CN106083894A - The synthetic method of Nitrocefin - Google Patents
The synthetic method of Nitrocefin Download PDFInfo
- Publication number
- CN106083894A CN106083894A CN201610417261.2A CN201610417261A CN106083894A CN 106083894 A CN106083894 A CN 106083894A CN 201610417261 A CN201610417261 A CN 201610417261A CN 106083894 A CN106083894 A CN 106083894A
- Authority
- CN
- China
- Prior art keywords
- compound
- reactant liquor
- solution
- nitrocefin
- react
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to the synthetic method of a kind of Nitrocefin, belong to pharmaceutical synthesis field.The invention provides a brand-new process route preparing Nitrocefin with compound I for raw material.Compound I may utilize 7 ACA and prepares.
Description
Technical field
The present invention relates to the synthetic method of a kind of Nitrocefin, belong to pharmaceutical synthesis field.
Background technology
Penicillin and cephalosporin are the antibiotic that a class has beta-lactam structure, and this kind of antibiotic is widely used in
In anti-infective therapy.But after this kind of medicine of life-time service, pathogen may produce the enzyme making drug inactivation, such as β-interior acyl
Amine enzyme.Beta-lactamase is a kind of hydrolytic enzyme, and it can make antibiotic lose drug effect, cause of disease with hydrolyzing penicillin or cephalosporin
Body will develop immunity to drugs.Nitrocefin is a kind of cephalosporin, and it can be used to detect whether antibacterial creates β-interior acyl
Amine enzyme, i.e. detects the drug resistance of antibacterial.Detection to bacterial drug resistance can avoid excessive, the mala praxis for the treatment of etc. as far as possible, from
And improve efficiency and the quality for the treatment of, reduce the misery of patient, reduce treatment cost.Further, by Nitrocefin detection method,
Can be used to help screening beta-lactamase inhibitor, contribute to the exploitation of newtype drug.But, the city of current Nitrocefin
Sell expensive, and domestic demand mostly is import, limit the application of this kind of detectable.We are in the present invention, it is proposed that
Article one, the new synthesis route of the synthesis Nitrocefin of report before being different from, it is cheap that this variation route has raw material, and yield is higher,
Easily operated, it is simple to industrialized feature.
One German patent DE 2249165 of Glaxo laboratory report in 1973 and an article of 1998
(Synthesis 1998,145-147), it was recently reported that the synthetic method of Nitrocefin, but their method is required for first to
In raw material mix, S aoxidizes and is finally reduced again, and synthesis step is loaded down with trivial details, and yield is low.Shahriar in 2005
Mobashery etc. report the synthetic method (J.Org.Chem.2005,70,367-369) of a kind of new Nitrocefin, should
Synthetic method step is short, and yield is higher, but initiation material used buy in market expensive, and be unfavorable for industrialization
Become to produce.
Summary of the invention
In order to overcome the problems and disadvantages in the existing synthetic method of Nitrocefin, the invention provides Nitrocefin
A kind of new synthetic method.
The synthetic method of Nitrocefin, including following processing step:
1., in oxolane, compound I and PBr is made3Reaction, is derived from compound II；
2., in ethyl acetate, compound II and PPh is made3Reaction, is derived from compound III；
3. in dichloromethane, in the presence of sodium carbonate, making compound III and 2,4-dinitrobenzal-dehyde reacts, thus
Obtain compound IV；
4., in dichloromethane, in the presence of trifluoroacetic acid, make compound IV react with methyl phenyl ethers anisole, be derived from cephalo nitre
Thiophene
In technique scheme, preferred steps 1. in, the most described reaction is carried out under Ar gas shielded, and reaction temperature is-5
℃；Preferably drip PBr3Speed be 2drops/min；Further, it is preferable to compound I and PBr3Mol ratio be 2:1.
Specifically, 1. described step can be carried out as follows: compound I is placed in oxolane formation solution, by molten
Liquid is cooled to-5 DEG C, drips PBr in above-mentioned solution3；After reaction completely, reactant liquor is poured in the frozen water added with ethyl acetate,
Extract, wash, be dried, filter, concentrate drying, obtain compound II.
Further, 1. described step can be carried out as follows: compound I is placed in oxolane formation solution, will
Solution is cooled to-5 DEG C, drips PBr in above-mentioned solution3；Reacting at room temperature, the response time is 15h.
Further, described " extract, wash, be dried, filter, concentrate drying " can carry out by following side's method: extraction
Once, once, saturated common salt is washed once, and anhydrous sodium sulfate is dried in washing, filters, and reduced pressure at room temperature concentrates, and draining
Compound II.
In technique scheme, preferred steps 2. in, compound II is dissolved in ethyl acetate, add PPh3, question response
After completing, reaction vessel separates out a large amount of solid, sucking filtration, washes three times by ethyl acetate, drain and obtain product III.
Further, it is preferable to compound II and PPh3Mol ratio be 1:1.2.
In technique scheme, preferred steps 3. in, compound III is dissolved in dichloromethane, is cooled to 0 DEG C, add
2,4-dinitrobenzal-dehydes, drip sodium carbonate liquor, react at least 1h, be warmed to room temperature, be stirred at least 1.5h；Utilize NaHSO4
Reactant liquor is neutralized to neutrality by solution, washs, is dried, crude product chromatography, obtains compound IV.
Further, it is preferable to compound III and 2, the mol ratio of 4-dinitrobenzal-dehyde is 1:1.2；Preferred compound III
It is 1:1.2 with the mol ratio of sodium carbonate.
Further, described " wash, be dried, crude product chromatography " can carry out by following side's method: washing is once, saturated
Sal is washed once, and anhydrous sodium sulfate is dried, and reduced pressure at room temperature is concentrated to dryness, and crude product column chromatography purification obtains compound IV.
In technique scheme, preferably NaHSO4The concentration of solution is 10%；The concentration of sodium carbonate liquor is 20%.
In technique scheme, preferred steps 4. in, compound IV is dissolved in dichloromethane, add methyl phenyl ethers anisole, cooling
To 0 DEG C, add trifluoroacetic acid (TFA), react at least 30min, and maintain this temperature to reduce pressure in quick extraction liquid easily to wave
The material sent out, when remaining a small amount of methyl phenyl ethers anisole in question response bottle, adds ether, separates out a large amount of yellow solid, sucking filtration at 0 DEG C,
Filter cake ether is washed twice, and product is 0 DEG C of decompressing and extracting；The product obtained is dissolved in containing dimethyl sulfoxide (DMSO)
CHCl3In, stir 2 days at 0 DEG C, at 0 DEG C, concentration is drained and is obtained Nitrocefin.
Further, it is preferable to the mol ratio of compound IV and methyl phenyl ethers anisole is 1:5.5；Preferred compound IV Yu TFA mole
Ratio is 1:45.
Further, the described " CHCl containing DMSO3In ", DMSO concentration is 10%.
In synthetic method of the present invention, the most described compound I prepares as follows:
I., in methanol aqueous solution, make 7-ACA with NaOH react, be derived from 7-AHCA；
Ii., in water, under pH=8,7-AHCA is made to react with thiophen acetyl chloride, it is thus achieved that intermediate compound；
Iii. make intermediate compound react with diazonium diphenyl methane, be derived from compound I.
In technique scheme, preferred steps i is carried out as follows: joined by 7-ACA in methanol aqueous solution, cooling
To-10～-20 DEG C, drip 2.2 equivalent 10mol/L NaOH solution, drip complete stirring 10min, maintain this temperature, react
It is 3.0 that liquid 1mol/L HCl is slowly neutralized to pH, sucking filtration after neutralization, and filter cake washs with methanol, acetone, ether successively,
Obtain product 7-AHCA,
Wherein, methanol and water volume ratio are 1:1, and the reactant liquor pH after neutralization is 3.0.
In technique scheme, preferred steps ii and iii are carried out as follows: be added to the water by 7-AHCA, cooling,
It is slowly added dropwise NaOH aqueous solution the most molten to 7-AHCA, and to make reactant liquor pH be 8；The thiophen acetyl chloride diluted with acetone is added drop-wise to
In reactant liquor, maintain reactant liquor pH to be 8 by dropping NaOH solution simultaneously, after treating thiophen acetyl chloride dropping, add acetic acid
Ethyl ester, is 2.5～3.0 with HCl solution acidification reaction liquid to pH at low temperatures；After acidifying, it is extracted with ethyl acetate, organic
Layer washes with water successively, and saturated common salt is washed, and anhydrous sodium sulfate is dried；Diazonium diphenyl methane is added to color not in reactant liquor
Taking off, and continue to stir 30min, reactant liquor is evaporated at normal temperatures do, obtains compound I；
Wherein, the concentration of NaOH solution is 2mol/L；Maintain reactant liquor pH NaOH solution concentration be respectively 2mol/L and
1mol/L；The concentration of HCl for acidifying is 1mol/L, and temperature during acidifying is 0 DEG C, the reactant liquor pH after acidifying be 2.5～
3.0。
Further, it is preferable to the mol ratio of 7-AHCA and thiophen acetyl chloride is 1:1.2；Described " the thiophene with acetone dilution
Chloroacetic chloride " in the mol ratio of acetone and thiophen acetyl chloride be 1:5.
One preferred technical scheme of the present invention is: with 7-ACA for Material synthesis Nitrocefin, walks including following technique
Rapid:
The first step: in methanol aqueous solution, makes 7-ACA with NaOH react, is derived from 7-AHCA；
Second step: under Yu Shuizhong, pH=8, makes 7-AHCA react with thiophen acetyl chloride, it is thus achieved that intermediate compound；
3rd step: make intermediate compound react with diazonium diphenyl methane, is derived from compound I；
4th step: in oxolane, makes compound I and PBr3Reaction, is derived from compound II；
5th step: in the presence of ethyl acetate, makes compound II and PPh3Reaction, is derived from compound III；
6th step: in dichloromethane, in the presence of sodium carbonate, makes compound III and 2, and 4-dinitrobenzal-dehyde reacts,
It is derived from compound IV；
7th step: in dichloromethane, in the presence of trifluoroacetic acid, makes compound IV react with methyl phenyl ethers anisole, is derived from
Nitrocefin.
Process route is as follows:
The invention have the benefit that the invention provides one brand-new prepares Nitrocefin with compound I for raw material
The process route of fen.Compound I utilizes 7-ACA to prepare.Preparation method used by the present invention can be with 7-ACA for initiation material through seven steps
Prepare Nitrocefin.Initiation material 7-ACA is cephalosporin key intermediates, and industrialization already, its cheap market price.
The present invention is simple to operate, reacts disposable, product easy purification, and yield is high, it is easy to industrialization, reduces production cost.
Accompanying drawing explanation
Fig. 1: 7-AHCA1H NMR
Fig. 2: compound I's1H NMR
Fig. 3: compound IV (Z:E=1:7.7's)1H NMR
Fig. 4: compound V's1H NMR
Detailed description of the invention
Following non-limiting example can make those of ordinary skill in the art that the present invention be more fully understood, but not with
Any mode limits the present invention.
Test method described in following embodiment, if no special instructions, is conventional method；Described reagent and material, as
Without specified otherwise, the most commercially obtain.
Embodiment 1
The first step: 20g 7-ACA is joined in the solution being made up of 140mL methanol and 140mL water, cool to-10～-
20 DEG C, the NaOH solution of dropping 15.6mL 10mol/L, drip complete stirring 10min, maintaining temperature is-10～-20 DEG C, reacts
It is 3 that the HCl solution of liquid 1mol/L is slowly neutralized to pH, sucking filtration after neutralization, and filter cake is washed with methanol, acetone, ether successively
Washing, receive the 7-AHCA of 14.5g white after vacuum drying, yield is 86%；
7-AHCA's1H NMR
1H NMR (400MHz, TFA) δ 5.62 (d, J=5.0Hz, 1H), 5.49 (d, J=5.1Hz, 1H), 5.31 5.13
(m, 2H), 4.09 (d, J=18.9Hz, 1H), 3.88 (d, J=19.0Hz, 1H).
Second and third step: the first step is prepared the 7.5g 7-AHCA of gained and is added to the water, and cools to 0 DEG C, drips 2mol/L
NaOH solution the most molten to 7-AHCA, and pH value of solution=8.6.2g thiophen acetyl chloride 14mL acetone is diluted, is slowly dropped to
In above-mentioned reactant liquor, simultaneously by the NaOH with 1mol/L of dropping 2mol/L, maintain the pH=8 of reaction, treat thiophen acetyl chloride
After dropping, add 80mL ethyl acetate, maintain 0 DEG C with the HCl solution acidification reaction liquid of 1mol/L to pH=2.5～3.0.
After acidifying, extracting by 80mL ethyl acetate every time, extract 4 times, organic layer is washed with 100mL respectively, 100mL saturated common salt
Washing, anhydrous sodium sulfate is dried.In reactant liquor, add diazonium diphenyl methane no longer take off to color, continue stirring 30min,
Reactant liquor is evaporated to do again.Obtaining 8.7g white product, yield is 51%.This white product is compound I.
Compound I's1H NMR
1H NMR(400MHz,CDCl3) δ 7.42 (d, J=7.2Hz, 2H), 7.36 7.27 (m, 8H), 7.25-7.27 (dd,
J=4.9,1.6Hz, 1H), 6.99 (dd, J=5.0,3.5Hz, 1H), 6.96 (d, J=3.1Hz, 1H), 6.90 (s, 1H), 6.51
(d, J=9.2Hz, 1H), 5.87 (dd, J=9.2,4.9Hz, 1H), 4.93 (d, J=4.9Hz, 1H), 4.39 (d, J=
13.0Hz, 1H), 3.93 (d, J=13.0Hz, 1H), 3.84 (s, 2H), 3.53 (s, 2H), 2.62 (s, 1H) .MS:[M+NH4]+=
538.03.
4th step: the 4.7g product that second and third step is prepared gained joins in reaction flask, Ar gas shielded, add
16mL THF, cools to-5 DEG C, drips 1.08g PBr3, dripping off in 5min, question response is complete, pours reactant liquor added with 25mL into
In the 20mL frozen water of ethyl acetate, once, 20mL washes once in extraction, and 20mL saturated common salt is washed, and anhydrous sodium sulfate is dried, mistake
Filter, reduced pressure at room temperature concentrates, and drains, obtains the white solid of quantitative yield.This white solid is compound II.
5th step: the 5.2g product that the 4th step is prepared gained is dissolved in 18mL ethyl acetate, adds 2.8g PPh3, instead
Should at room temperature carry out 15h, reaction bulb separate out white solid, sucking filtration, washes three times by 10mL ethyl acetate, drain and weigh.?
To 5.7g white solid, yield is 76%.This white solid is compound III.
6th step: the 3.38g product that the 5th step is prepared gained is dissolved in 20mL dichloromethane, is cooled to 0 DEG C, adds
0.94g 2,4-dinitrobenzal-dehyde, the sodium carbonate liquor of dropping 2.54g 20%, reacts 1h, is warmed to room temperature, is stirred for 1.5h.
Use 10%NaHSO4Reactant liquor is neutralized to neutrality by solution, then washes once, and saturated common salt is washed once, and anhydrous sodium sulfate is done
Dry, reduced pressure at room temperature is concentrated to dryness, and crude product column chromatography purification obtains 1.9g yellow solid, and yield is 70%.This yellow solid is
Compound IV.
Compound IV's1H NMR
1H NMR(400MHz,CDCl3) δ 8.86 (d, J=2.2Hz, 1H), 8.28 (dd, J=8.5,2.2Hz, 1H),
7.49-7.44 (m, 3H), 7.36-7.27 (m, 11H), 7.02 6.99 (m, 1H), 6.96 (d, J=3.2Hz, 1H), 6.92 (s,
1H), 6.84 (d, J=12.1Hz, 1H), 6.76 (d, J=12.1Hz, 1H), 6.26 (d, J=9.0Hz, 1H), 5.88 (dd, J=
9.0,5.0Hz, 1H), 4.96 (d, J=5.0Hz, 1H), 3.84 (s, 2H), 3.28 (d, J=18.4Hz, 1H), 2.85 (d, J=
18.4Hz,1H).MS:[M-H]-=681.27.
7th step: be dissolved in 11mL dichloromethane by the 1.3g product that purification in the 6th step obtains, adds 1mL methyl phenyl ethers anisole,
It is cooled to 0 DEG C, adds 6mL TFA, react 30min.Maintain volatile material in the 0 DEG C of quick extraction liquid that reduces pressure, treat anti-
Answering when remaining a small amount of methyl phenyl ethers anisole in bottle, add ether, separate out yellow solid, sucking filtration at 0 DEG C, filter cake ether is washed twice,
Product is decompressing and extracting under the conditions of 0 DEG C, obtains 0.86g yellow product, and yield is 87%.The product obtained is dissolved in containing 10%
The 20mL CHCl of DMSO3In, 0 DEG C is stirred two days, and then 0 DEG C of concentration is drained and obtained target product quantitatively.This product is final
Product Nitrocefin ,-20 DEG C of preservations.Nitrocefin1H NMR
1H NMR(400MHz,CDCl3) δ 8.80 (d, J=2.3Hz, 1H), 8.40 (dd, J=8.7,2.3Hz, 1H), 8.34
(d, J=8.6Hz, 1H), 7.91 (d, J=8.8Hz, 1H), 7.79 (d, J=16.2Hz, 1H), 7.30 (s, 1H), 7.26 (s,
1H), 7.22 (dd, J=4.9,1.3Hz, 1H), 6.97 (d, J=5.0Hz, 2H), 5.86 (dd, J=8.6,4.9Hz, 1H),
5.09 (d, J=5.0Hz, 1H), 3.91 3.82 (m, 2H), 3.78 (d, J=2.1Hz, 1H), 3.68 (d, J=17.5Hz, 1H)
.MS:[M+Na]+=538.96.
Claims (8)
1. the synthetic method of Nitrocefin, including following processing step:
1., in oxolane, compound I and PBr is made3Reaction, is derived from compound II；
2., in ethyl acetate, compound II and PPh is made3Reaction, is derived from compound III；
3. in dichloromethane, in the presence of sodium carbonate, making compound III and 2,4-dinitrobenzal-dehyde reacts, and is derived from
Compound IV；
4., in dichloromethane, in the presence of trifluoroacetic acid, make compound IV react with methyl phenyl ethers anisole, be derived from Nitrocefin
Method the most according to claim 1, it is characterised in that: described compound I prepares as follows:
I., in methanol aqueous solution, make 7-ACA with NaOH react, be derived from 7-AHCA；
Ii., in water, under pH=8,7-AHCA is made to react with thiophen acetyl chloride, it is thus achieved that intermediate compound；
Iii. make intermediate compound react with diazonium diphenyl methane, be derived from compound I.
Method the most according to claim 1, it is characterised in that: described step 1.: compound I is placed in oxolane formation
Solution, is cooled to-5 DEG C by solution, drips PBr in above-mentioned solution3；After reaction completely, reactant liquor is poured into added with ethyl acetate
Frozen water in, extract, wash, be dried, filter, concentrate drying, obtain compound II.
Method the most according to claim 1, it is characterised in that: described step 2.: compound II is dissolved in ethyl acetate,
Add PPh3, after question response completes, reaction vessel separates out solid, sucking filtration, washes three times by ethyl acetate, drain and obtain product
III。
Method the most according to claim 1, it is characterised in that: described step 3.: compound III is dissolved in dichloromethane
In, be cooled to 0 DEG C, add 2,4-dinitrobenzal-dehyde, drip sodium carbonate liquor, react at least 1h, be warmed to room temperature, be stirred for
Few 1.5h；Utilize NaHSO4Reactant liquor is neutralized to neutrality by solution, washs, is dried, crude product chromatography, obtains compound IV.
Method the most according to claim 1, it is characterised in that: described step 4.: compound IV is dissolved in dichloromethane,
Add methyl phenyl ethers anisole, be cooled to 0 DEG C, add TFA, react at least 30min, and maintain this temperature to reduce pressure in quick extraction liquid
Volatile material, when remaining a small amount of methyl phenyl ethers anisole in question response bottle, adds ether, separates out a large amount of yellow solid, take out at 0 DEG C
Filtering, filter cake ether is washed twice, and product is 0 DEG C of decompressing and extracting；The product obtained is dissolved in the CHCl containing DMSO3In, at 0 DEG C
Stirring 2 days, at 0 DEG C, concentration is drained and is obtained Nitrocefin.
Method the most according to claim 2, it is characterised in that: described step i: 7-ACA is joined in methanol aqueous solution,
Cool to-10～-20 DEG C, drip 2.2 equivalent 10mol/L NaOH solution, drip complete stirring 10min, maintain this temperature,
It is 3.0 that reactant liquor 1mol/L HCl is slowly neutralized to pH, sucking filtration after neutralization, and filter cake is washed with methanol, acetone, ether successively
Wash, obtain product 7-AHCA,
Wherein, methanol and water volume ratio are 1:1, and the reactant liquor pH after neutralization is 3.0.
Method the most according to claim 2, it is characterised in that: described step ii and iii: 7-AHCA is added to the water,
Cooling, is slowly added dropwise NaOH aqueous solution the most molten to 7-AHCA, and to make reactant liquor pH be 8；The thiophen acetyl chloride that will dilute with acetone
It is added drop-wise in reactant liquor, maintains reactant liquor pH to be 8 by dropping NaOH solution simultaneously, after treating thiophen acetyl chloride dropping, add
Enter ethyl acetate, be 2.5～3.0 with HCl solution acidification reaction liquid to pH at low temperatures；After acidifying, extract by ethyl acetate
Taking, organic layer washes with water successively, and saturated common salt is washed, and anhydrous sodium sulfate is dried；Diazonium diphenyl methane is added in reactant liquor
No longer taking off to color, and continue to stir 30min, reactant liquor is evaporated at normal temperatures do, obtains compound I；
Wherein, the concentration of NaOH solution is 2mol/L；The NaOH solution concentration maintaining reactant liquor pH is respectively 2mol/L and 1mol/
L；Concentration for the HCl of acidifying is 1mol/L, and temperature during acidifying is 0 DEG C, and the reactant liquor pH after acidifying is 2.5～3.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610417261.2A CN106083894B (en) | 2016-06-14 | 2016-06-14 | The synthetic method of Nitrocefin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610417261.2A CN106083894B (en) | 2016-06-14 | 2016-06-14 | The synthetic method of Nitrocefin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106083894A true CN106083894A (en) | 2016-11-09 |
| CN106083894B CN106083894B (en) | 2018-11-13 |
Family
ID=57845450
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610417261.2A Expired - Fee Related CN106083894B (en) | 2016-06-14 | 2016-06-14 | The synthetic method of Nitrocefin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106083894B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3830700A (en) * | 1971-10-07 | 1974-08-20 | Glaxo Lab Ltd | Test for beta-lactamase activity using chromogenic cephalosporin compound |
| US4107431A (en) * | 1970-01-23 | 1978-08-15 | Glaxo Laboratories Limited | Δ3 -3-Vinyl or substituted vinyl-4-carboxy cephalosporins |
-
2016
- 2016-06-14 CN CN201610417261.2A patent/CN106083894B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4107431A (en) * | 1970-01-23 | 1978-08-15 | Glaxo Laboratories Limited | Δ3 -3-Vinyl or substituted vinyl-4-carboxy cephalosporins |
| US3830700A (en) * | 1971-10-07 | 1974-08-20 | Glaxo Lab Ltd | Test for beta-lactamase activity using chromogenic cephalosporin compound |
Non-Patent Citations (2)
| Title |
|---|
| AHMAD GHAVAMI,ET AL.,: "Assay for drug discovery: Synthesis and testing of nitrocefin analogues for use as β-lactamase substrates", 《ANALYTICAL BIOCHEMISTRY》 * |
| MIJOON LEE,ET AL.,: "A Practical Synthesis of Nitrocefin", 《J. ORG. CHEM.》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106083894B (en) | 2018-11-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103524440B (en) | The preparation method of gout therapertics Lesinurad and Lesinurad intermediate | |
| CN101613359B (en) | Method for synthesizing cefuroxime sodium | |
| NO144169B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC APPLICABLE 6- (D (-) - ALFA-AMINOPHENYLACETAMIDO) PENICILLANIC ACID PHALIDESTES | |
| CN108164550A (en) | A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application | |
| CN103467486B (en) | A kind of preparation method of clopidogrel disulfate compound | |
| DK150201B (en) | ALFA-AZIDO-N-ACYL-6-AMINOPENICILLANIC ACID ESTABLES USED FOR PREPARING THE SIMILAR ALFA-AMINO COMPOUND | |
| CN105837648A (en) | Tilmicosin phosphate preparation method | |
| CN106256824A (en) | A kind of preparation method of high-purity De Lasha star meglumine salt | |
| CN103755722B (en) | The synthetic method of a kind of Levofloxacin and Ofloxacine USP 23 | |
| CN103102357B (en) | A kind of synthetic method of Cefuroxime sodium | |
| CN104193765B (en) | A kind of synthetic method of cefixime | |
| CN105017168A (en) | New preparation method of [5-bromo-4-(4-cyclopropyl-naphthalene-1-yl)-4H-[1, 2, 4]triazole-3-ylsulfanyl]-methyl acetate | |
| CN104311597A (en) | Industrial production method of s-(-)-ornidazole disodium phosphate | |
| CN105503904A (en) | Preparation method for cefotaxime acid | |
| CN109293513B (en) | Preparation method of sitafloxacin intermediate | |
| CN102633819A (en) | Preparation method of cefoxitin | |
| CN101805356A (en) | Preparation methods of sulbenicillin sodium and injection thereof | |
| CN106083894A (en) | The synthetic method of Nitrocefin | |
| CN104892674B (en) | Preparation method of ceftaroline fosamil | |
| CN104530085A (en) | New preparation method of ceftiofur sodium | |
| CN104876920A (en) | Isooxazole compounds and intermediates thereof, and preparation method and application thereof | |
| CN103570703B (en) | The preparation and purification method of Tiagabine Hydrochloride | |
| CN104230956B (en) | A kind of preparation method of cefoxitin | |
| CN107151246B (en) | The preparation method of one kind (R)-praziquantel amine salt and levo-praziquantel | |
| CN106967092A (en) | A kind of preparation method of Cefazedone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181113 Termination date: 20210614 |