CN107722084A - A kind of synthetic method of high-purity Gamithromycin - Google Patents
A kind of synthetic method of high-purity Gamithromycin Download PDFInfo
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Abstract
The invention provides a kind of synthetic method of high-purity Gamithromycin, this method is using thiocyanic acid E erythromycin oximes hydrochloride as initiation material, successively through configuration conversion reaction, Beckmann rearrangement, reduction reaction and aminating reaction, the Gamithromycin of obtained high-purity.Synthesis technique of the present invention is simple, and starting material and auxiliary material used are easily obtained, are cheap, being easily recycled, safely cleaning, shorten the reaction time, reduce the discharge of the three wastes, reduce unit cost；The inventive method energy consumption is small, pollution-free, and safety and environmental protection is easy to operate, and production controllability is strong, is easy to industrialized production；Product purity obtained by the inventive method is up to more than 99%, and amount of impurities and content are less, and product quality is stable.
Description
Technical field
The present invention relates to a kind of preparation method of macrolides veterinary antibiotic medicine, and in particular to a kind of high-purity adds rice
The synthetic method of mycin.
Background technology
Gamithromycin (English name Gamithromycin, molecular formula：C40H76N2O12, molecular weight：777.04), chemistry is entitled
(2R, 3S, 4R, 5S, 8R, 10R, 11R, 12S, 13S, 14R) -13- [(2,6- dideoxy -3-C- methyl -3-O- methyl-α-L-
Core-own pyranose) oxygen] -2- ethyls -3,4, the hydroxyls -3,5 of 10- tri-, 8,10,12,14- hexamethyl -7- propyl group -11- [[3,4,6-
Three deoxidation -3- (dimethylamino)-β-D- wood-own pyranose] oxygen] -1- oxa- -7- azepine cyclopentadecane -15- ketone, for white
Or off-white color crystalline powder, it is odorless, bitter, slightly draw moist, easily dissolved in chloroform, in methanol, watery hydrochloric acid
It is readily soluble, dissolve in ethanol, it is slightly molten in acetonitrile, it is almost insoluble in water.
Gamithromycin be 15 yuan of rings semi-synthetic azilide class veterinary antibiotic, its mainly by with bacterium ribose
Body 50S subunits combine, and polypeptide chain elongation are prevented, so as to suppress the synthesis of bacterioprotein.In vitro test as shown by data, add rice mould
Element is to Mannheimia haemolytica, pasteurella multocida, pleuropneumonia actinomyces, haemophilus parasuis, streptococcus, golden yellow Portugal
Grape coccus, enterococcus and mycoplasma etc. have inhibitory or killing effect.Gamithromycin is used for edible animal, has has a broad antifungal spectrum, antibacterial activity
Compared with strong, single-dose, many advantages, such as rapid, long half time, high bioavilability is absorbed, meets the hair of China's medicine dedicated for animals
Exhibition trend, there is good clinical value and market prospects.
At present, the existing method for preparing Gamithromycin has a lot, wherein more conventional method is same with 9- deoxidations -9-
Type Erythromycin A (E) oxime is raw material, and configuration is converted into 9- deoxidation -9- homoerythromycins A (Z) in the presence of base catalyst
Oxime, then generate through Beckmann rearrangement the mixture of erythromycin A iminoether, then by sodium borohydride reduction generate 9- deoxidations-
8 α-the α of azepine-8-homoerythromycin, then Gamithromycin is made through reductive amination process.It is same with 9- deoxidations -9- in the synthetic method
Type Erythromycin A (E) oxime is initiation material, and only need to carry out four-step reaction can obtain Gamithromycin, reduce reaction time, is reduced
Unit cost.But the purity of the synthetic method products obtained therefrom is relatively low, quality is not sufficiently stable, and post-processing operation complexity is numerous
It is trivial, it is necessary to by multiple column chromatography carry out end-product purifying, it is difficult to carry out industrialized production.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of high-purity Gamithromycin, to solve existing Gamithromycin system
Preparation Method products obtained therefrom purity is low and is difficult to industrialized problem.
The object of the present invention is achieved like this, a kind of synthetic method of high-purity Gamithromycin, comprises the following steps：
(1) configuration converts：Under room temperature condition, using water as reaction dissolvent, thiocyanic acid E- erythromycin oxime hydrochlorides are in hydroxide
Reacted in the presence of lithium, reaction solution is post-treated, obtains Z- erythromycin oximes；Reaction equation is：
Erythromycin group in thiocyanic acid E- erythromycin oxime hydrochlorides is the notable structure composition of Gamithromycin, and the salt is to close
Into the important intermediate of the medicines such as azithromycin, ROX, CLA, industrialized production has been realized at present, it is cheap and easy to get,
Reduce production cost.
(2) Beckmann rearrangement：Z- erythromycin oximes are dissolved in acetone, the volume mass ratio of acetone and Z- erythromycin oximes is 4
~10mL: 1g, pyridine and the acetone soln to benzene sulfonyl chloride are sequentially added, the volume mass ratio of pyridine and Z- erythromycin oximes is
0.2-1.0mL: 1g, finish, 2~6h is reacted under the conditions of 0~10 DEG C, after reaction terminates, dilute reaction is rushed with dichloromethane and water
Liquid, PH to 9~11 is adjusted, liquid separation, water layer is extracted with dichloromethane, merges organic layer, is dried, and adds isopropanol, and concentration is solid to having
Body occurs, and is cooled to room temperature, stirs 1~5h of cold analysis, filters, and dries, obtains faint yellow solid；Reaction equation is：
In formula, 2A is 9- deoxidation -6- deoxidation -6,9- imines ether-(8a- azepines -8a)-erythromycin, and 2B is that 9- deoxidations -6- takes off
Oxygen -9,12- imines ether-(8a- azepines -8a)-erythromycin, 2C are 9- carbonyl -8a- azepine -8a- homoerythromycins, wherein 2A and
2B is the target product of the reaction.The stage of reaction, pyridine serve as alkaline reagent, are advantageous to the progress and post processing of reaction；After locate
In the reason stage, recrystallized using isopropanol, effectively removes Z- erythromycin oximes, 2C and solvent, avoid dissolvent residual and
Introducing of the Z- erythromycin oximes to subsequent technique, has purified product, makes imines ether better quality, and purity is higher.
(3) reduction reaction：The faint yellow solid obtained in step (2) is dissolved in methanol, sodium borohydride is added portionwise,
8~20h are reacted in -5~5 DEG C, after reaction terminates, dilute reaction solution is rushed with cold water, add dichloromethane, under stirring condition, are added dropwise
Concentrated hydrochloric acid adjusts PH to 2~4, after stirring 10~30min, adjusts PH to 8~10 with sodium hydroxide solution, separates dichloromethane layer, do
It is dry, it is concentrated to dryness, then recrystallized with isopropanol, filter, obtain mother liquor and filter cake, filter cake is again with isopropyl alcohol reflux mashing
Reason, filter, dry, obtain white solid；Reaction mechanism is：
Using single solvent methanol as reaction dissolvent, be advantageous to industrialized production, sodium borohydride, which is added portionwise, to be kept away
Exempt from temperature of reaction system and acute variation occur, first rush dilute reaction system with cold water in post processing, sodium borohydride is lost activity,
Extracted again with dichloromethane, with recrystallisation from isopropanol, mashing, the product purity for ensureing to obtain is more than 95%.
(4) aminating reaction：White solid obtained by step (3) and positive propionic aldehyde are placed in autoclave, glacial acetic acid, ice second is added dropwise
Acid is 0.08~0.41: 1 with the mass ratio of white solid, adds palladium-carbon catalyst, at 35~45 DEG C catalytic hydrogenation 8~
20h, reaction terminate rear Filtration of catalyst, be spin-dried for solvent, Jia Shuichong is dilute, add dichloromethane, with glacial acetic acid adjust PH to 3~
4, aqueous phase is separated, adds dichloromethane, PH to 8~10 is adjusted with sodium hydroxide solution, liquid separation, aqueous phase is extracted with dichloromethane, then
Through recrystallizing methanol, acetonitrile/normal heptane mixed solvent backflow mashing, filter, dry, produce Gamithromycin；Reaction equation is：
PH is adjusted using glacial acetic acid in last handling process, and using acetonitrile/normal heptane mixed solvent as mashing solvent so that
The Gamithromycin purity finally given reaches more than 99%.
In step (1) of the present invention, the mol ratio of thiocyanic acid E- erythromycin oximes hydrochloride and lithium hydroxide is 1~5: 1, sulphur cyanogen
The mass volume ratio of sour E- erythromycin oximes hydrochloride and water is 1g: 7~16mL；Post processing is after question response terminates, and is filtered, filter cake
It is extracted with ethyl acetate, then is washed with saturated nacl aqueous solution, adds dichloromethane, 2~6h of stirring and crystallizing at -5~0 DEG C, mistake
Filter, air drying.
In step (2) of the present invention, the mass ratio of paratoluensulfonyl chloride and Z- erythromycin oximes is red mould for 0.25~0.75: 1, Z-
The mass volume ratio of plain oxime and isopropanol is 1g: 2~4mL.
In step (3) of the present invention, the mass volume ratio of faint yellow solid and methanol is 1g: 3~8mL, faint yellow solid with
The mass ratio of sodium borohydride is 1: 0.05~0.26；Secondary recovery is carried out to the product in mother liquid obtained, reclaims obtained solid
After merging with the filter cake, then with isopropyl alcohol reflux be beaten.
In step (4) of the present invention, the mass volume ratio of white solid and positive propionic aldehyde is 1g: 2~10mL, and palladium carbon is consolidated with white
The mass ratio of body is 0.1~0.5: 1, and the volume ratio of acetonitrile/normal heptane in the mixed solvent acetonitrile and normal heptane is 1: 4.
The present invention's concretely comprises the following steps：
(1) thiocyanic acid E- erythromycin oxime hydrochlorides are placed in reaction bulb, add distilled water, finish, stirring 10~
30min, suspension is obtained, weigh LiOHH2O is soluble in water, and resulting solution is added in suspension, finishes, and is protected in nitrogen
Under, 8~20h is stirred at room temperature, enters post processing after the completion of the monitoring reaction of TLC methods.
Post processing：Question response becomes clarification, filtering, adds ethyl acetate extraction, the ethyl acetate added for the first time at twice
Volume mass ratio with thiocyanic acid E- erythromycin oxime hydrochlorides is 3~6mL: 1g, second of the ethyl acetate and thiocyanic acid added
The volume mass ratio of E- erythromycin oxime hydrochlorides is 1~2mL: 1g, merges the organic layer extracted twice, the washing of saturated sodium-chloride salt
Wash once, the volume mass ratio of saturated sodium-chloride salt solution and thiocyanic acid E- erythromycin oxime hydrochlorides is 1~2mL: 1g, disposable to add
Entering dichloromethane, the volume mass ratio of dichloromethane and thiocyanic acid E- erythromycin oxime hydrochlorides is 3~6mL: 1g, is stirred,
There is crystallization to separate out soon, be cooled to -5 DEG C~0 DEG C, stir 2-6h, filtering, obtain product, air drying, obtain Z- erythromycin oximes.
(2) Z- erythromycin oximes are taken to be dissolved in acetone, the volume mass ratio of acetone and Z- erythromycin oximes is 4~10mL: 1g, is added
Entering pyridine in reaction solution, the volume mass ratio of pyridine and Z- erythromycin oximes is 0.2-1.0mL: 1g, 0 is cooled to frozen water~
5 DEG C, it is added dropwise the acetone soln of paratoluensulfonyl chloride, the body of the acetone in the acetone soln of paratoluensulfonyl chloride and Z- erythromycin oximes
Product mass ratio is 1~3mL: 1g, and process heat release is added dropwise, and pays attention to the speed that control is added dropwise, and about 1~2h is added, finished, and reaction solution exists
0~10 DEG C of 2~6h of reaction, enter post processing after the completion of the monitoring reaction of TLC methods.
Post processing：Add dichloromethane and water and rush dilute reaction solution, the volume mass ratio of dichloromethane and Z- erythromycin oximes is 4
~8mL: 1g, the volume mass ratio of water and Z- erythromycin oximes is 4~8mL: 1g, and the NaOH solution that concentration is 5~10M is added dropwise and adjusts
PH value is 9~11.Liquid separation, water layer are extracted with dichloromethane, and the volume mass ratio of dichloromethane and Z- erythromycin oximes is 2~6mL:
1g, merge organic layer, dry, be spin-dried for, add isopropanol and rush dilute magma, the volume mass ratio of isopropanol and Z- erythromycin oximes is 2
~4mL: 1g, continue to be concentrated into white solid appearance, stop concentrating and being cooled to 0~10 DEG C, stir 1~5h of cold analysis, filter,
Filter cake obtains imines ether mixture in 60~80 DEG C of dry 6~12h.
(3) imines ether obtained by upper step is dissolved in methanol, the volume mass ratio of methanol and imines ether is 3~8mL: 1g, cold
But to 0~5 DEG C, then sodium borohydride being added portionwise, exothermic heat of reaction, -5~5 DEG C of control system temperature, 1~3h is added, and is finished, from
Room temperature is so warming up to, enters post processing after the completion of the monitoring reaction of stirring reaction 8~20h, TLC method.
Post processing：Add cold water and rush dilute reaction, the volume mass ratio of water and imines ether is 3~8mL: 1g, adds dichloromethane
The volume mass ratio of alkane, dichloromethane and imines ether is 3~8mL: 1g, under stirring condition, dropwise addition concentrated hydrochloric acid regulation pH value to 2~
4, after stirring 10-30min, the pH to 8~10 of reaction system is adjusted with 5~10M NaOH solution, separates dichloromethane layer, water
Layer is extracted once with dichloromethane again, and the volume mass ratio of dichloromethane and imines ether is 1~3mL: 1g, merges organic phase, does
It is dry, it is concentrated to dryness, adds isopropanol stirring, the volume mass ratio of isopropanol and imines ether is 1~5mL: 1g, and it is solid to be concentrated into white
Body separates out, and cools to 20~25 DEG C, continues 2~6h of stirring, filtration drying, obtain mother liquor and solid.
Mother liquor is spin-dried for obtain solid, added methylene chloride complete molten, the volume mass ratio of dichloromethane and imines ether for 2~
4mL: 1g, add water, the volume mass ratio of water and imines ether is 2~4mL: 1g, and concentrated hydrochloric acid is added dropwise and adjusts pH value to 2~4, with 5M~
It is 8~10 that 10M sodium hydroxide solutions, which adjust pH value, and liquid separation, aqueous phase is extracted with dichloromethane, the volume matter of dichloromethane and imines ether
Amount merges organic phase, is filtered, be spin-dried for anhydrous sodium sulfate drying, add isopropanol to be back to sticky solid complete than being 2~4mL: 1g
Molten, the volume mass ratio of isopropanol and imines ether is 1~3mL: 1g, and control temperature filtering, obtains at 0~20 DEG C, 2~6h of cold analysis
To white solid.Collect two batches solid, with isopropanol in 60~80 DEG C of backflow mashing 2-6h, the volume mass of isopropanol and imines ether
Than for 1~3mL: 1g, control temperature stirs 1~5h at 0~20 DEG C, filter, drying, produce-8 α of the 9- deoxidations-α of azepine-8-homotype
Erythromycin A.
(4) positive propionic aldehyde and swollen amine (i.e.-8 α of the 9- deoxidations-α of azepine-8-homoerythromycin A) are added in autoclave, positive third
The volume mass ratio of aldehyde and swollen amine is 2~10mL: 1g, stirring, and glacial acetic acid is added dropwise, exothermic heat of reaction, adds rear system clarification, adds
The mass ratio of palladium carbon (wet basis 10%), palladium carbon and swollen amine is 0.1~0.5: 1, the catalytic hydrogenation 8 at 20~30atm, 35~45 DEG C
Enter post processing after the completion of the monitoring reaction of~20h, TLC method.
Post processing：Filtration of catalyst, wash palladium carbon layer, merge with filtrate, be spin-dried for solvent, add water rush it is dilute, water and
The volume mass ratio of swollen amine is 2~8mL: 1g, adds dichloromethane, the volume mass ratio of dichloromethane and swollen amine is 2~8mL:
1g, it is transferred in beaker, pH is adjusted to 3~4 with glacial acetic acid under stirring, discards organic phase, separate aqueous phase, adds dichloromethane, two
The volume mass ratio of chloromethanes and swollen amine is 2~8mL: 1g, and pH to 8~10, liquid separation, aqueous phase are adjusted with 5~10M NaOH solution
Being extracted again with dichloromethane, the volume mass ratio of dichloromethane and swollen amine is 1~5mL: 1g, liquid separation, merges organic phase, dries,
After being spin-dried for, with recrystallizing methanol, the volume mass ratio of methanol and swollen amine is 2~8mL: 1g, filters, dries, obtain white solid, Gu
Body uses 60 DEG C of acetonitrile/normal heptane mixed solvent (volume ratio of acetonitrile and normal heptane is 1/4) to flow back and is beaten 1~10h again, and acetonitrile/
The volume mass ratio of normal heptane mixed solvent and swollen amine is 2~8mL: 1g, cools to 10~20 DEG C, is filtered, and is dried, and produces and adds rice
Mycin.
The inventive method is using thiocyanic acid E- erythromycin oximes hydrochloride as initiation material, successively through configuration conversion reaction, Bake
Graceful rearrangement reaction, reduction reaction and aminating reaction, the Gamithromycin of high-purity is made.Synthesis technique of the present invention is simple, used
Beginning material and auxiliary material are easily obtained, are cheap, being easily recycled, safely cleaning, shorten the reaction time, reduce the row of the three wastes
Put, reduce unit cost；The inventive method energy consumption is small, pollution-free, and safety and environmental protection is easy to operate, and production controllability is strong, is easy to
Industrialized production；Product purity obtained by the inventive method is up to more than 99%, and amount of impurities and content are less, product quality
It is stable.
Embodiment
The present invention is expanded on further with reference to specific embodiment, in following embodiment, that is not described in detail is various
Process and method are conventional methods as known in the art, what agents useful for same did not indicated source and specification be commercially available analysis it is pure or
Chemistry is pure.
Embodiment 1
Configuration converts (synthesis of Z- erythromycin oximes)：
Thiocyanic acid E- erythromycin oximes hydrochloride (105.2g, 68.76mmol, content 55.20%) is taken to be placed in 2L reaction bulb
In, 840mL distilled water is added, is finished, 10min is stirred, obtains suspension；By LiOHH2O (10.0g, 238mmol) is dissolved in
In 210mL water, resulting solution is added in suspension, is finished, and under nitrogen protection, 16h, the monitoring reaction of TLC methods is stirred at room temperature
After the completion of enter post processing.
Post processing：Question response liquid becomes clarification, filtering, add at twice ethyl acetate extraction (first time 350mL, second
150mL), merge organic layer, washed once with 150mL saturated sodium-chloride salt solution, the disposable dichloromethane for adding 450mL, stir
Mix uniformly, there is crystallization to separate out quickly, be cooled to -5 DEG C~0 DEG C, stir 4h, filtering, air drying, obtain Z- erythromycin oximes
45.66g, mass yield 43.53%, content 94.44%, purity 92.26%, molar yield 83.73%.
Beckmann rearrangement (synthesis of imines ether mixture)：
Take Z- erythromycin oximes (150.1g, 200mmol) to be dissolved in 600mL acetone, add 80mL pyridines in reaction solution, use
Frozen water is cooled to 0~5 DEG C, and the acetone soln 150mL of paratoluensulfonyl chloride (60.2g, 316mmol, 1.6eq) is added dropwise, was added dropwise
Cheng Fangre, about 1h are added, and are finished, and reaction solution reacts 3h under the conditions of 0~5 DEG C, locates after entering after the completion of the monitoring reaction of TLC methods
Reason.
Post processing：Add 900mL dichloromethane and 900mL water rushes dilute reaction solution, the NaOH solution that concentration is 10M is added dropwise and adjusts
It is 9.5 to save pH value.Liquid separation, water layer are extracted with 500mL dichloromethane, merge organic layer, are dried, are spin-dried for, and add isopropanol 500mL
Continue to be concentrated into white solid appearance, stop concentrating and being cooled to 0~5 DEG C, stir cold analysis 4h, filtering, filter cake is in 60 DEG C of drums
Dry 8h is air-dried, obtains faint yellow imines ether mixture 66.34g, mass yield 44.20%, purity 85.21%.
Reduction reaction (- 8 α of the 9- deoxidations-α of azepine-8-homoerythromycin A synthesis)：
Imines ether mixture (535.7g, 733mmol) is dissolved in 2.8L methanol, is cooled to 0 DEG C, then boron is added portionwise
Sodium hydride (80.7g, 2.1mol, 2.9eq), exothermic heat of reaction, about 0-5 DEG C of control system temperature, 2h add sodium borohydride, finished,
Warm naturally to that reaction 12h is stirred at room temperature, enter post processing after the completion of the monitoring reaction of TLC methods.
Post processing：The cold water for adding 2.8L rushes dilute reaction, adds 2.8L dichloromethane, under stirring condition, is added dropwise 12M's
Salt acid for adjusting pH value after stirring 15min, adjusts the pH=9.5 of reaction system with 10M NaOH solution, separates dichloromethane to 3.5
Alkane layer, water layer are extracted once with 700mL dichloromethane again, merge organic phase, are dried, are concentrated to dryness, and are added 1.2L isopropanols and are stirred
Mix, have white solid and slowly separate out, be down to room temperature, continue to stir 4h, filtration drying, obtain mother liquor and 377.62g solids.
Mother liquor is spin-dried for obtaining solid, adds 1.5L dichloromethane entirely molten, then adds 1.5L water, concentrated hydrochloric acid tune pH value, which is added dropwise, is
3.5, it is 9.5 to adjust pH value with 10M sodium hydroxide solutions, and liquid separation, aqueous phase is extracted with 1L dichloromethane, merges organic phase, and use is anhydrous
Sodium sulphate dry filter, is spin-dried for, and adds 1L isopropanols to be back to sticky solid entirely molten, and control temperature is at 0~20 DEG C, cold analysis 3h, mistake
Filter, obtains white solid 93.2g.Collect two batches solid, stirred with 1L isopropanols in 60 DEG C of backflow mashing 4h, control temperature at 0-20 DEG C
3h is mixed, is filtered, drying, obtains white solid 426.42g, mass yield 79.60%, purity 98.27%.
Aminating reaction (synthesis of Gamithromycin)：
In 1L autoclave, the positive propionic aldehyde of 350mL and swollen amine (80.1g, 109mmol) are added, stirring, glacial acetic acid is added dropwise
26.2g (0.4mol, 4eq), exothermic heat of reaction, the clarification of rear system is added, adds 16g palladium carbons (wet basis 10%), in 24~28atm,
Catalytic hydrogenation 14h at 33~38 DEG C, enter post processing after the completion of the monitoring reaction of TLC methods.
Post processing：Filtration of catalyst, palladium carbon layer is washed with dichloromethane 50mL, merges with filtrate, is spin-dried for as far as possible
Solvent, add 400mL water rush it is dilute, add 400mL dichloromethane, be transferred in beaker, pH be adjusted to 3.0 with glacial acetic acid under stirring,
Organic phase is discarded, separates aqueous phase, adds 400mL dichloromethane, adjusts pH=9.5 with 10M NaOH solution, liquid separation, aqueous phase is again
Extracted with 200mL dichloromethane, liquid separation, merge organic phase, dried, after being spin-dried for, with 300mL recrystallizing methanols, filtered, dry
To 68.5g white solids.Solid 300mL acetonitriles/60 DEG C of normal heptane=1/4 (volume ratio) backflow mashing 5h, cools to 20 DEG C,
Filtering, dry Gamithromycin 62.21g, mass yield 77.67%, purity 99.40%.
Embodiment 2
Configuration converts：
Thiocyanic acid E- erythromycin oximes hydrochloride (105.2g, 68.76mmol, content 55.20%) is taken to be placed in 2L reaction bulb
In, 630mL distilled water is added, is finished, 10min is stirred, obtains suspension；By LiOHH2O (2.89g, 68.76mmol) is dissolved in
In 105mL water, resulting solution is added in suspension, is finished, and under nitrogen protection, 8h is stirred at room temperature, the monitoring of TLC methods has been reacted
Enter post processing into rear.
Post processing：Question response liquid becomes clarification, filtering, add at twice ethyl acetate extraction (first time 315mL, second
105mL), merge organic layer, washed once with 150mL saturated sodium-chloride salt solution, the disposable dichloromethane for adding 315mL, stir
Mix uniformly, there is crystallization to separate out quickly, be cooled to -5 DEG C~0 DEG C, stir 2h, filtering, air drying, obtain Z- erythromycin oximes
41.97g, mass yield 39.90%, content 95.71%, purity 93.61%, molar yield 78.00%.
Beckmann rearrangement：
Take Z- erythromycin oximes (150.1g, 200mmol) to be dissolved in 600mL acetone, add 30ml pyridines in reaction solution, use
Frozen water is cooled to 0~5 DEG C, and the acetone soln 150mL of paratoluensulfonyl chloride (38.13g, 200mmol, 1.0eq) is added dropwise, was added dropwise
Cheng Fangre, about 1h are added, and are finished, and reaction solution reacts 2h under the conditions of 0~5 DEG C, locates after entering after the completion of the monitoring reaction of TLC methods
Reason.
Post processing：Add 600mL dichloromethane and 600mL water rushes dilute reaction solution, the NaOH solution that concentration is 10M is added dropwise and adjusts
It is 9 to save pH value.Liquid separation, water layer with 300mL dichloromethane extract, merge organic layer, dry, be spin-dried for, add isopropanol 300mL after
It is continuous to be concentrated into white solid appearance, stop concentrating and being cooled to 0~5 DEG C, stir cold analysis 1h, filtering, filter cake is in 60 DEG C of air blast
6h is dried, obtains faint yellow imines ether mixture 58.34g, mass yield 38.87%, purity 86.78%.
Reduction reaction：
Imines ether mixture (535.7g, 733mmol) is dissolved in 1.6L methanol, is cooled to 0 DEG C, then boron is added portionwise
Sodium hydride (27.73g, 733mmol, 1eq), exothermic heat of reaction, about 0-5 DEG C of control system temperature, 1h add sodium borohydride, finished,
Warm naturally to that reaction 8h is stirred at room temperature, enter post processing after the completion of the monitoring reaction of TLC methods.
Post processing：The cold water for adding 1.6L rushes dilute reaction, adds 1.6L dichloromethane, under stirring condition, is added dropwise 12M's
Salt acid for adjusting pH value after stirring 10min, adjusts the pH=8 of reaction system with 10M NaOH solution, separates dichloromethane to 4
Layer, water layer are extracted once with 730mL dichloromethane again, merge organic phase, are dried, are concentrated to dryness, and are added 730mL isopropanols and are stirred
Mix, have white solid and slowly separate out, be down to room temperature, continue to stir 2h, filtration drying, obtain mother liquor and 364.79g solids.
Mother liquor is spin-dried for obtaining solid, adds 1.1L dichloromethane entirely molten, then adds 1.1L water, it is 4 that concentrated hydrochloric acid, which is added dropwise, and adjusts pH value,
It is 8 to adjust pH value with 10M sodium hydroxide solutions, and liquid separation, aqueous phase is extracted with 1.1L dichloromethane, is merged organic phase, is used anhydrous slufuric acid
Sodium dry filter, is spin-dried for, and adds 730mL isopropanols to be back to sticky solid entirely molten, and control temperature is at 0~20 DEG C, cold analysis 2h, mistake
Filter, obtains white solid 97.4g.Collect two batches solid, stirred with 1L isopropanols in 60 DEG C of backflow mashing 2h, control temperature at 0-20 DEG C
1h is mixed, is filtered, drying, obtains white solid 417.66g, mass yield 77.97%, purity 96.27%.
Aminating reaction：
In 1L autoclave, the positive propionic aldehyde of 160mL and swollen amine (80.1g, 109mmol) are added, stirring, glacial acetic acid is added dropwise
6.55g (0.1mol, 1eq), exothermic heat of reaction, the clarification of rear system is added, adds 8.1g palladium carbons (wet basis 10%), in 20~25atm,
Catalytic hydrogenation 8h at 35~40 DEG C, enter post processing after the completion of the monitoring reaction of TLC methods.
Post processing：Filtration of catalyst, palladium carbon layer is washed with dichloromethane 50mL, merges with filtrate, is spin-dried for as far as possible
Solvent, add 160mL water rush it is dilute, add 160mL dichloromethane, be transferred in beaker, pH be adjusted to 4.0 with glacial acetic acid under stirring,
Organic phase is discarded, separates aqueous phase, adds 160mL dichloromethane, adjusts pH=8, liquid separation with 10M NaOH solution, aqueous phase is used again
80mL dichloromethane extracts, liquid separation, merges organic phase, dries, and after being spin-dried for, with 160mL recrystallizing methanols, filtering, is dried to obtain
65.1g white solids.Solid 300mL acetonitriles/60 DEG C of normal heptane=1/4 (volume ratio) backflow mashing 1h, cools to 20 DEG C, mistake
Filter, dry Gamithromycin 59.86g, mass yield 74.73%, purity 99.24%.
Embodiment 3
Configuration converts：
Thiocyanic acid E- erythromycin oximes hydrochloride (105.2g, 68.76mmol, content 55.20%) is taken to be placed in 2L reaction bulb
In, 1260mL distilled water is added, is finished, 10min is stirred, obtains suspension；By LiOHH2O (14.44g, 68.76mmol) is dissolved in
In 420mL water, resulting solution is added in suspension, is finished, and under nitrogen protection, 20h, the monitoring reaction of TLC methods is stirred at room temperature
After the completion of enter post processing.
Post processing：Question response liquid becomes clarification, filtering, add at twice ethyl acetate extraction (first time 630mL, second
210mL), merge organic layer, washed once with 200mL saturated sodium-chloride salt solution, the disposable dichloromethane for adding 630mL, stir
Mix uniformly, there is crystallization to separate out quickly, be cooled to -5 DEG C~0 DEG C, stir 6h, filtering, air drying, obtain Z- erythromycin oximes
46.84g, mass yield 44.52%, content 92.63%, purity 92.09%, molar yield 84.25%.
Beckmann rearrangement：
Take Z- erythromycin oximes (150.1g, 200mmol) to be dissolved in 1500mL acetone, add 150ml pyridines in reaction solution,
0~5 DEG C is cooled to frozen water, the acetone soln 450mL of paratoluensulfonyl chloride (114.39g, 600mmol, 3.0eq), drop is added dropwise
Add process heat release, about 2h is added, finished, and reaction solution reacts 2h under the conditions of 5~10 DEG C, enters after the completion of the monitoring reaction of TLC methods
Post processing.
Post processing：Add 1200mL dichloromethane and 1200mL water rushes dilute reaction solution, the NaOH solution that concentration is 10M is added dropwise
It is 11 to adjust pH value.Liquid separation, water layer are extracted with 900mL dichloromethane, merge organic layer, are dried, are spin-dried for, and add isopropanol
600mL continues to be concentrated into white solid appearance, stops concentrating and being cooled to 0~5 DEG C, stirs cold analysis 1h, filtering, filter cake is in 60
DEG C forced air drying 12h, obtains faint yellow imines ether mixture 68.07g, mass yield 45.35%, purity 83.79%.
Reduction reaction：
Imines ether mixture (535.7g, 733mmol) is dissolved in 4.3L methanol, is cooled to 0 DEG C, then boron is added portionwise
Sodium hydride (138.6g, 3.7mol, 5eq), exothermic heat of reaction, about -5-0 DEG C of control system temperature, 3h add sodium borohydride, finished,
Warm naturally to that reaction 20h is stirred at room temperature, enter post processing after the completion of the monitoring reaction of TLC methods.
Post processing：The cold water for adding 4.3L rushes dilute reaction, adds 4.3L dichloromethane, under stirring condition, is added dropwise 12M's
Salt acid for adjusting pH value after stirring 30min, adjusts the pH=10 of reaction system with 10M NaOH solution, separates dichloromethane to 2
Layer, water layer are extracted once with 1.6L dichloromethane again, merge organic phase, are dried, are concentrated to dryness, and add the stirring of 2.7L isopropanols,
Have white solid slowly to separate out, be down to room temperature, continue to stir 6h, filtration drying, obtain mother liquor and 384.97g solids.
Mother liquor is spin-dried for obtaining solid, adds 2.1L dichloromethane entirely molten, then adds 2.1L water, it is 2 that concentrated hydrochloric acid, which is added dropwise, and adjusts pH value,
It is 10 to adjust pH value with 10M sodium hydroxide solutions, and liquid separation, aqueous phase is extracted with 2.1L dichloromethane, is merged organic phase, is used anhydrous slufuric acid
Sodium dry filter, is spin-dried for, and adding 1.6L isopropanols to be back to, sticky solid is entirely molten, and control temperature is at 0~20 DEG C, cold analysis 6h, filtering,
Obtain white solid 97.4g.Collect two batches solid, with 1L isopropanols in 80 DEG C of backflow mashing 6h, control temperature is in 0-20 DEG C of stirring
5h, filter, drying, obtain white solid 433.33g, mass yield 80.89%, purity 97.41%.
Aminating reaction：
In 1L autoclave, the positive propionic aldehyde of 800mL and swollen amine (80.1g, 109mmol) are added, stirring, glacial acetic acid is added dropwise
32.73g (0.5mol, 5eq), exothermic heat of reaction, the clarification of rear system is added, adds 40.05g palladium carbons (wet basis 10%), in 25~
30atm, enter post processing after the completion of catalytic hydrogenation 20h, TLC method monitoring reaction at 40~45 DEG C.
Post processing：Filtration of catalyst, palladium carbon layer is washed with dichloromethane 100mL, merges with filtrate, is spin-dried for as far as possible
Solvent, add 640mL water rush it is dilute, add 640mL dichloromethane, be transferred in beaker, pH be adjusted to 3.0 with glacial acetic acid under stirring,
Organic phase is discarded, separates aqueous phase, adds 640mL dichloromethane, adjusts pH=10, liquid separation with 10M NaOH solution, aqueous phase is used again
400mL dichloromethane extracts, liquid separation, merges organic phase, dries, and after being spin-dried for, with 640mL recrystallizing methanols, filtering, is dried to obtain
70.6g white solids.Solid 640mL acetonitriles/60 DEG C of normal heptane=1/4 (volume ratio) backflow mashing 10h, cools to 10 DEG C,
Filtering, dry Gamithromycin 63.55g, mass yield 79.34%, purity 99.10%.
Comparative example 1：
Beckmann rearrangement
Take Z- erythromycin oximes (150.1g, 200mmol) to be dissolved in 600mL acetone, add 80mL triethylamines in reaction solution,
0~5 DEG C is cooled to frozen water, the acetone soln 150mL of paratoluensulfonyl chloride (60.2g, 316mmol, 1.6eq) is added dropwise, is added dropwise
Process heat release, about 1h add, and finish, and reaction solution reacts 3h under the conditions of 0~5 DEG C, locates after entering after the completion of the monitoring reaction of TLC methods
Reason.
Post processing：Filter and discard insoluble matter, add 900mL dichloromethane and 900mL water rushes dilute reaction solution, concentration is added dropwise
It is 9.5 for 10M NaOH solution regulation pH value.Liquid separation, water layer are extracted with 500mL dichloromethane, merge organic layer, are dried, rotation
It is dry, add isopropanol 500mL and continue to be concentrated into white solid appearance, stop concentrating and being cooled to 0~5 DEG C, stir cold analysis 5h,
Filtering, filter cake obtain faint yellow imines ether mixture 46.12g, mass yield 30.75%, purity in 60 DEG C of forced air drying 8h
75.21%.
Comparative example 2：
Aminating reaction (synthesis of Gamithromycin)
In 1L autoclave, the positive propionic aldehyde of 350mL and swollen amine (80.1g, 109mmol) are added, stirring, excessive ice is added dropwise
Acetic acid 52.36g (0.9mol, 8eq), exothermic heat of reaction, the clarification of rear system is added, adds 16g palladium carbons (wet basis 10%), in 24~
28atm, enter post processing after the completion of catalytic hydrogenation 14h, TLC method monitoring reaction at 33~38 DEG C.
Post processing：Filtration of catalyst, palladium carbon layer is washed with dichloromethane 50mL, merges with filtrate, is spin-dried for as far as possible
Solvent, add 400mL water and rush dilute, add 400mL dichloromethane, be transferred in beaker, it is 2.7 to stir lower detection architecture pH, is discarded
Organic phase, aqueous phase is separated, add 400mL dichloromethane, adjust pH=9.5, liquid separation with 10M NaOH solution, aqueous phase is used again
200mL dichloromethane extracts, liquid separation, merges organic phase, dries, and after being spin-dried for, with 300mL recrystallizing methanols, filtering, is dried to obtain
64.87g white solids.Solid 300mL acetonitriles/60 DEG C of normal heptane=1/4 (volume ratio) backflow mashing 5h, cools to 20 DEG C,
Filtering, dry Gamithromycin 59.06g, mass yield 73.73%, purity 97.66%.
Claims (10)
1. a kind of synthetic method of high-purity Gamithromycin, it is characterized in that, comprise the following steps：
（1）Configuration converts：Under room temperature condition, using water as reaction dissolvent, thiocyanic acid E- erythromycin oxime hydrochlorides are in lithium hydroxide
Effect is lower to react, and reaction solution is post-treated, obtains Z- erythromycin oximes；
（2）Beckmann rearrangement：Z- erythromycin oximes are dissolved in acetone, the volume mass ratio of acetone and Z- erythromycin oximes is 4 ~ 10mL
: 1g, pyridine, the acetone soln to benzene sulfonyl chloride are sequentially added, the volume mass ratio of pyridine and Z- erythromycin oximes is 0.2-1.0mL
: 1g, finish, 2 ~ 6h is reacted under the conditions of 0 ~ 10 DEG C, it is post-treated after reaction terminates, obtain faint yellow solid；
（3）Reduction reaction：By step（2）In obtained faint yellow solid be dissolved in methanol, sodium borohydride is added portionwise, in -5 ~ 5
DEG C reaction 8 ~ 20h, reaction solution is post-treated, obtains white solid；
（4）Aminating reaction：By step（3）Gained white solid and positive propionic aldehyde are placed in autoclave, be added dropwise glacial acetic acid, glacial acetic acid with
The mass ratio of white solid is 0.08 ~ 0.41: 1, addition palladium-carbon catalyst, 8 ~ 20h of catalytic hydrogenation at 35 ~ 45 DEG C, instead
Filtration of catalyst after should terminating, solvent is spin-dried for, Jia Shuichong is dilute, adds dichloromethane, adjusts PH to 3 ~ 4 with glacial acetic acid, separates
Aqueous phase, dichloromethane being added, PH to 8 ~ 10 is adjusted with sodium hydroxide solution, liquid separation, aqueous phase is extracted with dichloromethane, then through methanol weight
Crystallization, acetonitrile/normal heptane mixed solvent backflow mashing, filters, dries, produce Gamithromycin.
2. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（1）In, rear place
Reason is after question response terminates, and filtering, filter cake is extracted with ethyl acetate, then is washed with saturated nacl aqueous solution, adds dichloromethane
Alkane, 2 ~ 6h of stirring and crystallizing at -5 ~ 0 DEG C, filtering, air drying.
3. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（1）In, sulphur cyanogen
The mol ratio of sour E- erythromycin oximes hydrochloride and lithium hydroxide is 1 ~ 5: 1, the quality of thiocyanic acid E- erythromycin oximes hydrochloride and water
Volume ratio is 1g: 7 ~ 16 mL.
4. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（2）In, rear place
Reason is after question response terminates, and rushes dilute reaction solution with dichloromethane and water, adjusts PH to 9 ~ 11, and liquid separation, water layer is extracted with dichloromethane,
Merge organic layer, dry, add isopropanol, concentration, to there is solid appearance, be cooled to room temperature, stir 1 ~ 5h of cold analysis, filter, do
It is dry.
5. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（2）In, to first
The mass ratio of benzene sulfonyl chloride and Z- erythromycin oximes is that the mass volume ratio of 0.25 ~ 0.75: 1, Z- erythromycin oximes and isopropanol is 1g:
2~4mL。
6. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（3）In, rear place
Reason is to rush dilute reaction solution with cold water after question response terminates, and adds dichloromethane, under stirring condition, be added dropwise concentrated hydrochloric acid adjust PH to 2 ~
4, after stirring 10 ~ 30min, PH to 8 ~ 10 is adjusted with sodium hydroxide solution, separates dichloromethane layer, dries, is concentrated to dryness, then with different
Propyl alcohol is recrystallized, filtering, obtains mother liquor and filter cake, and filter cake is handled with the mashing of isopropyl alcohol reflux again, is filtered, and is dried.
7. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（3）In, to institute
Product in mother liquor carries out secondary recovery, after the solid for reclaiming to obtain merges with the filter cake, then with the mashing of isopropyl alcohol reflux.
8. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（3）In, it is yellowish
The mass volume ratio of color solid and methanol is 1g: 3 ~ 8mL, and the mass ratio of faint yellow solid and sodium borohydride is 1: 0.05 ~ 0.26.
9. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（4）In, white
The mass volume ratio of solid and positive propionic aldehyde be 1g: 2 ~ 10mL, and the mass ratio of palladium carbon and white solid is 0.1 ~ 0.5: 1, catalysis hydrogen
The pressure for changing reaction is 20 ~ 30atm.
10. the synthetic method of high-purity Gamithromycin according to claim 1, it is characterized in that, the step（4）In, second
The volume ratio of nitrile/normal heptane in the mixed solvent acetonitrile and normal heptane is 1: 4.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114878703A (en) * | 2022-03-01 | 2022-08-09 | 浙江国邦药业有限公司 | Method for determining substance related to gamithromycin |
| CN115057895A (en) * | 2022-07-19 | 2022-09-16 | 华北制药集团动物保健品有限责任公司 | Preparation method of gamithromycin and intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102239174A (en) * | 2008-10-24 | 2011-11-09 | 梅里亚有限公司 | Method of synthesizing macrolide compounds |
| CN103554201A (en) * | 2013-08-21 | 2014-02-05 | 安徽中升药业有限公司 | Gamithromycin preparation method |
| CN106699823A (en) * | 2017-01-04 | 2017-05-24 | 中牧实业股份有限公司 | Method for preparing gamithromycin |
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2017
- 2017-11-24 CN CN201711193759.6A patent/CN107722084A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102239174A (en) * | 2008-10-24 | 2011-11-09 | 梅里亚有限公司 | Method of synthesizing macrolide compounds |
| CN103554201A (en) * | 2013-08-21 | 2014-02-05 | 安徽中升药业有限公司 | Gamithromycin preparation method |
| CN106699823A (en) * | 2017-01-04 | 2017-05-24 | 中牧实业股份有限公司 | Method for preparing gamithromycin |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114878703A (en) * | 2022-03-01 | 2022-08-09 | 浙江国邦药业有限公司 | Method for determining substance related to gamithromycin |
| CN114878703B (en) * | 2022-03-01 | 2024-03-29 | 浙江国邦药业有限公司 | Method for determining gamithromycin related substances |
| CN115057895A (en) * | 2022-07-19 | 2022-09-16 | 华北制药集团动物保健品有限责任公司 | Preparation method of gamithromycin and intermediate thereof |
| CN115057895B (en) * | 2022-07-19 | 2023-12-26 | 华北制药集团动物保健品有限责任公司 | Preparation method of gamithromycin and intermediate thereof |
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