CN110357816A - A kind of synthetic method of gatifloxacin cyclized ester - Google Patents
A kind of synthetic method of gatifloxacin cyclized ester Download PDFInfo
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Abstract
The invention belongs to the production technologies of pharmaceutical intermediate, specifically disclose a kind of synthetic method of gatifloxacin cyclized ester, synthetic method is with 3,4,5,6- tetra- fluoro- N-Methyl-o-phthalimides are starting material, 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides are obtained by hydrolysis, decarboxylation, methylation, 2,4,5- tri- fluoro- 3- methoxy benzoyl chloride elder generations and N, N- dimethylamino ethyl acrylate are coupled, it is replaced again with cyclopropylamine, finally cyclization generates gatifloxacin cyclized ester under the action of DMF and potassium fluoride；The synthetic route of reaction is short, and raw material sources are easier to, and reaction condition is mild, easy operation control, reduces consumption of raw materials, convenient post-treatment reduces costs；Reaction using potassium fluoride replace potassium carbonate, the generation of exhaust gas can not only be reduced, and the potassium fluoride after can be adjusted by potassium hydroxide after continue to use, further reduce costs.
Description
Technical field
The invention belongs to the production technologies of pharmaceutical intermediate, and in particular to a kind of synthetic method of gatifloxacin cyclized ester.
Background technique
Quinolone drugs is also known as pyridonecarboxylic acids or pyridinone drug, using the DNA of bacterium as target, antibacterial
Spectrum is wide.Quinolone drugs since the advent of the world is quickly grown, at present one of key agents of written bacterial-infection resisting, is used extensively
In treating various infection, important function has been played to the cure rate and the critical infection case fatality rate of reduction that improve infection caused by sensitive bacteria.
Gatifloxacin, the entitled gatifloxacin of English are the fluoro- 8- of new 6- of Japanese Anzurin Pharmaceutical Co., Ltd's initiative
BAY 128039 compound, to Glan negative bacterium, gram-positive bacterium, anaerobic bacteria, mycoplasma, Chlamydia and mycobacteria etc.
Preferable antibacterial action is all had, by inhibiting bacterium DNA replication, transcription and repair process to play the role of killing bacterium, tool
Have the advantages that broad-spectrum high efficacy, phototoxicity are low.It is clinically used for the infectious diseases such as respiratory system, digestive system, skin soft tissue
Treatment also can be used as drug combination treatment tuberculosis.
Quinolone drugs can be prepared by a variety of initial feeds.The fluoro- 3- methoxy benzoyl chloride of 2,4,5- tri-
It is a kind of important synthesis material, document (Shandong chemical industry, 2013,42 (1): 11-13) uses benzene using tetrachlorophthalic anhydride as starting material
Amine carries out imidization, and then fluorine replaces in DMF solvent, and through basic hydrolysis open loop, while hydroxyl replaces, in alkaline item after decarboxylation
It methylates under part, acidification obtains 2,4,5- tri- fluoro- 3- methoxybenzoyl acid.Imines is carried out using aniline in the synthetic method
Change, the price of aniline is higher, if do not recycled, raw material is caused largely to waste, increases cost of material, and if recycling benzene
Amine, because aniline boiling point is high, it is also desirable to pay higher cost.
Quinolone drugs can also be produced with 2,3,4,5- phenyl tetrafluoride formyl chloride.If patent document CN1461748A is with 2,
4,5- tetra- fluoro- 3- methoxy benzoyl chlorides be starting material, be substituted, the condensation of hydrolysis decarboxylation, triethyl orthoformate, enamine,
Cyclization obtains main cyclic quinoline.Decarboxylation and by-product is more when grignard reaction, product separation is difficult, three wastes discharge amount in above-mentioned reaction
Greatly, it needs using the biggish raw material of the security risks such as triethyl orthoformate, and with 2,4,5- tetra- fluoro- 3- methoxy benzoyl chlorides
As starting material, the cost of synthesis is increased.
Further, it is also possible to which 4,5,6- ptfe phthalates are starting material with 3, patent document EP0352123A2 is introduced
3,4,5,6- ptfe phthalate successively by hydrolysis, decarboxylation, methylation, acylation, condensation, hydrolysis, condensation, amination and
Cyclization obtains quinolone main structure, but the synthetic route step is long, and yield is lower, and the Atom economy in reaction is poor,
The utilization rate of raw material reduces.
In view of this, that it is necessary to provide a kind of synthesis steps is short, atom utilization is high in reaction and the production technology of environmental protection.
Summary of the invention
It is an object of the invention to combine the deficiencies in the prior art, provide that a kind of quality is good, high income, and less energy consumption plus
For husky star synthetic method.
To achieve the above object of the invention, the present invention adopts the following technical scheme that:
A kind of synthetic method of gatifloxacin cyclized ester, comprising:
(1) 3,4,5,6- tetra- fluoro- N-Methyl-o-phthalimides are uniformly mixed with lye, temperature rising reflux reacts
To the fluoro- 3- hydroxyl phthalic sodium of 2,4,5- tri-；Then in the obtained fluoro- 3- hydroxyl phthalic sodium of 2,4,5- tri-
Acid is added to carry out decarboxylic reaction and be acidified to obtain 2,4,5 trifluoro 3 hydroxy benzoic acid；
(2) by obtained 2,4,5 trifluoro 3 hydroxy benzoic acid and dimethyl suflfate, hybrid reaction is again under alkaline condition
Acidification obtains the fluoro- 3- methoxy benzoic acid of 2,4,5- tri-；Then the fluoro- 3- methoxy benzoic acid of 2,4,5- tri- and chlorine that will be obtained
Changing sulfoxide, hybrid reaction obtains the fluoro- 3- methoxy benzoyl chloride of 2,4,5- tri- in a solvent；
(3) 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides and N, N- dimethylamino ethyl acrylate are added in toluene, adds
Enter triethylamine, react, cooling is added cyclopropylamine, after temperature reaction, water is added to extract, and concentration organic phase obtains aminate；
(4) aminate is added into dipolar aprotic solvent, and puts into potassium fluoride and catalyst, reacts, cooling is simultaneously
It is concentrated under reduced pressure, cool down crystallization, and filtering obtains gatifloxacin cyclized ester.
Preferably, 3,4,5,6- tetra- fluoro- N-Methyl-o-phthalimides and NaOH reaction, temperature rising reflux in step (1)
8-12 h is reacted, 2,4,5- tri- fluoro- 3- hydroxyl phthalic sodium are obtained；The solution that directly above-mentioned reaction is obtained, which turns reaction, to be held
Acid is added in device and carries out decarboxylic reaction, and is acidified and obtains 2,4,5- tri- fluoro- 3- hydroxybenzoic acids.
Preferably, the lye in step (1) is the NaOH aqueous solution of 20-40%.
Preferably, the acid that decarboxylation and acidification use in step (1) is sulfuric acid and/or hydrochloric acid；Decarboxylation and acidification when acid adding extremely
PH value is 0-4.Specifically, after 2,4,5- tri- fluoro- 3- hydroxyl phthalic sodium are transferred to reaction vessel, sulfuric acid and/or salt are added
Acid for adjusting pH controls temperature less than 70 DEG C, increases temperature to 100-110 DEG C after regulating pH, heat preservation is anti-to 0-4 when adjusting pH
6-10h is answered, is cooled to 20-30 DEG C after appropriate water supplement after fully reacting, is then 2,4,5- tri- fluoro- 3- hydroxyls by effective component
The solution of benzoic acid is transferred in next step.
Preferably, the acid that acidification uses in step (2) is sulfuric acid and/or hydrochloric acid, and acid adding is to pH value less than 0.5 when acidification.
Step (2) is specifically, the solution that above-mentioned effective component is 2,4,5- tri- fluoro- 3- hydroxybenzoic acids is transferred to methyl makeup
In setting, adding alkali to adjust pH is 9.0-9.5, controls temperature less than 35 DEG C, adds dimethyl suflfate, while passing through addition lye control
PH is 8.5-9.5, and temperature is increased after dimethyl suflfate has added to 75-85 DEG C, adjusts pH and is greater than 12, insulation reaction 1-3h,
It is cooled to 30 DEG C or less after complete reaction and is transferred to acidizing device, after acidified, centrifugation, it is fluoro- that drying solid obtains 2,4,5- tri-
3- methoxy benzoic acid；Then 2,4,5- tri- fluoro- 3- methoxy benzoic acids, thionyl chloride are mixed, is to slowly warm up to 75-82
DEG C, back flow reaction 4-5.5h removes thionyl chloride and obtains 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides.
In step (3), after triethylamine is added, the insulation reaction 1-4h at 20-60 DEG C；The cooling is to cool the temperature to 30
Within DEG C；The temperature reaction is specially that temperature is risen to insulation reaction 1-3h at 40-50 DEG C.
Preferably, the catalyst in step (4) is any one of tetrabutylammonium bromide, PEG, crown ether.
Preferably, the dosage of the catalyst is the 0.01- of 3,4,5,6-N- tetra- fluoro- methyl phthalimide weight
3%；
Preferably, in step (4), reaction heat preservation at 110-130 DEG C carries out 1-3h.
Preferably, the additive amount of potassium fluoride is the 15- of 3,4,5,6-N- tetra- fluoro- methyl phthalimide weight
55%.
Preferably, in step (4), the content of water is within 0.05% in the dipolar aprotic solvent.
In step (4), the aminate adds under atmosphere of inert gases, and the aminate has added in 3-5h
Finish.Inert gas is preferably nitrogen or argon gas.
Preferably, above-mentioned dipolar aprotic solvent is n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl Asia
One of sulfone, N-Methyl pyrrolidone are a variety of.
Specifically, step (4) specifically, into cyclization reaction device be added moisture≤0.3% solvent, put into potassium fluoride
And catalyst, heating dehydration to bottle internal solvent moisture≤0.05% are transferred to pressurizing device, with nitrogen or argon gas displaced air, rise
It flows back when temperature is to 110-130 DEG C, starts to add aminate, add and finish in 3-5 hour, in 0-0.2MPa, 110-130 DEG C of item
1-3 hours are kept the temperature under part, is filtered while hot, mother liquor is concentrated under reduced pressure into the 10-50% of its original volume, and cooling crystallization is filtered, successively passed through
It drains to obtain gatifloxacin cyclized ester after methanol washing and water washing.
Preferably, potassium fluoride is to be spray-dried fine powder obtained.
Technical solution of the present invention is with 3,4,5,6- tetra- fluoro- N-Methyl-o-phthalimides for raw material, and preparation process is such as
Shown in lower:
With 3,4,5,6- tetra- fluoro- N-Methyl-o-phthalimides for starting material, by hydrolysis, decarboxylation, methylate
To 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides, elder generation and N, N- dimethylamino ethyl acrylate are coupled, then are replaced with cyclopropylamine,
Finally cyclization generates gatifloxacin cyclized ester under the action of DMF and potassium fluoride, and molar yield can achieve 88% or more.This
The synthetic method for inventing the gatifloxacin cyclized ester provided has the advantages that
(1) step (1) and step (2) are not post-processed, are directly transferred in next step after having reacted, are equivalent to one pot of change
Reaction, avoids the loss of material；
(2) synthetic route is short, and raw material sources are easier to, and reaction condition is mild, easy operation control, reduces consumption of raw materials,
Convenient post-treatment reduces costs；
(3) potassium carbonate is replaced using potassium fluoride, the generation of exhaust gas can not only be reduced, and the potassium fluoride after use can lead to
It crosses after potassium hydroxide is adjusted and continues to use, further reduce costs；
(4) compressive reaction when cyclization, reduces reaction temperature, not only reduces energy consumption, also reduces the production of tarry materials
It is raw.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail.
Embodiment 1
A kind of synthetic method of gatifloxacin cyclized ester, comprising:
(1) into 500mL reaction kettle, the sodium hydroxide solution of 100mL 30% is added, it is fluoro- by the 3 of 100g, 4,5,6- tetra-
N- methyl phthalimide is uniformly mixed with sodium hydroxide, temperature rising reflux 10h, and reaction obtains 2,4,5- tri- fluoro- 3- hydroxyls
Sodium phthalate；Then temperature is controlled at 70 DEG C hereinafter, in 2 obtained, in 4,5- tri- fluoro- 3- hydroxyl phthalic sodium
Sulfuric acid is added, carries out decarboxylic reaction and be acidified to pH value to be 3.05；Later, the temperature was then adjusted to 105 DEG C, insulation reaction 8h, drop
Temperature obtains 2,4,5- tri- fluoro- 3- hydroxybenzoic acids to 25 DEG C；
(2) 2 will obtained, 4,5- tri- fluoro- 3- hydroxybenzoic acids are transferred in methylation device, and adding alkali to adjust pH is 9.07,
Temperature is controlled less than 35 DEG C, adds dimethyl suflfate, meanwhile, controlling pH by addition lye is 8.55, is added to dimethyl suflfate
Temperature is increased after adding to 80 DEG C, is adjusted pH and is greater than 12, insulation reaction 2h, is cooled to 30 DEG C or less after complete reaction and is transferred to acid
Makeup is set, then plus sulfuric acid or hydrochloric acid to system pH less than 0.5, after acidified, centrifugation, it is fluoro- that drying solid obtains 2,4,5- tri-
3- methoxy benzoic acid；Then 2,4,5- tri- fluoro- 3- methoxy benzoic acids, thionyl chloride are mixed, is to slowly warm up to 80 DEG C, returned
Stream reaction 5h, removes thionyl chloride and obtains 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides；
(3) 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides and N, N- dimethylamino ethyl acrylate are added in toluene, adds
Enter triethylamine, the insulation reaction 3h at 55 DEG C is cooled the temperature within 30 DEG C, and cyclopropylamine is added, temperature is risen at 45 DEG C and is protected
Temperature reaction 2h, after fully reacting plus water extraction, concentration organic phase obtain aminate；
(4) n,N-Dimethylformamide of moisture≤0.3% is added into cyclization reaction device, puts into and puts into 15g fluorine
Change potassium and 1g tetrabutylammonium bromide, heating dehydration is transferred to pressurizing device, with nitrogen or argon gas to bottle internal solvent moisture≤0.05%
Displaced air, reflux when being warming up to 120 DEG C start to add aminate obtained in step (3), and addition in 4 hours finishes,
0.15MPa keeps the temperature 2 hours at 120 DEG C, filters while hot, and mother liquor is concentrated under reduced pressure into the 30% of its original volume, and cooling crystallization filters,
Successively drain to obtain gatifloxacin cyclized ester, yield 90.2%, purity 99.6% after methanol washing and water washing.
Embodiment 2
A kind of synthetic method of gatifloxacin cyclized ester, comprising:
(1) into 500mL reaction kettle, the sodium hydroxide solution of 100mL 30% is added, it is fluoro- by the 3 of 100g, 4,5,6- tetra-
N- methyl phthalimide is uniformly mixed with sodium hydroxide, temperature rising reflux 8h, and reaction obtains 2,4,5- tri- fluoro- 3- hydroxyls
Sodium phthalate；Then temperature is controlled at 70 DEG C hereinafter, in 2 obtained, in 4,5- tri- fluoro- 3- hydroxyl phthalic sodium
Sulfuric acid or hydrochloric acid is added, carries out decarboxylic reaction and be acidified to pH value to be 0.87；Later, the temperature was then adjusted to 100 DEG C, insulation reaction
6h is cooled to 20 DEG C, obtains 2,4,5- tri- fluoro- 3- hydroxybenzoic acids；
(2) 2 will obtained, 4,5- tri- fluoro- 3- hydroxybenzoic acids are transferred in methylation device, and adding alkali to adjust pH is 9.49,
Temperature is controlled less than 35 DEG C, adds dimethyl suflfate, while controlling pH by addition lye is 8.51, is added to dimethyl suflfate
Temperature is increased after complete to 75 DEG C, is adjusted pH and is greater than 12, insulation reaction 1h, is cooled to 30 DEG C or less after complete reaction and is transferred to acidification
Device, then plus sulfuric acid or hydrochloric acid to system pH less than 0.5, after acidified, centrifugation, drying solid obtains 2,4,5- tri- fluoro- 3-
Methoxy benzoic acid；Then 2,4,5- tri- fluoro- 3- methoxy benzoic acids, thionyl chloride are mixed, is to slowly warm up to 75 DEG C, reflux
4h is reacted, thionyl chloride is removed and obtains 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides；
(3) 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides and N, N- dimethylamino ethyl acrylate are added in toluene, adds
Enter triethylamine, the insulation reaction 1h at 20 DEG C is cooled the temperature within 30 DEG C, and cyclopropylamine is added, temperature is risen at 40 DEG C and is protected
Temperature reaction 1h, after fully reacting plus water extraction, concentration organic phase obtain aminate；
(4) n,N-Dimethylformamide of moisture≤0.3% is added into cyclization reaction device, puts into and puts into 55g fluorine
Change potassium and 0.01g PEG, heating dehydration to bottle internal solvent moisture≤0.05% is transferred to pressurizing device, is replaced with nitrogen or argon gas
Air, reflux when being warming up to 110 DEG C start to add aminate obtained in step (3), and addition in 3 hours finishes, in 0MPa, 110
1 hour is kept the temperature at DEG C, is filtered while hot, mother liquor is concentrated under reduced pressure into the 10% of its original volume, and cooling crystallization is filtered, successively washed through methanol
It washs and drains to obtain gatifloxacin cyclized ester after water washing, yield 89.7%, 99.5%.
Embodiment 3
A kind of synthetic method of gatifloxacin cyclized ester, comprising:
(1) into 500mL reaction kettle, the sodium hydroxide solution of 100mL 30% is added, it is fluoro- by the 3 of 100g, 4,5,6- tetra-
N- methyl phthalimide is uniformly mixed with sodium hydroxide, temperature rising reflux 12h, and reaction obtains 2,4,5- tri- fluoro- 3- hydroxyls
Sodium phthalate；Then temperature is controlled at 70 DEG C hereinafter, in 2 obtained, in 4,5- tri- fluoro- 3- hydroxyl phthalic sodium
Sulfuric acid or hydrochloric acid is added, carries out decarboxylic reaction and be acidified to pH value to be 3.98；Later, the temperature was then adjusted to 110 DEG C, insulation reaction
10h is cooled to 30 DEG C, obtains 2,4,5- tri- fluoro- 3- hydroxybenzoic acids；
(2) 2 will obtained, 4,5- tri- fluoro- 3- hydroxybenzoic acids are transferred in methylation device, and adding alkali to adjust pH is 9.53,
Temperature is controlled less than 35 DEG C, adds dimethyl suflfate, while controlling pH by addition lye is 9.47, is added to dimethyl suflfate
Temperature is increased after complete to 85 DEG C, is adjusted pH and is greater than 12, insulation reaction 3h, is cooled to 30 DEG C or less after complete reaction and is transferred to acidification
Device, then plus sulfuric acid or hydrochloric acid to system pH less than 0.5, after acidified, centrifugation, drying solid obtains 2,4,5- tri- fluoro- 3-
Methoxy benzoic acid；Then 2,4,5- tri- fluoro- 3- methoxy benzoic acids, thionyl chloride are mixed, are to slowly warm up to 75-82 DEG C,
Back flow reaction 5.5h removes thionyl chloride and obtains 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides；
(3) 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides and N, N- dimethylamino ethyl acrylate are added in toluene, adds
Enter triethylamine, the insulation reaction 4h at 60 DEG C is cooled the temperature within 30 DEG C, and cyclopropylamine is added, temperature is risen at 50 DEG C and is protected
Temperature reaction 3h, after fully reacting plus water extraction, concentration organic phase obtain aminate；
(4) N-Methyl pyrrolidone of moisture≤0.3% is added into cyclization reaction device, put into and puts into 50g fluorination
Potassium and 3g crown ether, heating dehydration are transferred to pressurizing device to bottle internal solvent moisture≤0.05%, with nitrogen or argon gas displaced air,
Reflux when being warming up to 130 DEG C starts the DMF solution for adding aminate obtained in step (3), and addition in 5 hours finishes,
0.2MPa keeps the temperature 3 hours at 130 DEG C, filters while hot, and mother liquor is concentrated under reduced pressure into the 50% of its original volume, and cooling crystallization filters,
Successively drain to obtain gatifloxacin cyclized ester, yield 88.5%, purity 99.7% after methanol washing and water washing.
Comparative example 1
Compare with embodiment 1, catalyst amount is different, the method is as follows:
A kind of synthetic method of gatifloxacin cyclized ester, comprising:
Step (1)-(3) are the same as embodiment 1；
(4) n,N-Dimethylformamide of moisture≤0.3% is added into cyclization reaction device, puts into and puts into 15g fluorine
Change potassium and 7g tetrabutylammonium bromide, heating dehydration is transferred to pressurizing device, with nitrogen or argon gas to bottle internal solvent moisture≤0.05%
Displaced air, reflux when being warming up to 120 DEG C start to add aminate obtained in step (3), and addition in 4 hours finishes,
0.15MPa keeps the temperature 2 hours at 120 DEG C, filters while hot, and mother liquor decompression is dense, until the 30% of its original volume, cooling crystallization filters,
Successively drain to obtain gatifloxacin cyclized ester, yield 80.1%, purity 91.4% after methanol washing and water washing.
Comparative example 2
Compare with embodiment 1, fluorination potassium application rate is different, the method is as follows:
A kind of synthetic method of gatifloxacin cyclized ester, comprising:
Step (1)-(3) are the same as embodiment 1；
(4) into cyclization reaction device be added moisture≤0.3% dimethyl sulfoxide, put into and put into 35g potassium fluoride and
1g tetrabutylammonium bromide, heating dehydration to bottle internal solvent moisture≤0.05%, is transferred to pressurizing device, is replaced with nitrogen or argon gas empty
Gas, reflux when being warming up to 120 DEG C start to add aminate obtained in step (3), and addition in 4 hours finishes, in 0.15MPa,
2 hours are kept the temperature at 120 DEG C, is filtered while hot, mother liquor is concentrated under reduced pressure into the 30% of its original volume, and cooling crystallization filters, successively through first
It drains to obtain gatifloxacin cyclized ester, yield 74.5%, purity 90.6% after alcohol washing and water washing.
Comparative example 3
Compare with embodiment 1, pH value is different in step (1), the method is as follows:
A kind of synthetic method of gatifloxacin cyclized ester, comprising:
(1) into 500mL reaction kettle, the sodium hydroxide solution of 100mL 30% is added, it is fluoro- by the 3 of 100g, 4,5,6- tetra-
N- methyl phthalimide is uniformly mixed with sodium hydroxide, temperature rising reflux 10h, and reaction obtains 2,4,5- tri- fluoro- 3- hydroxyls
Sodium phthalate；Then temperature is controlled at 70 DEG C hereinafter, in 2 obtained, in 4,5- tri- fluoro- 3- hydroxyl phthalic sodium
Sulfuric acid is added, carries out decarboxylic reaction and be acidified to pH value to be 6.01；Later, the temperature was then adjusted to 105 DEG C, insulation reaction 8h, drop
Temperature obtains 2,4,5- tri- fluoro- 3- hydroxybenzoic acids to 25 DEG C；
(2) gatifloxacin cyclized ester, yield 72.1%, purity 94.7% is made with embodiment 1 in-(4) step.
Comparative example 4
Compare with embodiment 1, pH value is different in step (2), the method is as follows:
(1) with (1) the step of embodiment 1；
(2) 2 will obtained, 4,5- tri- fluoro- 3- hydroxybenzoic acids are transferred in methylation device, and adding alkali to adjust pH is 11.01,
Temperature is controlled less than 35 DEG C, adds dimethyl suflfate, meanwhile, controlling pH by addition lye is 10.3, is added to dimethyl suflfate
Temperature is increased after adding to 80 DEG C, is adjusted pH and is greater than 12, insulation reaction 2h, is cooled to 30 DEG C or less after complete reaction and is transferred to acid
Makeup is set, then plus sulfuric acid or hydrochloric acid to system pH less than 0.5, after acidified, centrifugation, it is fluoro- that drying solid obtains 2,4,5- tri-
3- methoxy benzoic acid；Then 2,4,5- tri- fluoro- 3- methoxy benzoic acids, thionyl chloride are mixed, is to slowly warm up to 80 DEG C, returned
Stream reaction 5h, removes thionyl chloride and obtains 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides；
(3)-(4) obtain gatifloxacin cyclized ester, yield 79.2%, purity with (3)-(4) the step of embodiment 1
95.1%.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, the embodiment not to
The scope of the patents of the invention is limited, all equivalence enforcements or change without departing from carried out by the present invention are intended to be limited solely by the technology of the present invention
In the range of scheme.
Claims (10)
1. a kind of synthetic method of gatifloxacin cyclized ester characterized by comprising
(1) 3,4,5,6- tetra- fluoro- N-Methyl-o-phthalimides are mixed with lye, reaction obtains 2,4,5- tri- fluoro- 3- hydroxyls
Base sodium phthalate；Then acid is added in the obtained fluoro- 3- hydroxyl phthalic sodium of 2,4,5- tri- and carries out decarboxylic reaction
And it is acidified and obtains 2,4,5 trifluoro 3 hydroxy benzoic acid；
(2) by obtained 2,4,5 trifluoro 3 hydroxy benzoic acid, hybrid reaction is acidified again under alkaline condition with dimethyl suflfate
Obtain the fluoro- 3- methoxy benzoic acid of 2,4,5- tri-；Then the fluoro- 3- methoxy benzoic acid of 2,4,5- tri- and thionyl chloride that will be obtained
It mixes in a solvent, reaction obtains 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides；
(3) 2,4,5- tri- fluoro- 3- methoxy benzoyl chlorides and N, N- dimethylamino ethyl acrylate are added in toluene, is added three
Cyclopropylamine is added in ethamine, reaction, and after fully reacting plus water extraction, concentration organic phase obtain aminate；
(4) aminate is added into dipolar aprotic solvent, and puts into potassium fluoride and catalyst, reacts, crystallization is added
For husky star cyclized ester.
2. synthetic method as described in claim 1, which is characterized in that the acid that decarboxylation and acidification use in step (1) is sulfuric acid
And/or hydrochloric acid；Acid adding to pH value is 0-4 when decarboxylation and acidification.
3. synthetic method as described in claim 1, which is characterized in that the NaOH that the lye in step (1) is 20-40% is water-soluble
Liquid.
4. synthetic method as described in claim 1, which is characterized in that the acid that acidification uses in step (2) is sulfuric acid and/or salt
Acid；Acid adding is to pH value less than 0.5 when acidification.
5. synthetic method as described in claim 1, which is characterized in that catalyst in step (4) be tetrabutylammonium bromide,
Any one of PEG, crown ether；The dosage of the catalyst is the fluoro- methyl phthalimide weight of 3,4,5,6-N- tetra-
0.01-3%；The additive amount of potassium fluoride is the 15-55% of the fluoro- methyl phthalimide weight of 3,4,5,6-N- tetra-.
6. synthetic method as described in claim 1, which is characterized in that in step (4), water in the dipolar aprotic solvent
Content is within 0.05%；Reaction heat preservation at 110-130 DEG C carries out 1-3h.
7. synthetic method as described in claim 1, which is characterized in that in step (4), the aminate is in atmosphere of inert gases
Lower addition, and add and finish in 3-5h.
8. synthetic method as claimed in claim 1, which is characterized in that the dipolar aprotic solvent is N, N- diformazan
One of base formamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, N-Methyl pyrrolidone are a variety of.
9. synthetic method as described in claim 1, which is characterized in that step (4) into cyclization reaction device specifically, be added
The solvent of moisture≤0.3%, puts into potassium fluoride and catalyst, and heating dehydration is transferred to pressurization to bottle internal solvent moisture≤0.05%
Device, with nitrogen or argon gas displaced air, reflux when being warming up to 110-130 DEG C started to add aminate liquid, in 3-5 hours
After addition, 1-3 hours are kept the temperature under the conditions of 0-0.2MPa, 110-130 DEG C, is filtered while hot, mother liquor is concentrated under reduced pressure into its original
The 10%-50% of volume, cooling crystallization filter, and successively drain after methanol washing and water washing, obtain gatifloxacin cyclized ester.
10. synthetic method as described in claim 1, which is characterized in that the potassium fluoride is to be spray-dried fine powder obtained.
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| CN114716373A (en) * | 2022-04-14 | 2022-07-08 | 内蒙古源宏精细化工有限公司 | Preparation method of gatifloxacin cyclized ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110878082A (en) * | 2019-12-09 | 2020-03-13 | 怀化学院 | Gatifloxacin and its synthesis method |
| CN110878082B (en) * | 2019-12-09 | 2021-06-01 | 怀化学院 | Gatifloxacin and its synthesis method |
| CN111635307A (en) * | 2020-05-25 | 2020-09-08 | 浙江华基生物技术有限公司 | Synthesis method of 2,4, 5-trifluoro-3-methoxybenzoyl chloride |
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| CN114716373A (en) * | 2022-04-14 | 2022-07-08 | 内蒙古源宏精细化工有限公司 | Preparation method of gatifloxacin cyclized ester |
| CN114716373B (en) * | 2022-04-14 | 2023-01-10 | 内蒙古源宏精细化工有限公司 | Preparation method of gatifloxacin cyclized ester |
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