CN109096224A - A kind of synthetic method of Ceftobiprole side-chain acid - Google Patents
A kind of synthetic method of Ceftobiprole side-chain acid Download PDFInfo
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- CN109096224A CN109096224A CN201811129772.XA CN201811129772A CN109096224A CN 109096224 A CN109096224 A CN 109096224A CN 201811129772 A CN201811129772 A CN 201811129772A CN 109096224 A CN109096224 A CN 109096224A
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- compound
- chemical formula
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- ceftobiprole
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 15
- 239000002253 acid Substances 0.000 title claims abstract description 9
- VOAZJEPQLGBXGO-SDAWRPRTSA-N ceftobiprole Chemical group S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(\C=C/4C(N([C@H]5CNCC5)CC\4)=O)CS[C@@H]32)C(O)=O)=O)=N1 VOAZJEPQLGBXGO-SDAWRPRTSA-N 0.000 title claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 7
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 6
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims abstract description 4
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 27
- 239000000126 substance Substances 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 239000000908 ammonium hydroxide Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 6
- CXDLCBQVUTXRRK-UHFFFAOYSA-N C(C)(=O)O.CON=C(N=N)N Chemical compound C(C)(=O)O.CON=C(N=N)N CXDLCBQVUTXRRK-UHFFFAOYSA-N 0.000 abstract description 4
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 description 1
- 229960004069 cefditoren Drugs 0.000 description 1
- 229950004259 ceftobiprole Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a kind of synthetic methods of important antibiotic intermediates Ceftobiprole side-chain acid, by malononitrile under acetic acid effect, with sodium nitrite oximate, then alkalinity effect is lower is etherified with triphenylchloromethane, next the amidification in the case where concentrated ammonia liquor acts on, then with potassium rhodanide cyclization, finally hydrolyzed in sodium hydroxide, obtain corresponding (Z) -2-(5- amino -1,2,4- thiadiazoles -3- base) -2- triphen methoxy imino guanidine-acetic acid.Synthesis step of the invention is few, at low cost, and each material used is cheap and easy to get, be conducive to industrialized production, pollution it is small.
Description
Technical field
The invention belongs to antibiotic intermediates synthesis technical fields, and in particular to (Z) -2-(5- amino -1,2,4- thiophene two
Azoles -3- base) -2- triphen methoxy imino guanidine-acetic acid synthetic method.
Background technique
Ceftobiprole is the 5th generation cephalosporins, be broad-spectrum cephalosporin class drug, it to gram positive bacteria,
Gram-negative bacteria and anaerobic bacteria have antibacterial activity, are first to the effective cephalosporin medicament of MRSA and VRSA, and
Drug resistance can seldom be caused, therefore its side-chain acid compound probability is of great significance.
Summary of the invention
It is few, at low cost that the present invention provides a kind of synthesis steps, and each material used is cheap and easy to get, is conducive to industrialize
Produce, pollute the synthetic method of small Ceftobiprole side-chain acid.
The invention adopts the following technical scheme:
A kind of synthetic method of Ceftobiprole side-chain acid, the Ceftobiprole side-chain acid are (Z) -2-(5- amino -1,2,4- thiophene two
Azoles -3- base) -2- triphen methoxy imino guanidine-acetic acid chemical formula it is as follows,
(I)
Method includes the following steps:
A) it using compound malononitrile as raw material, reacts to obtain compound (II a) with sodium nitrite, is then (II b) with chemical formula
Compound carry out William inferior (Williamson) synthesis obtain chemical formula be (III) compound:
(Ph)3CCl
(II a) (II b) (III)
B) compound that a walks that resulting chemical formula is (III) is reacted with ammonium hydroxide progress amidification, obtains the chemical combination that chemical formula is (IV)
Object:
(IV)
C) chemical formula obtained in b step is that the compound of (IV) and potassium rhodanide are cyclized, and obtains the chemical combination that chemical formula is (V)
Object:
(V)
D) c walks the compound that resulting chemical formula is (V), hydrolyzes under the action of highly basic, obtains the target that chemical formula is (I)
Compound.
In above-mentioned synthetic method, alkali used in the inferior synthesis of William in the step a is triethylamine, and reaction temperature is 5
℃；The ammonium hydroxide for reacting described in b is necessary for concentrated ammonia liquor, and reaction temperature is -5 DEG C；The reaction system is reacted in c is necessary for anhydrous
Condition, no more than 0 DEG C, the temperature of reaction system is reacted in d must control at 55 DEG C of 50 ∽ reaction temperature.
Chemical formula in above-mentioned synthesis step are as follows:
A)
(II a) (II b) (III)
B)
(IV)
C)
(I)
Compared with the existing technology, 5(Z provided by the invention) -2-(5- amino -1,2,4- thiadiazoles -3- base) -2- triphen methoxy Asia
The synthetic method of glycine has route short, and synthetic operation is simple, is easy to the advantages that industrializing.In addition, product of the invention
Purity (LC) can achieve 99%, therefore the product that this method provides has great advantage in terms of purity, while also be subsequent height
The general synthesis of pure cefditoren pyrrole provides guarantee.
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
(Z) -2-(5- amino -1,2,4- thiadiazoles -3- base of the invention) -2- triphen methoxy imino guanidine-acetic acid synthetic method tool
Body the following steps are included:
The third two eyeball 1mol, water 1.5mol and glacial acetic acid 2.6mol are added in there-necked flask, is cooled to 0 ~ 5 DEG C, nitrous is added portionwise
Sour sodium 1.5mol, 0 ~ 5 DEG C of reaction 1h, with concentrated hydrochloric acid tune PH=2, ethyl acetate is extracted three times, and anhydrous magnesium sulfate is dry, and decompression is de-
It is molten to obtain rufous liquid, (II a) compound is obtained, yield: 85% ∽ 90%, LC:95% ∽ 97%.
Under nitrogen protection, (II a) compound 1mol is added in there-necked flask, cools to 0 ~ 5 DEG C of addition triethylamine 2.5mol and stirs
Mix 1h, 0 ~ 5 DEG C of addition chemical formula is (II b) compound 1.3mol, and 25 DEG C are warmed to room temperature after adding, and is then reacted at 5 ± 2 DEG C
5h.Washing, ethyl acetate extraction, anhydrous magnesium sulfate is dry, and decompression precipitation obtains rufous oily liquids.Obtaining general formula is (III)
Compound, yield: 80% ∽ 85%, LC:85% ∽ 90%.
The compound 1mol that chemical formula is (III) is added in there-necked flask, ammonium hydroxide 3mol is added, ethyl alcohol 4mol cools to -5 ~ 0
DEG C reaction 4h stop.Washing, methylene chloride extraction, anhydrous magnesium sulfate is dry, and rufous granular solids are concentrated under reduced pressure to obtain, obtain
General formula is the compound of (IV), yield: 50%, LC:80%.
Compound 1mol, the methanol 20g that chemical formula is (IV) are added in there-necked flask, cools to -5 ~ 0 DEG C of addition triethylamine
2mol stirs 1h, and -15 ~ -10 DEG C are slowly added to bromine 1mol, stirs 1h, and potassium rhodanate, -5 ~ 0 DEG C of reaction is added in -15 ~ -10 degree
3h.Filtering is buff powder after methanol elution vacuum drying, obtains the compound that general formula is (V), yield: 60%, LC:
98%。
The compound mol that chemical formula is (V) is added in there-necked flask, sodium hydroxide 1.1mol, water 16.87g, 50 ~ 55 DEG C anti-
6h is answered to stop.30 DEG C are cooled to, concentrated hydrochloric acid tune PH=1, ethyl acetate extracts three times, and anhydrous magnesium sulfate is dry, is concentrated under reduced pressure.Second
Acetoacetic ester petroleum ether 1:3 recrystallization obtains the compound that faint yellow solid i.e. general formula is (I), yield 72%, LC:99%.
H-NMR(DMSO-d6,): δ 7.19-7.21(6H, m, ArH), 7.25-7.33(9H, m, ArH), 8.17(2H, s,
NH2)
LC-MS
Overall yield of reaction is 20%, LC:99%.
Identification method used in above-mentioned synthetic method: Brooker Avance III 400MHz superconduction nuclear magnetic resonance spectrometer
Analysis method: LC(liquid chromatogram purity);Shimadzu LC-10AT VP, Shimadzu C-18 chromatographic column, mobile phase: acetonitrile: water=55:45,
Flow velocity 2ml/min.
The above description is only a preferred embodiment of the present invention, is not intended to restrict the invention, although with reference to the foregoing embodiments
Invention is explained in detail, for those skilled in the art, still can be to foregoing embodiments institute
The technical solution of record is modified or equivalent replacement of some of the technical features.It is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (5)
1. a kind of synthetic method of Ceftobiprole side-chain acid, the Ceftobiprole side-chain acid is the 5- amino as shown in general formula (I)
Alkoximino -1,2,4- thiadiazoles -3- acetic acid,
(I)
Method includes the following steps:
A) it using compound malononitrile as raw material, reacts to obtain compound (II a) with sodium nitrite, is then (II b) with chemical formula
Compound carry out William it is inferior synthesis obtain chemical formula be (III) compound；
(Ph)3CCl
(II a) (II b) (III)
B) the resulting general formula of step a is that the compound of (III) and ammonium hydroxide carry out amidification and reacts, and obtains the chemical combination that chemical formula is (IV)
Object；
(IV)
C) the resulting general formula of step b is that the compound of (IV) and potassium rhodanide are cyclized, and obtains the compound that chemical formula is (V)；
(V)
D) the resulting chemical formula of step c is the compound of (V), is hydrolyzed under the action of highly basic, and the mesh that chemical formula is (I) is obtained
Mark compound.
2. requiring the synthetic method according to right 1, it is characterised in that: used in the inferior synthesis of William in the step a
Alkali is triethylamine, and reaction temperature is at 5 DEG C.
3. requiring the synthetic method according to right 1, it is characterised in that: the ammonium hydroxide in the step b is concentrated ammonia liquor, reaction temperature
Degree is -5 DEG C.
4. requiring the synthetic method according to right 1, it is characterised in that: reaction system is anhydrous condition in the step c, instead
Answer temperature≤0 DEG C.
5. requiring the synthetic method according to right 1, it is characterised in that: temperature of reaction system control is in 50- in the step d
55℃。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811129772.XA CN109096224A (en) | 2018-09-27 | 2018-09-27 | A kind of synthetic method of Ceftobiprole side-chain acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811129772.XA CN109096224A (en) | 2018-09-27 | 2018-09-27 | A kind of synthetic method of Ceftobiprole side-chain acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109096224A true CN109096224A (en) | 2018-12-28 |
Family
ID=64867162
Family Applications (1)
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|---|---|---|---|
| CN201811129772.XA Pending CN109096224A (en) | 2018-09-27 | 2018-09-27 | A kind of synthetic method of Ceftobiprole side-chain acid |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2094794A (en) * | 1981-03-06 | 1982-09-22 | Fujisawa Pharmaceutical Co | Processes for preparing 2- substituted hydroxyimino-2-(5- amino-1,2,4-thiadiazol-3-yl)acetic acid or its salt, and intermediates thereof |
| JPH09221482A (en) * | 1995-12-15 | 1997-08-26 | Tokuyama Corp | Thiazoleacetic acid ammonium salt derivative and its production |
| CN101962371A (en) * | 2010-10-13 | 2011-02-02 | 浙江工业大学 | Method for preparing ceftobiprole side chain acid and key intermediate thereof |
| CN103804321A (en) * | 2014-02-18 | 2014-05-21 | 陕西思尔生物科技有限公司 | Method for preparing (Z)-5-amino-alpha-(ethoxy imino group)-1, 2, 4-thiadiazole-3-acetic acid |
-
2018
- 2018-09-27 CN CN201811129772.XA patent/CN109096224A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2094794A (en) * | 1981-03-06 | 1982-09-22 | Fujisawa Pharmaceutical Co | Processes for preparing 2- substituted hydroxyimino-2-(5- amino-1,2,4-thiadiazol-3-yl)acetic acid or its salt, and intermediates thereof |
| JPH09221482A (en) * | 1995-12-15 | 1997-08-26 | Tokuyama Corp | Thiazoleacetic acid ammonium salt derivative and its production |
| CN101962371A (en) * | 2010-10-13 | 2011-02-02 | 浙江工业大学 | Method for preparing ceftobiprole side chain acid and key intermediate thereof |
| CN103804321A (en) * | 2014-02-18 | 2014-05-21 | 陕西思尔生物科技有限公司 | Method for preparing (Z)-5-amino-alpha-(ethoxy imino group)-1, 2, 4-thiadiazole-3-acetic acid |
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