White solid is dried in vacuo to get to high-purity tebipenem crystalline esters at 50 DEG C, during the preparation process, adjusts water by filter
Test of many times is carried out with the stirring rate in the volume ratio of acetonitrile, crystallization temperature, crystallization time and Crystallization Process, and is measured every
It is secondary to test the obtained purity of sample, the content of residual solvent acetonitrile, melting range, its yield respectively is calculated, as a result such as
Shown in following table:
Polarized light microscope observing is carried out to above-mentioned sample, it will be seen that gained sample is that the white without package solvent is spherical
Object, form is regular uniformly, as shown in Fig. 1.
Embodiment 3 prepares tebipenem crystal using water and methanol
Methanol is added dropwise thereafter in water in 1 gained L-084 crude product 100g of Example stirring, slightly rising temperature for dissolving,
Side stirring is added dropwise in 60 DEG C of crystallization temperature below, and continues to stir 5h progress crystallization after being added dropwise, and filters thereafter, by crystal
It is dried in vacuo at 50 DEG C, obtains contrast sample 1, discovery is compared under the volume ratio of different water and methanol in experiment
1 average purity of sample is 99.04%, and Determination of Residual Methanol 0.8%, observing its polarised light displaing micro picture as shown in Fig. 3 can
To find out that crystal shape is uneven, solvent wrappage is formd with residual solvent.
Embodiment 4 prepares tebipenem crystal using water and acetone
Acetone is added dropwise thereafter in water in 1 gained L-084 crude product 100g of Example stirring, slightly rising temperature for dissolving,
Side stirring is added dropwise in 60 DEG C of crystallization temperature below, and continues to stir 5h progress crystallization after being added dropwise, and filters thereafter, by crystal
It is dried in vacuo at 50 DEG C, obtains contrast sample 2, discovery is compared under the volume ratio of different water and acetone in experiment
2 average purity of sample is 99.31%, and acetone residue amount is 1.1%, and observing its polarised light displaing micro picture as shown in Fig. 4 can
To find out that crystal shape is uneven, solvent wrappage is formd with residual solvent.
Embodiment 5 prepares tebipenem crystal using ethyl acetate and normal heptane
1 gained L-084 crude product 100g of Example stirring, slightly rising temperature for dissolving are added dropwise thereafter just in ethyl acetate
Heptane is added dropwise side in 60 DEG C of crystallization temperatures below and stirs, and continues to stir 5h progress crystallization after being added dropwise, thereafter mistake
Filter, crystal is dried in vacuo at 50 DEG C, obtains contrast sample 3, and discovery is in different ethyl acetate and normal heptane in experiment
Under volume ratio, obtaining 3 average purity of contrast sample is 99.72%, Determination of Residual Ethyl Acetate 0.7%, and normal heptane residual quantity is
0.07%, its polarised light displaing micro picture is observed, as shown in Fig. 5, it can be seen that crystal shape is uneven, is formed with residual solvent
Solvent wrappage.
Embodiment 6 prepares tebipenem crystal using ethyl acetate and the tertiary ether of first
First is added dropwise thereafter in ethyl acetate in 1 gained L-084 crude product 100g of Example stirring, slightly rising temperature for dissolving
Tertiary ether is added dropwise side in 60 DEG C of crystallization temperatures below and stirs, and continues to stir 5h progress crystallization after being added dropwise, thereafter mistake
Filter, crystal is dried in vacuo at 50 DEG C, obtains contrast sample 4, discovery is in different ethyl acetate and the tertiary ether of first in experiment
Under volume ratio, obtaining 4 average purity of contrast sample is 99.75%, Determination of Residual Ethyl Acetate 1.2%, and the tertiary ether residue amount of first is
0.6%, its polarised light displaing micro picture is observed, as shown in Fig. 6, it can be seen that crystal shape is uneven, is formed with residual solvent
Solvent wrappage.
Embodiment 7 prepares tebipenem crystal using ethyl acetate purifying
1 gained L-084 crude product 100g of Example is dissolved using the heating of 1000mL ethyl acetate, is dropped thereafter
Temperature filters thereafter to 20 DEG C of stirring and crystallizings, stirring rate 300rpm, stirring and crystallizing 5h, and filter cake is eluted with a small amount of ethyl acetate
White solid is obtained, solid obtains contrast sample 5, the HPLC purity of contrast sample 5 is after tested in 50 DEG C of vacuum drying 10h
99.71%, yield is only 62.1%, and product fusing point is 133.1~136.2 DEG C.
The preparation of 8 high-purity tebipenem crystalline esters of embodiment
The stirring of crude product 100g made from Example 1 is heated to 60 DEG C of dissolutions using 800mL water, is cooled to 50 DEG C thereafter
Acetonitrile 2400mL is added dropwise, is stirred when being added dropwise, and continues after being added dropwise stirring a period of time, stirring rate 300rpm,
It is filtered after stirring 3h, filter cake elutes to obtain white solid with a small amount of acetonitrile, which is dried in vacuo to 8h at 50 DEG C to get arriving
High-purity tebipenem crystal, the crystal purity known to statistics are 99.85%, yield 95.6%, fusing point 134.5~135.2
DEG C, the HPLC spectrogram of purity test is as shown in Fig. 2.
Claims (10)
1. a kind of preparation method of high-purity tebipenem crystalline esters, it is characterised in that: the following steps are included:
(1) the first solvent is added into L-084 crude product, stirs, obtains just molten product；
(2) at the reaction temperatures, the second solvent is added dropwise into the just molten product, stirring and crystallizing, crystal is filtered thereafter, and drying is
It can；
First solvent includes water, and second solvent is acetonitrile, and the reaction temperature is 0~60 DEG C；The L-084
Structural formula such as formula (I) shown in:
2. the preparation method of high-purity tebipenem crystalline esters according to claim 1, it is characterised in that: described for than training
The volume ratio of southern ester crude product and first solvent is 1:1~1:10, preferably 1:5~1:8；Second solvent and described the
The volume ratio of one solvent is 0.5:1~5:1, preferably 2:1~3:1.
3. the preparation method of high-purity tebipenem crystalline esters according to claim 1, it is characterised in that: the reaction temperature
Degree is 40~60 DEG C, preferably 50 DEG C.
4. the preparation method of high-purity tebipenem crystalline esters according to requiring 1, it is characterised in that: in the step (2)
Stirring rate be 200~400rpm, preferably 300~350rpm.
5. the preparation method of high-purity tebipenem crystalline esters according to claim 4, it is characterised in that: the step (2)
Described in the crystallization time be 0.5~5h, preferably 2~3h.
6. the preparation method of high-purity tebipenem crystalline esters according to claim 1, it is characterised in that: the step
(2) temperature of the drying described in is 50~60 DEG C.
7. the preparation method of high-purity tebipenem crystalline esters according to claim 1, it is characterised in that: described for than training
Southern ester crude product includes following preparation step:
S1: addition four hydrate of raw material tebipenem, dimethylformamide (DMF), N, N- diisopropylethylamine (DIPEA),
Benzyltriethylammoinium chloride reacts at room temperature；
S2: chloromethyl pivalate being added into the mixed liquor of reaction, is warming up to 45 DEG C of reactions thereafter；
S3: after the reaction was completed to S2, by mixed liquor cooling, adding water and stirring, organic solvent be added thereafter and is extracted one or more times,
The organic phase being obtained by extraction is adjusted with acid liquid separation after pH to 4.0 ± 0.1, the water phase that liquid separation is obtained is extracted using organic solvent
It takes, water phase remaining after extraction alkali is adjusted into pH to 7.5 ± 0.1, organic solvent extraction is reused thereafter, will be obtained by extraction
Organic phase washing one or more times, organic phase is dried, filtered thereafter, concentration to get arrive L-084 crude product.
8. the preparation method of high-purity tebipenem crystalline esters according to claim 7, it is characterised in that: the step S3
Described in organic solvent be ethyl acetate.
9. the preparation method of high-purity tebipenem crystalline esters according to claim 7, it is characterised in that: the step S1
Described in reaction time be 50~70min.
10. the preparation method of high-purity tebipenem crystalline esters according to claim 7, it is characterised in that: the step
The time of reaction described in S2 is 4.5~5.5h.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112812116A (en) * | 2020-12-31 | 2021-05-18 | 山东华鲁制药有限公司 | Preparation method of medicinal tebipenem pivoxil |
| US12048691B2 (en) | 2020-11-11 | 2024-07-30 | Spero Therapeutics, Inc. | High dosage tebipenem pivoxil tablet formulation |
| US12098155B2 (en) | 2023-06-09 | 2024-09-24 | Spero Therapeutics, Inc. | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use |
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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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| CN112812116A (en) * | 2020-12-31 | 2021-05-18 | 山东华鲁制药有限公司 | Preparation method of medicinal tebipenem pivoxil |
| US12098155B2 (en) | 2023-06-09 | 2024-09-24 | Spero Therapeutics, Inc. | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use |
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