CN110372631A - A kind of preparation method of cefotaxime amide acetaldehyde - Google Patents
A kind of preparation method of cefotaxime amide acetaldehyde Download PDFInfo
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- CN110372631A CN110372631A CN201910670384.0A CN201910670384A CN110372631A CN 110372631 A CN110372631 A CN 110372631A CN 201910670384 A CN201910670384 A CN 201910670384A CN 110372631 A CN110372631 A CN 110372631A
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- cefotaxime
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
Abstract
The present invention is a kind of preparation method of cefotaxime amide acetaldehyde; the preparation method is with 2- (2 '-aminothiazole base) -2- carbonyl acetamide III and the methoxamine hydrochloride back flow reaction in solvent A of amido protecting; prepare cefotaxime amide acetals II; back flow reaction reacts to obtain cefotaxime amide acetaldehyde I, reaction equation in solvent B with trifluoroacetic acid again are as follows:Wherein, R is alkyl.The present invention is to enter 2- (thiazolamine -4- base) glyoxylic ester as raw material; using four step synthetic methods; amino is first protected, amide groups is gone up again, is protected at oxime, deamination and aldehyde radical; cefotaxime amide acetaldehyde (i.e. compound of formula I) has finally been made; operation is simple, and raw material is easy to get.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields.More particularly to a kind of preparation method of cefotaxime amide acetaldehyde.
Background technique
Ceftiofur sodium is cephalosporins veterinary clinic special broad-spectrum antibiotic, equal to gram-positive bacteria and negative bacterium
There is stronger antibacterial action.Ceftiofur has stable beta-lactam nucleus, is not easy to be destroyed by drug-fast bacteria, acts on transcription peptide
Enzyme and the synthesis for blocking mucopeptide make bacteria cell wall lack and reach bactericidal effect.
Ainothiazoly loximate and its derivative are its important medicine intermediates, are mainly used for the synthesis of cefotaxime.
The 1980s mid-term, it has been found that had by the third-generation cephalosporin of cefotaxime acids compound synthesis and attracted people's attention
Antibacterial activity, and it is small to people's toxic side effect, there are resistance to beta-lactamase, curative effect decades of times higher than mycillin.Hereafter,
Cefotaxime acid compounds gain great popularity as antibiotic side chain.
Rarely have both at home and abroad to the report of ainothiazoly loximate and its derivative at present and refers to cefotaxime amide derivatives, and cefotaxime
There is the ainothiazoly loximate of amide derivatives ratio structure easily to modify, the advantages such as side-chain structure different transform.
In view of the potential medical value of cefotaxime amide derivatives, the present invention provides a kind of preparation of cefotaxime amide acetaldehyde
Method, molecular skeleton feature of the substance based on ainothiazoly loximate, and contain amide groups and aldehyde radical, and it is modified convenient for subsequent structural, it is right
Studying novel cephalosporin class drug has important theoretical and practical significance.
Summary of the invention
Technical problem: it is an object of that present invention to provide a kind of preparation methods of cefotaxime amide acetaldehyde.The present invention is with 2- (2-
Aminothiazole -4- base) glyoxylic ester is raw material, using four step synthetic methods, first protect amino, again upper amide groups, at oxime, deamination
It is protected with aldehyde radical, cefotaxime amide acetaldehyde (i.e. compound of formula I) has finally been made, operation is simple, and raw material is easy to get.
Technical solution: a kind of preparation method of cefotaxime amide acetaldehyde of the invention is realized as follows:
It is returned in solvent A with 2- (2 '-aminothiazole the base) -2- carbonyl acetamide III and methoxamine hydrochloride of amido protecting
Stream reaction, prepares cefotaxime amide acetals II, then back flow reaction reacts to obtain cefotaxime amide acetaldehyde in solvent B with trifluoroacetic acid
I, reaction equation are as follows:
Wherein:
R is alkyl.
The molar ratio of 2- (2 '-aminothiazole base) -2- carbonyl acetamide III and methoxamine hydrochloride of the amido protecting
For 1:(1~5).
The solvent A is methanol or ethyl alcohol.
The back flow reaction, product need column chromatography for separation to purify.
The molar ratio of the cefotaxime amide acetals II and trifluoroacetic acid are 1:(1~5).
The solvent B is methylene chloride, chloroform, tetrahydrofuran or dioxane.
2- (2 '-aminothiazole the base) -2- carbonyl acetamide III of the amido protecting is by 2- (thiazolamine -4- base)
Glyoxylic ester V is raw material, successively reacts preparation with di-tert-butyl dicarbonate and aminoacetaldehyde contracting glycol, specific reaction equation is as follows:
Wherein: R ' and R is alkyl.
The utility model has the advantages that cefotaxime amide acetaldehyde remains the molecular skeleton feature of ainothiazoly loximate, and increase amide groups and
Aldehyde radical is modified and is transformed convenient for subsequent structural, has important theoretical and practical significance to research novel cephalosporin class drug.
However, amino and aldehyde radical belong to reactive group, it is introduced directly into and is difficult, therefore, it is necessary to is first protected to amino and aldehyde radical, finally
It is deprotected again.The present invention, as raw material, using four step synthetic methods, first protects ammonia to enter 2- (thiazolamine -4- base) glyoxylic ester
Base, again upper amide groups are protected at oxime, deamination and aldehyde radical, cefotaxime amide acetaldehyde (i.e. compound of formula I) have finally been made, instead
Answer easy to operate, raw material is easy to get.
Detailed description of the invention
The mass spectrogram of Fig. 1 compound III (R is methyl),
The mass spectrogram of Fig. 2 compound II (R is methyl),
The mass spectrogram of Fig. 3 compound I.
Specific embodiment
The purpose of the present invention can be achieved by the following measures:
The preparation method of cefotaxime amide acetaldehyde (i.e. compound of formula I), elder generation is with 2- (the 2 '-aminothiazoles of amido protecting
Base) -2- carbonyl acetamide (i.e. formula III compound) reacts with methoxamine hydrochloride, prepare cefotaxime amide acetals (i.e. Formula II
Close object), then compound of formula I, process are reacted to obtain with trifluoroacetic acid are as follows:
Wherein, R is alkyl.
With the 2- of amido protecting (2 '-aminothiazole base) -2- carbonyl acetamide by 2- (thiazolamine-shown in general formula III
4- yl) glyoxylic ester be raw material, successively react preparation with di-tert-butyl dicarbonate and aminoacetaldehyde contracting glycol, can refer to document
Nat.Chem.Biol.2011,7,538-543 etc., wherein R ' and R is alkyl.
(1) in 100mL single-necked flask, 2- (thiazolamine -4- base) glyoxalic acid the preparation process of compound IV: is added
Ester (5mmol), 6.7mL sodium hydrate aqueous solution (2.0mol/L) and 30mL acetone, stirring dissolve solid all.It is slowly added dropwise
Acetone (15mL) solution of 2.4g di-tert-butyl dicarbonate (11mmol) drips and finishes addition magnetic agitation rotor, and room temperature reaction is for 24 hours.
The solid that stirring and dissolving generates in 15mL water is added in reaction solution, revolving removal acetone washs burning with about 40mL methylene chloride
Cup, until oil mutually all dissolutions, extract liquid separation, stay water phase.Water phase stirs in ice-water bath, and the cold hydrochloric acid solution of about 40mL is added dropwise
(3.0mol/L) adjusts pH to 3~4.Water phase is extracted with dichloromethane (3 × 30mL), merges organic phase, and anhydrous sodium sulfate is added
It dries, filters, concentrated by rotary evaporation, obtains compound IV.
(2) preparation process of compound III: in 100mL single-necked flask, under ice bath, 0.38g is sequentially added
(1.4mmol) compound IV, 0.29g (1.4mmol) dicyclohexylcarbodiimide (DCC), aminoacetaldehyde contracting glycol (1.4mmol)
With catalytic amount 4-dimethylaminopyridine (DMAP), 30mL methylene chloride dissolved solid, first ice bath stirring 0.5h, then room temperature is added and stirs
Mix 12h.Reaction solution is rotated into removal methylene chloride.Crude product obtains compound III through column chromatography (PE:EA=4:1) separating-purifying.
Key factor in cefotaxime amide acetaldehyde preparation method:
(1) compound IV and aminoacetaldehyde contracting glycol, DCC (i.e. dicyclohexylcarbodiimide) and DMAP (4- dimethylamino
Pyridine) molar ratio be 1:1:1, methylene chloride, ice bath reaction, product needs column chromatography for separation to purify.
(2) molar ratio of compound III and methoxamine hydrochloride be 1:1~5, solvent be methanol or ethyl alcohol, back flow reaction,
Product needs column chromatography for separation to purify；
(3) molar ratio of compound II and trifluoroacetic acid is 1:1~5, and solvent is methylene chloride, chloroform, tetrahydro furan
It mutters or dioxane, room temperature to back flow reaction, product needs column chromatography for separation to purify.
Following specific embodiments are used to further illustrate the present invention.
Synthetic example
2- (thiazolamine -4- base) glyoxylic ester is purchased from Shanghai Aladdin biochemical technology limited liability company.
Embodiment 1: the synthesis of 2- (2 '-aminothiazole base) -2- carbonylic acetic acid (compound IV) of amido protecting
In 100mL single-necked flask, addition 2- (thiazolamine -4- base) glyoxylic acid ethyl ester 1g (compound V, 5mmol),
6.7mL sodium hydrate aqueous solution (2.0mol/L) and 30mL acetone, stirring dissolve solid all.Bis- carbonic acid of 2.4g is slowly added dropwise
Acetone (15mL) solution of di tert butyl carbonate (11mmol) drips and finishes addition magnetic agitation rotor, and room temperature reaction is for 24 hours.In reaction solution
The solid that stirring and dissolving generates in 15mL water is added, revolving removal acetone washs beaker with about 40mL methylene chloride, until oily phase
All dissolutions extract liquid separation, stay water phase.Water phase stirs in ice-water bath, and the cold hydrochloric acid solution of about 40mL (3.0mol/L) is added dropwise and adjusts
Save pH to 3~4.Water phase is extracted with dichloromethane (3 × 30mL), merges organic phase, and anhydrous sodium sulfate is added and dries, filters, revolves
Inspissation contracting, obtains compound IV.
Embodiment 2: the conjunction of 2- (2 '-aminothiazole the base) -2- carbonyl acetamide (compound III, R are methyl) of amido protecting
At
In 100mL single-necked flask, under ice bath, 0.38g (1.4mmol) compound IV, 0.29g are sequentially added
(1.4mmol) dicyclohexylcarbodiimide (DCC), 0.15g (1.4mmol) aminoacetaldehyde dimethyl acetal and catalytic amount 4- diformazan ammonia
Yl pyridines (DMAP) are added 30mL methylene chloride dissolved solid, first ice bath stirring 0.5h, then 12h are stirred at room temperature.Reaction solution is revolved
It boils off except methylene chloride.Crude product obtains compound III through column chromatography (PE:EA=4:1) separating-purifying.Mass spectral results are as follows: [M+
H]+=360.09, [2M+H]+=719.27 (measured values)；[M+H]+=360.12, [2M+H]+=719.24 (theoretical values), reason
It is consistent substantially by with measured value.(mass spectrogram See Figure 1)
Embodiment 3: the synthesis of cefotaxime amide acetals (compound II, R are methyl)
In 100mL single-necked flask, 0.36g (1mmol) compound III, 0.415g (5mmol) methoxamine hydrochloride is added
With 20mL ethyl alcohol, 50 DEG C are heated to, then the sodium hydrate aqueous solution that 1.2g mass fraction is 33.3% is added into reaction solution, is returned
Stream reaction 8h, TLC monitoring reaction.Concentration has a large amount of solids to be precipitated with the hydrochloric acid solution tune pH to 4~5 of 6mol/L, filtering, second
Alcohol washing.Mother liquor is extracted with ethyl acetate, concentration.Crude product obtains compound II through column chromatography (PE:EA=4:1) separating-purifying.
Mass spectral results are as follows: [M+H]+=389.04, [2M+H]+=777.40 (measured values)；[M+H]+=389.44, [2M+H]+=
777.88 (theoretical values), theory are consistent substantially with measured value.(mass spectrogram See Figure 2)
Embodiment 4: the synthesis of cefotaxime amide acetaldehyde (compound I)
In 100mL single-necked flask, 0.388g (1mmol) compound II and 20mL methylene chloride is added, adds 0.228g
(2mmol) trifluoroacetic acid, back flow reaction, LC-MS monitoring.Revolving removal methylene chloride.Crude product through column chromatograph (PE:EA=2:
1) separating-purifying obtains compound I.Mass spectral results are as follows: [M+H]+=243.04 (measured values)；[M+H]+=243.05 is (theoretical
Value), theory is consistent substantially with measured value.(mass spectrogram See Figure 3)
Embodiment 5: the synthesis of 2- (2 '-aminothiazole base) -2- carbonylic acetic acid (compound IV) of amido protecting
In 100mL single-necked flask, addition 2- (thiazolamine -4- base) glyoxalic acid methylester 0.93g (compound V,
5mmol), 6.7mL sodium hydrate aqueous solution (2.0mol/L) and 30mL acetone, stirring dissolve solid all.It is slowly added dropwise
Acetone (15mL) solution of 2.4g di-tert-butyl dicarbonate (11mmol) drips and finishes addition magnetic agitation rotor, and room temperature reaction is for 24 hours.
The solid that stirring and dissolving generates in 15mL water is added in reaction solution, revolving removal acetone washs burning with about 40mL methylene chloride
Cup, until oil mutually all dissolutions, extract liquid separation, stay water phase.Water phase stirs in ice-water bath, and the cold hydrochloric acid solution of about 40mL is added dropwise
(3.0mol/L) adjusts pH to 3~4.Water phase is extracted with dichloromethane (3 × 30mL), merges organic phase, and anhydrous sodium sulfate is added
It dries, filters, concentrated by rotary evaporation, obtains compound IV.
Embodiment 6: the conjunction of 2- (2 '-aminothiazole the base) -2- carbonyl acetamide (compound III, R are ethyl) of amido protecting
At
In 100mL single-necked flask, under ice bath, 0.38g (1.4mmol) compound IV, 0.29g are sequentially added
(1.4mmol) dicyclohexylcarbodiimide (DCC), 0.19g (1.4mmol) aminoacetaldehyde diethyl acetal and catalytic amount 4- diformazan ammonia
Yl pyridines (DMAP) are added 30mL methylene chloride dissolved solid, first ice bath stirring 0.5h, then 12h are stirred at room temperature.Reaction solution is revolved
It boils off except methylene chloride.Crude product obtains compound III through column chromatography (PE:EA=4:1) separating-purifying.Mass spectral results are as follows: [M+
H]+=388.14, [2M+H]+=775.28 (measured values)；[M+H]+=388.15, [2M+H]+=775.30 (theoretical values), reason
It is consistent substantially by with measured value.
Embodiment 7: the synthesis of cefotaxime amide acetals (compound II, R are ethyl)
In 100mL single-necked flask, 0.39g (1mmol) compound III, 0.332g (4mmol) methoxamine hydrochloride is added
With 20mL ethyl alcohol, 50 DEG C are heated to, then the sodium hydrate aqueous solution that 0.96g mass fraction is 33.3% is added into reaction solution,
Back flow reaction 8h, TLC monitoring reaction.Concentration has a large amount of solids to be precipitated with the hydrochloric acid solution tune pH to 4~5 of 6mol/L, filtering,
Ethanol washing.Mother liquor is extracted with ethyl acetate, concentration.Crude product obtains compound through column chromatography (PE:EA=5:1) separating-purifying
II.Mass spectral results are as follows: [M+H]+=417.16, [2M+H]+=833.32 (measured values)；[M+H]+=417.17, [2M+H]+
=833.34 (theoretical values), theory are consistent substantially with measured value.
Embodiment 8: the synthesis of cefotaxime amide acetaldehyde (compound I)
In 100mL single-necked flask, 0.416g (1mmol) compound II and 20mL chloroform is added, adds 0.342g
(3mmol) trifluoroacetic acid, back flow reaction, TLC monitoring.Revolving removal chloroform.Crude product chromatographs (PE:EA=2:1) through column
Separating-purifying obtains compound I.Mass spectral results are as follows: [M+H]+=243.04 (measured values)；[M+H]+=243.05 (theoretical values),
Theory is consistent substantially with measured value.
Embodiment 9: the synthesis of 2- (2 '-aminothiazole base) -2- carbonylic acetic acid (compound IV) of amido protecting
In 100mL single-necked flask, addition 2- (thiazolamine -4- base) acetaldehyde propyl propionate 1.07g (compound V,
5mmol), 6.7mL sodium hydrate aqueous solution (2.0mol/L) and 30mL acetone, stirring dissolve solid all.It is slowly added dropwise
Acetone (15mL) solution of 2.4g di-tert-butyl dicarbonate (11mmol) drips and finishes addition magnetic agitation rotor, and room temperature reaction is for 24 hours.
The solid that stirring and dissolving generates in 15mL water is added in reaction solution, revolving removal acetone washs burning with about 40mL methylene chloride
Cup, until oil mutually all dissolutions, extract liquid separation, stay water phase.Water phase stirs in ice-water bath, and the cold hydrochloric acid solution of about 40mL is added dropwise
(3.0mol/L) adjusts pH to 3~4.Water phase is extracted with dichloromethane (3 × 30mL), merges organic phase, and anhydrous sodium sulfate is added
It dries, filters, concentrated by rotary evaporation, obtains compound IV.
Embodiment 10: 2- (2 '-aminothiazole the base) -2- carbonyl acetamide (compound III, R are propyl) of amido protecting
Synthesis
In 100mL single-necked flask, under ice bath, 0.38g (1.4mmol) compound IV, 0.29g are sequentially added
(1.4mmol) dicyclohexylcarbodiimide (DCC), the pure and mild catalytic amount 4- diformazan ammonia of 0.23g (1.4mmol) aminoacetaldehyde contracting dipropyl
Yl pyridines (DMAP) are added 30mL methylene chloride dissolved solid, first ice bath stirring 0.5h, then 12h are stirred at room temperature.Reaction solution is revolved
It boils off except methylene chloride.Crude product obtains compound III through column chromatography (PE:EA=4:1) separating-purifying.Mass spectral results are as follows: [M+
H]+=416.19, [2M+H]+=831.38 (measured values)；[M+H]+=415.18, [2M+H]+=831.36 (theoretical values), reason
It is consistent substantially by with measured value.
Embodiment 11: the synthesis of cefotaxime amide acetals (compound II, R are propyl)
In 100mL single-necked flask, 0.415g (1mmol) compound III, 0.249g (3mmol) methoxamine hydrochloric acid is added
Salt and 20mL methanol, are heated to 50 DEG C, then the sodium hydroxide that addition 0.72g mass fraction is 33.3% into reaction solution is water-soluble
Liquid, back flow reaction 8h, TLC monitoring reaction.Concentration has a large amount of solids to be precipitated, mistake with the hydrochloric acid solution tune pH to 4~5 of 6mol/L
Filter, methanol washing.Mother liquor is extracted with ethyl acetate, concentration.Crude product obtains compound through column chromatography (PE:EA=5:1) separating-purifying
II.Mass spectral results are as follows: [M+H]+=444.19, [2M+H]+=889.38 (measured values)；[M+H]+=444.20, [2M+H]+
=889.40 (theoretical values), theory are consistent substantially with measured value.
Embodiment 12: the synthesis of cefotaxime amide acetaldehyde (compound I)
In 100mL single-necked flask, 0.416g (1mmol) compound II and 20mL tetrahydrofuran is added, adds 0.456g
(4mmol) trifluoroacetic acid, back flow reaction, TLC monitoring.Revolving removal tetrahydrofuran.Crude product chromatographs (PE:EA=2:1) through column
Separating-purifying obtains compound I.Mass spectral results are as follows: [M+H]+=243.04 (measured values)；[M+H]+=243.05 (theoretical values),
Theory is consistent substantially with measured value.
Although detailing the present invention with preferred embodiment, it is not intended to limit the present invention.Any this field
Technical staff, without departing from the spirit and scope of the present invention, should can with various modification can be adapted with change.Therefore
Protection scope of the present invention should be considered as appended claims limited range.
Claims (7)
1. a kind of preparation method of cefotaxime amide acetaldehyde, it is characterised in that the preparation method is realized as follows:
It is flowed back in solvent A instead with 2- (2 '-aminothiazole the base) -2- carbonyl acetamide III and methoxamine hydrochloride of amido protecting
It answers, prepares cefotaxime amide acetals II, then back flow reaction reacts to obtain cefotaxime amide acetaldehyde I in solvent B with trifluoroacetic acid,
Reaction equation are as follows:
Wherein, R is alkyl.
2. a kind of preparation method of cefotaxime amide acetaldehyde according to claim 1, it is characterised in that: the amino is protected
2- (2 '-aminothiazole the base) -2- carbonyl acetamide III of shield and the molar ratio of methoxamine hydrochloride are 1:(1~5).
3. a kind of preparation method of cefotaxime amide acetaldehyde according to claim 1, it is characterised in that: the solvent A
For methanol or ethyl alcohol.
4. a kind of preparation method of cefotaxime amide acetaldehyde according to claim 1, it is characterised in that: the reflux is anti-
It answers, product needs column chromatography for separation to purify.
5. a kind of preparation method of cefotaxime amide acetaldehyde according to claim 1, it is characterised in that: the cefotaxime
The molar ratio of amide acetals II and trifluoroacetic acid is 1:(1~5).
6. a kind of preparation method of cefotaxime amide acetaldehyde according to claim 1, it is characterised in that: the solvent B
For methylene chloride, chloroform, tetrahydrofuran or dioxane.
7. a kind of preparation method of cefotaxime amide acetaldehyde according to claim 1, it is characterised in that: the amino is protected
2- (2 '-aminothiazole the base) -2- carbonyl acetamide III of shield is raw material by 2- (thiazolamine -4- base) glyoxylic ester V, successively
Preparation is reacted with di-tert-butyl dicarbonate and aminoacetaldehyde contracting glycol, specific reaction equation is as follows:
Wherein, R ' and R is alkyl.
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| CN113402416A (en) * | 2021-05-29 | 2021-09-17 | 浙江锦华新材料股份有限公司 | Preparation method of methoxylamine hydrochloride |
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