CN109608478A - A kind of synthetic method of Flomoxef acid - Google Patents
A kind of synthetic method of Flomoxef acid Download PDFInfo
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- CN109608478A CN109608478A CN201811361109.2A CN201811361109A CN109608478A CN 109608478 A CN109608478 A CN 109608478A CN 201811361109 A CN201811361109 A CN 201811361109A CN 109608478 A CN109608478 A CN 109608478A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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
- C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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 substituted in position 7
- C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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 substituted in position 7 with hetero atoms directly attached in position 7
- C07D505/16—Nitrogen atoms
- C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
- C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/02—Preparation
- C07D505/06—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 synthetic methods of Flomoxef acid.The present invention includes the following steps: 1) compound (I) and 3 tetrazole side chains generation condensation reactions generations compound (II);2) compound (II) sloughs 2 carboxyl-protecting groups under the action of lewis acid and catalyst and generates compound (III);3) compound (III) sloughs amino protecting group under the action of amino-acylase and obtains compound (IV);4) compound (IV) generates target product (V) through acylation reaction with 7 side chains.Rationally, synthesis step is simple, and reaction condition is mildly easily-controllable in synthesis process, and solvent is easy to be recycled, environmentally friendly, yield high income for synthetic route design of the present invention.
Description
Technical field
The present invention relates to chemical pharmaceutical technology fields, more particularly, to a kind of synthetic method of Flomoxef acid.
Background technique
Flomoxef Sodium, entitled (6R, 7R) -7- ﹝ 2- (difluoro methyl mercapto) second acyl amine base ﹞ -7- methoxyl group -3- { the ﹝ 1- of chemistry
- 5 Ji ﹞ sulphomethyl of (2- ethoxy) -1H-TETRAZOLE } miscellaneous 4,2,0 ﹞ oct-2-ene of the Shuan Huan ﹝-formic acid of -8- oxo -5- oxa- -1- Dan
Sodium, the compound are developed by Japanese Shionogi Seiyaku Kabushiki Kaisha, which, which has, stablizes beta-lactamase, renal toxicity
It is low, the advantages of has a broad antifungal spectrum.
Currently, the synthesis of antibiotic Flomoxef acid, mainly there is following six kinds of routes:
(1) patent US4532233 discloses one kind by -7 beta-amino -3- chloromethyl of 7 α-methoxyl group-oxacephem acid benzhydrol
Ester is starting material, synthesizes the route of Flomoxef acid;
Although reaction route is short in the route, it is deprotected using metal chloride, causes post-processing complicated, have gold in product
Belong to residual.
(2) document The Journal of Antibiotics.4, P466-476 (1985) is reported by 7- benzene carbon amide
Base -3- chloromethyl-oxacephem acid benzhydrol ester is starting material, the route through five steps synthesis Flomoxef acid;
The route reaction step is more, moreover, using metal chloride SnCl in reaction process2Deprotection reaction acutely, by-product
More, post-reaction treatment is complicated, has metal residual in product.
(3) patent WO2007105253 is disclosed with tunning 7- amino -3- chloromethyl-oxacephem lipoid substance
For starting material, the route through five steps synthesis Flomoxef acid;
The route uses alkyl sulfide chlorine reagent, and mercaptan that is easily generated toxic and polluting environment is not easy to handle.
(4) patent CN102952149A is reported is with -7 β of 7 α-methoxyl group-amide groups -3- chloromethyl-oxacephem
Beginning raw material synthesizes the route of Flomoxef intermediate;
Intermediate after route phosphorus pentachloride deprotection is not sufficiently stable, and reaction yield is low.
(5) patent CN105399755A is disclosed to be that starting material synthesizes Flomoxef sour (VII) by compound (I)
Method;
Reactions steps of this method is more, and synthesis cycle is long.
(6) it is that starting material synthesizes Flomoxef acid (VII) that patent CN105037393A, which discloses one kind by compound (I),
Method;
Reactions steps of this method is more, and synthesis cycle is long, and expensive ammonium ceric nitrate reagent, production cost have been used in synthesis process
It is high.
Summary of the invention
In order to make up for the deficiencies of the prior art, the present invention provides a kind of synthetic methods of Flomoxef acid.
The technical solution adopted by the present invention are as follows:
A kind of synthetic method of Flomoxef acid, which comprises the steps of:
(1) compound (I) dissolution in organic solvent, is urged with the sodium salt or sylvite aqueous solution of 3 tetrazole side chains in phase transfer
The lower reaction of agent effect generates compound (II);
(2) compound (II) dissolution in organic solvent, 2 carboxyls is sloughed under the collective effect of lewis acid and catalyst and are protected
Base is protected, is generated compound (III);
(3) compound (III) is dissolved in inorganic solvent, is sloughed amino protecting group under the action of amino-acylase, is obtained compound
(IV);
(4) compound (IV) is reacted with 7 side chain difluoromethyl sulphur acetic acid active esters, generates target product Flomoxef acid
(V);
Specific reaction synthetic route is as follows:
R in formula1For acyl residue, R2For carboxyl-protecting group, R3For active group of easily leaving away.
Preferably, R1For aminomethyl phenyl or phenyl;R2Have on the benzyl or phenyl ring of substituted base for tert-butyl, on phenyl ring
The benzhydryl of substituent group;R3For 2- sulphur benzothiazolyl, benzotriazole base or diethyl sulfo-phosphoryl base.
Preferably, in step (1), reaction temperature is 0~30 DEG C;The organic solvent be halogenated hydrocarbon, ethers, esters and
One of aromatic hydrocarbon solvent is a variety of;The sodium salt of 3 tetrazole side chains or the dosage of sylvite are the 1 of compound (I)
~2 times of molar equivalents;The phase transfer catalyst is quaternary ammonium salt-type phase transfer catalyst, the quaternary ammonium salt phase transfer catalyst
Dosage is 0.05~0.3 times of molar equivalent of compound (I).
Preferably, the quaternary ammonium compound is tetrabutylammonium bromide, benzyltriethylammoinium chloride or tetraethyl chlorination
Ammonium.
Preferably, in step (1), the halogenated hydrocarbon solvent is methylene chloride, chloroform, 1,2- dichloroethanes or four chlorinations
Carbon;The ether solvent is ether, propyl ether or isopropyl ether;The esters solvent is ethyl acetate, methyl acetate or butyl acetate;
The aromatic hydrocarbon solvent is benzene, toluene or dimethylbenzene.
Preferably, in step (2), reaction temperature is 40~-70 DEG C;The organic solvent is halogenated hydrocarbon, nitroparaffins
One of class, ethers, esters, arene and ketones solvent are a variety of;The lewis acid is alchlor, four chlorinations
Tin, titanium tetrachloride or trifluoroacetic acid, the lewis acidic dosage are 1~30 times of molar equivalent of compound (II);It is described to urge
Agent is ether compound, and dosage is 1~20 times of molar equivalent of compound (II).
Preferably, in step (3), reaction temperature is 0~40 DEG C, and reaction PH is 6~9;The inorganic solvent is water, boric acid
Salt buffer aqueous solution or phosphate-buffered aqueous solution;The dosage of the amino-acylase is the 0.3~1.5 of compound (III) weight
Times.
Preferably, in step (4), compound (IV), 7 side chain difluoromethyl sulphur acetic acid active esters are added in solvent,
It is sour (V) that base catalysis generates target product Flomoxef;In step (4), reaction temperature is 0~40 DEG C;7 side chain difluoros
The dosage of methyl sulphur acetic acid active ester is 1~2 times of molar equivalent of compound (IV).
Preferably, in step (4), the alkali that the base catalysis uses is organic base or inorganic base;The organic base is organic
Aminated compounds, the inorganic base are ammonium hydrogen carbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide and second
One of sour sodium is a variety of.
Preferably, organic amine compound is in triethylamine, ethylenediamine, diethylamine, pyridine, quinoline, piperidines and morpholine
It is one or more.
Preferably, in step (4), solvent is one or more of water, alcohols solvent and halogenated hydrocarbon solvent.
Preferably, the alcohols solvent are as follows: one of methanol, ethyl alcohol, ethylene glycol and diethanol are a variety of;It is described halogenated
Hydrocarbon solvent is one of methylene chloride, chloroform, 1,2- dichloroethanes and carbon tetrachloride or a variety of.
Compared with prior art, the present invention has the advantages that:
The present invention provides a kind of synthetic methods of completely new Flomoxef acid.The compounds of this invention (I) and 3 tetrazole side chains
Condensation reaction occurs and generates compound (II), compound (II) is sloughed 2 carboxyls under the action of lewis acid and catalyst and protected
It protecting base and generates compound (III), compound (III) sloughs amino protecting group under the action of amino-acylase and obtains compound (IV),
Compound (IV) generates target product (V) through acylation reaction with 7 side chains;Synthetic route of the present invention simply only needs four steps i.e.
Target product can be synthesized, the product of synthesis is without metal residual, moreover, reaction condition is mildly easily-controllable in synthesis process of the present invention, it is molten
Agent is easy to be recycled, environmentally friendly.
Specific embodiment
Following specific embodiments are used only as that further explanation of the invention is not used in and is limited the scope of the invention.
Embodiment one:
One, the preparation of midbody compound (II)
Take compound (I) 20g(36.56mmol) it is added in methylene chloride 300ml and dissolves, wherein R in compound (I)1For methyl
Phenyl, R2Then 3 side chain sodium-salt aqueous solution 9.2g(54.84mmol are sequentially added for benzhydryl compounds) 100ml, four
Butylammonium bromide 3.5g(10.97mmol), 25 DEG C of temperature control, stirring to compound (I) fully reacting.Stratification, methylene chloride
It is mutually concentrated to dryness after dry filter, obtains compound (II) 24g, yield 100%;Compound (II) is foaming solid, to chemical combination
Object (II) carries out NMR analysis, as a result as follows:
1H NMR (DMSO):
δ: 2.326 (3H, s, Ph-CH3 ), 3.512(3H,s,C7-OCH3 ),
7.266~7.855 (14H, d, m, 2C6H5、C6H4), 6.903(1H,s,CHPh), 5.055(1H,t,-OH),3.692
~3.710 (2H, q ,-CH2 -OH),
4.200(2H,t,-CH2 -CH2-OH), 4.567(2H,s,C3-CH2 -S),
4.257~4.291 (2H, q, C4-CH2 ),5.190(1H,C6- H),
9.320(1H,s,-NH-)。
Two, the preparation of midbody compound (III)
Under nitrogen protection, compound (II) 24g(36.56mmol) is added in solvent carbon tetrachloride 300ml and is dissolved, cooled down
To -25 DEG C, solid aluminum trichloride 48.7g(365.6 mmol is added) it is allowed to be dissolved in the molten of methyl phenyl ethers anisole 59ml (548.4mmol)
In liquid, 0.5~1h is reacted after dripping off, and ice 1N HCL aqueous solution 300ml, stratification, organic phase 1N HCL aqueous solution is added dropwise
200ml washing;Organic to be added to water 200ml, being slowly added into sodium bicarbonate tune PH is between 6~8, and stratification, organic phase waits for
Recycling;Ethyl acetate 200ml is added in water phase, and hydrochloric acid tune PH is 1.0~2.0, and stratification, organic phase is dry, is concentrated to give chemical combination
Object (III) 14.3g, yield 80%, compound (III) are foaming solid.
Three, the preparation of midbody compound (IV)
Phosphate buffer solution 200ml is added in compound (III) 14.3g(29.15mmol), the monitoring of PH meter is lower to be added sodium bicarbonate
It adjusts PH=7.0 to be completely dissolved compound (III), amino-acylase 7g is added, controlled at 25 DEG C, sodium bicarbonate solution is tieed up
Hold PH=7.0, stirring to compound (III) fully reacting;Filtering is added ethyl acetate and washs water phase, and organic phase is to be recycled, is added dropwise
The crystallization of hydrochloric acid tune PH=3~4, filtering, dry compound (IV) 10.3g, yield 95%.
Four, the preparation of Flomoxef sour (1)
Compound (IV) 10.3g(27.66mmol), 7 side chain difluoromethyl sulphur acetic acid active esters 12.2 (41.53mmol) are added
Enter the in the mixed solvent being made of water 50ml, methanol 50ml, methylene chloride 50ml, be added with stirring triethylamine 7.7ml, controls PH
=7.0, temperature is 25 DEG C, until compound (IV) fully reacting;Water 100ml is added, stratification recycles organic phase, and water phase is added
Hydrochloric acid tune PH=1.0~2.0, stratification are added dropwise in ethyl acetate 150ml, and dry organic phase filters, and acetone, two is added in concentration
Chloromethanes is crystallized, wherein the volume ratio of acetone and methylene chloride is 1:4, obtains product Flomoxef acid (V) 12.7g, is received
Rate 93%;NMR analysis is carried out after product Flomoxef sour (V) is switched to sodium salt, as a result as follows:
1H NMR (DMSO):
δ: 3.391 (3H, s ,-OCH3 ), 4.171~4.469 (2H, q, C4-CH2 ),
4.389(2H,s,C3-CH2 - S), 4.298~4.330 (2H, t ,-CH2 -CH2-OH),
3.731~3.780(2H, q ,-CH2-CH2 - OH), 4.967 (1H, s, C6-H),
3.588~3.731 (2H, q ,-CH2 - S), 7.152~7.528 (1H, t, 2F-CH-S),
9.265(1H,s,-NH-),5.250(1H,s,-OH)。
Embodiment two:
One, the preparation of midbody compound (II)
Take compound (I) 25g(45.7mmol) it is added in 1,2- methylene chloride 400ml and dissolves, wherein R in compound (I)1For first
Base phenyl, R2Then 3 side chain sodium-salt aqueous solution 9.2g(54.84mmol are sequentially added for benzhydryl compounds) 100ml,
Benzyltriethylammoinium chloride 5g, 25 DEG C of temperature control, stirring to compound (I) fully reacting.Stratification, methylene chloride Xiang Jinggan
It is concentrated to dryness after dry filtering, obtains compound (II) 30g, yield 100%.
Two, the preparation of midbody compound (III)
Under nitrogen protection, compound (II) 30g(45.7mmol) is added in solvent chloroform 300ml and is dissolved, is cooled to -25
DEG C, methyl phenyl ethers anisole 59ml (548.4mmol) is added, trifluoroacetic acid 30ml is added dropwise, 0.5~1h is reacted after dripping off, is concentrated under reduced pressure organic
Water 200ml is added in phase, and being slowly added into sodium bicarbonate tune PH is stratification between 6~8, and organic phase is to be recycled;Water phase is added
Ethyl acetate 200ml, hydrochloric acid tune PH are 1.0~2.0, and stratification, organic phase is dry, are concentrated to give compound (III) 15.6g, are received
Rate 70%.
Three, the preparation of midbody compound (IV)
Water 200ml is added in compound (III) 15.6g(31.8mmol), the monitoring of PH meter is lower to be added making of sodium bicarbonate tune PH=7.0
It closes object (III) to be completely dissolved, amino-acylase 10g is added, controlled at 25 DEG C, sodium bicarbonate solution maintains PH=7.0, stirs
It mixes to compound (III) fully reacting;Filtering is added ethyl acetate and washs water phase, and organic phase is to be recycled, and hydrochloric acid tune PH=3 are added dropwise
~4 crystallizations, filtering, dry compound (IV) 10.6g, yield 90%.
Four, the preparation of Flomoxef sour (1)
Compound (IV) 10.6g(28.43mmol), 7 side chain difluoromethyl sulphur acetic acid active esters 12.2 (41.53mmol) are added
Enter the in the mixed solvent being made of water 50ml, methanol 50ml, methylene chloride 50ml, stir lower dropwise addition triethylamine, control PH=7.0,
Temperature is 25 DEG C, until compound (IV) fully reacting;Water 100ml is added, stratification recycles organic phase, and acetic acid is added in water phase
Hydrochloric acid tune PH=1.0~2.0, stratification are added dropwise in ethyl ester 150ml, and dry organic phase filters, and acetone, dichloromethane is added in concentration
Alkane is crystallized, wherein the volume ratio of acetone and methylene chloride is 1:4, obtains product Flomoxef acid (V) 13g, yield 93%.
Embodiment three:
One, the preparation of midbody compound (II)
Take compound (I) 10g(18.28mmol) it is added in ethyl acetate 200ml and dissolves, wherein R in compound (I)1For methyl
Phenyl, R2Then 3 side chain sodium-salt aqueous solution 3.4g(20.11mmol are sequentially added for benzhydryl compounds) 100ml, four
Ethyl ammonium chloride 2g, 25 DEG C of temperature control, stirring to compound (I) fully reacting.Stratification, methylene chloride is mutually through dry filter
After be concentrated to dryness, obtain compound (II) 12g, yield 100%.
Two, the preparation of midbody compound (III)
Under nitrogen protection, compound (II) 12g(18.28mmol) is added in solvent chloroform 300ml and is dissolved, is cooled to -25
DEG C, methyl phenyl ethers anisole 20ml (185.9mmol) is added, tin tetrachloride 10ml is added dropwise, 0.5~1h is reacted after dripping off, ice 1N HCL is added dropwise
Aqueous solution 100ml, stratification, organic phase are washed with 1N HCL aqueous solution 100ml, and water 100ml is added, is slowly added into bicarbonate
Sodium tune PH is stratification between 6~8, and organic phase is to be recycled;Water phase be added ethyl acetate 100ml, hydrochloric acid tune PH be 1.0~
2.0, stratification, organic phase is dry, is concentrated to give compound (III) 7.15g, yield 80%.
Three, the preparation of midbody compound (IV)
Aqueous borate buffer solution 100ml is added in compound (III) 7.15g(14.58mmol), the monitoring of PH meter is lower to be added carbonic acid
Hydrogen sodium tune PH=7.0 are completely dissolved compound (III), amino-acylase 7g are added, controlled at 25 DEG C, sodium bicarbonate is molten
Liquid maintains PH=7.0, stirring to compound (III) fully reacting;Filtering is added ethyl acetate and washs water phase, and organic phase is to be recycled,
It is added dropwise the crystallization of hydrochloric acid tune PH=3~4, filtering, dry compound (IV) 5.15g, yield 95%.
Four, the preparation of Flomoxef sour (1)
Compound (IV) 5.15g(13.8mmol), 7 side chain difluoromethyl sulphur acetic acid active ester 4.5g (15.23mmol) are added
Enter the in the mixed solvent being made of water 50ml, methanol 50ml, methylene chloride 50ml, stir lower dropwise addition triethylamine, control PH=7.0,
Temperature is 25 DEG C, until compound (IV) fully reacting;Water 100ml is added, stratification recycles organic phase, and acetic acid is added in water phase
Hydrochloric acid tune PH=1.0~2.0, stratification are added dropwise in ethyl ester 150ml, and dry organic phase filters, and acetone, dichloromethane is added in concentration
Alkane is crystallized, wherein the volume ratio of acetone and methylene chloride is 1:4, obtains product Flomoxef acid (V) 6.35g, yield
93%。
Claims (10)
1. a kind of synthetic method of Flomoxef acid, which comprises the steps of:
(1) compound (I) dissolution in organic solvent, is urged with the sodium salt or sylvite aqueous solution of 3 tetrazole side chains in phase transfer
The lower reaction of agent effect generates compound (II);
(2) compound (II) dissolution in organic solvent, 2 carboxyls is sloughed under the collective effect of lewis acid and catalyst and are protected
Base is protected, is generated compound (III);
(3) compound (III) is dissolved in inorganic solvent, is sloughed amino protecting group under the action of amino-acylase, is obtained compound
(IV);
(4) compound (IV) is reacted with 7 side chain difluoromethyl sulphur acetic acid active esters, generates target product Flomoxef acid
(V);
Specific reaction synthetic route is as follows:
R in formula1For acyl residue, R2For carboxyl-protecting group, R3For active group of easily leaving away.
2. the synthetic method of Flomoxef acid according to claim 1, it is characterised in that: R1For aminomethyl phenyl or phenyl;R2
For tert-butyl, on phenyl ring on the benzyl or phenyl ring of substituted base substituted base benzhydryl;R3For 2- sulphur benzothiazolyl,
Benzotriazole base or diethyl sulfo-phosphoryl base.
3. the synthetic method of Flomoxef acid according to claim 1 or 2, it is characterised in that: in step (1), reaction temperature
Degree is 0~30 DEG C;The organic solvent is one of halogenated hydrocarbon, ethers, esters and aromatic hydrocarbon solvent or a variety of;It is described
The sodium salt of 3 tetrazole side chains or the dosage of sylvite are 1~2 times of molar equivalent of compound (I);The phase transfer catalyst is
Quaternary ammonium salt-type phase transfer catalyst, the dosage of the quaternary ammonium salt phase transfer catalyst are 0.05~0.3 times moles of compound (I)
Equivalent.
4. the synthetic method of Flomoxef acid according to claim 1 or 2, it is characterised in that: in step (2), reaction temperature
Degree is 40~-70 DEG C;The organic solvent is halogenated hydrocarbon, nitroparaffin hydro carbons, ethers, esters, arene and ketones solvent
One of or it is a variety of;The lewis acid is alchlor, tin tetrachloride, titanium tetrachloride or trifluoroacetic acid, the Louis
The dosage of acid is 1~30 times of molar equivalent of compound (II);The catalyst is ether compound, and dosage is compound
(II) 1~20 times of molar equivalent.
5. the synthetic method of Flomoxef acid according to claim 1 or 2, it is characterised in that: in step (3), reaction temperature
Degree is 0~40 DEG C, and reaction PH is 6~9;The inorganic solvent is water, aqueous borate buffer solution or phosphate-buffered aqueous solution;
The dosage of the amino-acylase is 0.3~1.5 times of compound (III) weight.
6. the synthetic method of Flomoxef acid according to claim 1 or 2, it is characterised in that: in step (4), by chemical combination
Object (IV) and 7 side chain difluoromethyl sulphur acetic acid active esters are added in solvent, and base catalysis generates target product Flomoxef acid
(V);Reaction temperature is 0~40 DEG C;The dosage of 7 side chains difluoromethyl sulphur acetic acid active ester be compound (IV) 1~
2 times of molar equivalents.
7. the synthetic method of Flomoxef acid according to claim 6, it is characterised in that: in step (4), the base catalysis
The alkali used is organic base or inorganic base;The organic base is organic amine compound, and the inorganic base is ammonium hydrogen carbonate, carbonic acid
One of hydrogen sodium, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide and sodium acetate are a variety of.
8. the synthetic method of Flomoxef acid according to claim 7, it is characterised in that: organic amine compound is three second
One of amine, ethylenediamine, diethylamine, pyridine, quinoline, piperidines and morpholine are a variety of.
9. the synthetic method of Flomoxef acid according to claim 6, it is characterised in that: in step (4), solvent be water,
One or more of alcohols solvent and halogenated hydrocarbon solvent.
10. the synthetic method of Flomoxef acid according to claim 9, it is characterised in that: the alcohols solvent are as follows: first
One of alcohol, ethyl alcohol, ethylene glycol and diethanol are a variety of;The halogenated hydrocarbon solvent is methylene chloride, chloroform, 1,2- dichloro
One of ethane and carbon tetrachloride are a variety of.
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Citations (6)
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WO2007105253A2 (en) * | 2006-03-15 | 2007-09-20 | Carthesia S.A.S. Di Emanuela Migliavacca & C. | PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES |
CN102180888A (en) * | 2011-03-02 | 2011-09-14 | 河北科技大学 | Preparation method for 7-amino-3-non-3-cephem-4-carboxylic acid(7-ANCA) |
CN102952149A (en) * | 2012-11-09 | 2013-03-06 | 浙江新和成股份有限公司 | One-pot synthesis method of flomoxef intermediate |
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CN105399755A (en) * | 2015-11-03 | 2016-03-16 | 浙江永宁药业股份有限公司 | Method for synthesizing flomoxef acid |
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CN102952149A (en) * | 2012-11-09 | 2013-03-06 | 浙江新和成股份有限公司 | One-pot synthesis method of flomoxef intermediate |
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