CN107501364B - The salt of tulathromycin intermediate - Google Patents

Abstract

The invention discloses a kind of salt of intermediate for preparing Tulathromycin, specifically the salt is oxalates, and preparation method thereof and the application in the method for preparing Tulathromycin.

Description

The salt of tulathromycin intermediate

Technical field

The invention belongs to field of medicine production, are related to the salt of tulathromycin intermediate and its answering in Tulathromycin preparation With.

Background technique

Respiratory tract infection is one of epidemic disease more rambunctious in animal husbandry, has serious harm to Animal husbandry production.Currently, big Cyclic lactone class antibiotic is a kind of common drug for treating the respiratory tract infection of pig, ox, wherein widely used in China There are tylosin and Tilmicosin.Although the use of this 2 kinds of drugs all achieves good effect, with using the time Extend, occurs different degrees of drug resistance in many areas, and this 2 kinds of drugs generally use spice or drinking water administration side Formula generally requires multiplicating administration competence exertion drug effect.Therefore, it is badly in need of in the market efficient to respiratory tract infection, safe, wide The novel antibacterial drug of spectrum, low-residual.Tulathromycin with its antibacterial activity strong, has a broad antifungal spectrum, animal specific, overlength half-life period and Single-dose can complete the advantages that entire therapeutic process, once the extensive concern for just causing people that comes out.

Tulathromycin (Tulathromycin) is the semi-synthetic big ring developed by Pfizer animal health company in 2002 Lactone antibiotic, 10% Tulathromycin injection of trade name Rui Kexin (Draxxin) is in 2004 in European Union and beauty State's listing.The Ministry of Agriculture, China allowed Tulathromycin to use in animal productiong for the first time in 2008 in No. 957 bulletin.Currently, Tulathromycin is mainly used for the respiratory infectious disease of the pig as caused by sensitive bacteria and ox.

Tulathromycin as other macrolide antibiotics, is blocked in conjunction with bacterial ribosome 50S subunit And the combination of messenger RNA (tRNA), so that bacterio protein be inhibited to turn the synthesis of peptide, make the synthesis of peptide chain and extend by Resistance, influences the synthesis of bacterio protein, eventually leads to bacterium differentiation death, and structure is as follows:

CN1259136 discloses the compound structure and preparation method of Tulathromycin, the preparation in 1998.05.29 application Method are as follows:

But the route is longer, and low yield, and certain synthetic intermediates are unstable, and there are unwanted impurity, uncomfortable Close industrial-scale production.

Then, Pfizer is in the improvement preparation method patent CN1503804 of 2002.04.11 application Tulathromycin, this method It is as follows:

With 3 compound of trifluoroacetic acid processing formula, the trifluoroacetic acid addition salts of 3 compound of formula are obtained, DMSO is recycled to try The oxidation of agent low temperature sulfur ylide, obtains 2 compound of formula.But this method yield is not high enough, and makees reagent Sulfur-Vapor of Lower Temperature leaf using DMSO Temperature needed for vertical moral oxidation is -80 to -45 DEG C, high to reaction condition requirement, is also not suitable for industrial-scale production.

Pfizer is in the improvement preparation method patent CN1384108 of 2002.04.25 application Tulathromycin, 3 chemical combination of formula Object remains as trifluoroacetic acid addition salts, and epoxidation is still to be aoxidized using sulfur ylide, yield under -80 to -45 DEG C of reaction temperatures Still not high enough.

In addition, domestic enterprise has also applied for the improvement preparation method patent of more Tulathromycin:

CN102295672 is disclosed following preparation method:

Although this method makes formula (III) compound to formula (V) compound, due to having used new oxidation system to make instead It answers temperature at -10~10 DEG C, avoids the process that ketone is reacted with sulfur ylide under ultralow temperature, but entire oxidation reaction needs two Step, i.e., carbonyl is reoxidised into epoxy at alkene, is not still optimal industrialized process for preparing.

CN102786569 is using azithromycin A as raw material, with 2 '-position hydroxyls in di-tert-butyl dicarbonate protection azithromycin A Then base and 6 '-bit aminos carry out Swern oxidation, react to obtain 4 "-position epoxides with trimethylsulfonium bromide；Finally With n-propylamine to 4, "-position epoxide carries out nucleophilic addition, obtains target compound Tulathromycin, is reacted using Swern, needs It to be reacted under ultralow temperature, industrialization has safety and cost.Di-tert-butyl dicarbonate price is higher.

CN103073603 using demethyl azithromycin as raw material, by Cymag introduce carbon nitrogen base, finally by reduction and Addition reaction prepares Tulathromycin, which uses extremely toxic substance Cymag, in the safety and operability in industrial application It has difficulties.

CN102260306 acetyl group is protected remove 2 '-position hydroxyls and 6a bit amino in first azithromycin simultaneously, then to it 4 "-position hydroxyl aoxidized, epoxidation, then under the conditions of alkaline alcohol solution deprotection base and with n-propylamine to 4 "-position ring Oxygen carries out nucleophilic addition, and Tulathromycin is made, and the double protection hydroxyls of acetyl group are used in the synthetic route and amino, alkaline alcohol are molten The method of deacetylate under the conditions of liquid, since prepared compound is ten ternary macrolide compounds, this body structure In have an ester group, the big ring of ten ternarys is easy open loop under the conditions of alkaline alcohol solution, and by-product is more, and anti-using Swern It answers, needs to be reacted under ultralow temperature, be unfavorable for industrialized production.

Hydroxyl is removed first azithromycin by what acetyl group was protected by CN103497227, using dimethyl sulfoxide and acetic anhydride body System aoxidizes 4 '-position hydroxyls to obtain ketone under mild conditions, and then uses phase transfer catalyst, and obtained ketone is continued It carries out epoxidation and obtains epoxides, the intermediate epoxide of this Tulathromycin can introduce n-propylamine and remove-insurance through open loop Shield obtains Tulathromycin.The synthetic route byproduct of reaction is more, is not easy purifies and separates, and phase transfer catalyst influences the steady of product Qualitative, conversion ratio is lower.

CN104876983 route is as follows, and using bichromate as oxidant in route, zinc amalgam is as reducing agent Serious pollution reagent, and yield is not high.

The low yield of Tulathromycin purity that method disclosed in CN104861018 obtains is low, and chromic anhybride is used in route As oxidant, subsequent contamination is serious, and route is as follows:

Summary of the invention

The present invention provides the following methods for preparing Tulathromycin:

(1) intermediate TA04 is reacted with hydroxyl protection base reagent, obtains TA05；

(2) TA05 aoxidizes to obtain TA06；

(3) after TA06 is at oxalates TA06-OX, dissociate；

(4) TA06 aoxidizes to obtain TA07；

(5) TA07 Deprotection obtains TA08；

(6) TA08 is reacted with n-propylamine, obtains TA；

(7) after TA is at oxalates TA-OX, dissociates, obtain finished product Tulathromycin (TA).

Wherein, the hydroxyl protection base reagent in step (1) can be alkoxy carbonyl group class protecting group reagent, as benzyloxycarbonyl group class is protected Protect base reagent, tertiary butyloxycarbonyl base class protecting group reagent, tablet held before the breast by officials methoxycarbonyl group class protecting group reagent etc., preferably benzyl chloroformate.

The oxidation system of step (2) is DMSO and IBX, is reacted at 20-30 DEG C.

The oxidation system of step (4) is trimethyl sulfur bromide and potassium tert-butoxide.

The deprotection condition of step (5) can be any method that can remove hydroxyl protection base, and in general, which is In the presence of palladium carbon, deprotection base is hydrogenated.

The main improvement of preparation method patent 200510082063.7 that the present invention applies for Tulathromycin Yuan Yan company It is:

1. 200510082063.7 technical solution is to react to obtain with trifluoroacetic acid by it after reaction obtains TA-06 The trifluoroacetate TA06-TFA of TA06, dissociates later, carries out the reaction of next step, and technical solution of the present invention is by itself and grass Acid reaction, obtains the oxalates TA06-OX of TA06, dissociates later, carry out the reaction of next step.

2. in step (2), oxidation system used in 200510082063.7 technical solution is DMSO and trifluoroacetic acid Acid anhydride, reaction temperature are ultralow temperature -75~-65 DEG C, and the high requirements on the equipment, high production cost is unfavorable for large-scale industrial production, And oxidation system used in step (2) of the present invention is DMSO and IBX, is reacted at 20-30 DEG C.

3. TA08 is reacted with n-propylamine in step (6), after obtaining TA, 200510082063.7 technical solution is by it With phosphatase reaction, obtain the Diphosphonate TA-PA of TA, dissociate later, obtain final product, and technical solution of the present invention be by its with Oxalic acid reaction, obtains the oxalates TA-OX of TA, dissociates later, obtain final product.

Specifically, technical solution of the present invention are as follows:

Intermediate TA04 is reacted with benzyl chloroformate, obtains TA05；TA05 is aoxidized by DMSO and IBX at 20-30 DEG C, Obtain TA06；After TA06 is at oxalates TA06-OX, dissociate, post-processing obtains TA06 after purification；TA06 passes through front three bromide After changing sulphur and potassium tert-butoxide oxidation, TA07 is obtained；TA07 hydrogenates Deprotection, obtains TA08；TA08 is reacted with n-propylamine, is obtained To TA；After TA is at oxalates TA-OX, dissociate, post-processing obtains final product Tulathromycin after purification.

Technology disclosed by technical solution of the present invention and the preparation method patent 200510082063.7 of Yuan Yan company application Scheme is compared, the beneficial effect is that: 1.TA06 at dissociating again after oxalates TA06-OX, so that preparing the receipts of TA06 from TA04 Rate is improved from 78.9% to 89.2%；2.TA05 is aoxidized by DMSO and IBX at 20-30 DEG C, is avoided original and is ground technical solution In ultralow temperature reaction, be conducive to industrialized production；3.TA is produced at dissociating again after oxalates TA-OX so that preparing from TA08 eventually The yield of object Tulathromycin is improved from 41.7% to 67.6%；4. preparing final product Tulathromycin using TA04 as starting material Total recovery is improved from 25.3% to 46.2%, improves the yield more than 20%, and purity is preferable, HPLC purity 99.0%, most Big single miscellaneous < 0.2%.

Specific embodiment

Summary of the invention is made further explanation and description below with reference to specific embodiment, still, they are not constituted Limitation of the scope of the invention or restriction, following reagent and prepare raw material unless otherwise specified, are commercially available.(the comparison of embodiment 1 Example, referring to patent 200510082063.7)

29Kg TA04 is put into 500L reaction kettle, 160Kg methylene chloride stirs 20~30min, puts into 5Kg thereto Anhydrous sodium sulfate, stirs drying, and entire mixture is filtered, is concentrated into substantially without fraction by 1~2h.System after concentration is turned It moving in 1000L reaction kettle, while 660Kg methylene chloride is added, open stirring, system is cooled to -5 simultaneously by nitrogen protection~ 5 DEG C, the solution of the methylene chloride of 16Kg/33Kg benzyl chloroformate sum is added dropwise into system.1.5h is added dropwise altogether, is added dropwise.It protects 0~5 DEG C, 2~4h of temperature, raw material conversion finish.(HPLC monitors raw material conversion), reaction mixture is concentrated by temperature control T≤30 DEG C 0~10 DEG C of 250Kg. low temperature preservation.

The reaction solution of TA05,85kgDMSO, mechanical stirring, nitrogen protection, with liquid nitrogen second are added into 300L ultralow temperature kettle System is cooled to -80~-70 DEG C by alcohol, and 21Kg trifluoroacetic anhydride is added dropwise thereto, and temperature control -80~-65 DEG C are added dropwise.Drop finishes, and protects - 75~-65 DEG C of temperature, 1h.22Kg triethylamine is added dropwise thereto, 1h is added dropwise in temperature control -75~-65 DEG C altogether；Drop finishes, and heat preservation -75~- 65 DEG C, 1.5h is reacted, HPLC detection raw material conversion finishes.The system of end of reaction is poured into the tap water of 120Kg, is terminated anti- It answers, stirs system, rise again to 15~25 DEG C.By its liquid separation, water phase is extracted with dichloromethane once, 100Kg*1；Merge organic Phase with originally water washing, 60Kg*2, then washs 60Kg*1 with saturated brine.It is anhydrous that 15Kg is added into the organic phase after washing Sodium sulphate, it is dry.It filters, filter cake elution, filtrate merges concentration, is concentrated into about 90Kg and 9Kg trifluoroacetic acid is added thereto, stirs 15~30min；185Kg isopropanol is added thereto whole system is concentrated, is concentrated into 120Kg or so, then add thereto The isopropanol for entering 40Kg continues to be concentrated, and solid is precipitated in the process.Mixture is finally concentrated into 120Kg or so, system is carried out 5~15 DEG C are cooled to, is filtered.Filter cake rejoins in flask, and 120Kg isopropanol is added, and is warming up to 45~55 DEG C, stirring 0.5 ~1h is cooled to 0~10 DEG C, filters, and filter cake drying obtains the white solid TA06-TFA of 34.2Kg.

34.2KgTA06-TFA and 95Kg methylene chloride is added into a 500L reaction kettle, the potassium carbonate of 72Kg10% is molten Liquid (potassium carbonate of 7.2Kg and the tap water of 65Kg), stirs 20~30min, liquid separation, and water phase extracts one with 20Kg methylene chloride It is secondary, merge organic phase washing once, 40Kg*1.The dry system of 5Kg anhydrous sodium sulfate is added, filters, elution, is concentrated into nothing and evaporates Point, 50kg normal heptane, stirring, the solid was filtered TA06 27Kg is added.

The total recovery of step 1, step 2 and step 3 is 78.9%

Into 300L reaction kettle, 8.6Kg trimethyl sulfur bromide (with the tetrahydrofuran band water of 27Kg), 85Kg tetrahydro is added Furans, is cooled to -10~-5 DEG C, and stirring is added portionwise 10.3Kg potassium tert-butoxide about 0.5h and finishes；- 10~-5 DEG C of heat preservation, reaction 2h, for use；135Kg methylene chloride and 19Kg TA06 are added into another 500L ultralow temperature kettle, stirring is cooled to -85 ~-70 DEG C, the mixture in 300L reaction kettle is suitably cooled down, mixture is slowly pressed by ultralow temperature by bottom insert canal with nitrogen In kettle, about 30~45min of whole transfer times.After transfer, temperature control -75~-65 DEG C, low-temp reaction, while whole attention Nitrogen protection.2~3h is kept the temperature, raw material conversion finishes.Reaction system is poured slowly into the ammonium chloride solution equipped with 150Kg10% In container, stirring terminates reaction.Stirring mixture is risen again to 15~25 DEG C, and liquid separation, water phase is extracted with dichloromethane once, 40Kg*1, organic phase merging washed once with 10% ammonium chloride solution, and 85Kg*1. is washed with water once, and 80Kg*1. is added 10Kg anhydrous sodium sulfate dries organic phase, filters, concentration, until substantially without fraction, wait throw in next step.

The crude product and 160Kg acetone of 21KgTA07 are added into the hydriding reactor of 500L, under stirring, is added thereto The palladium carbon of 3.8Kg10% seals reaction kettle, is replaced 4 times with nitrogen；It is replaced 3 times with hydrogen；Hydrogen Vapor Pressure >=0.25MPa is kept, 60min is reacted, pressure is constant, and raw material conversion completely directly filters system, and filter cake is eluted with acetone, and filtrate is brown, concentration After dry, the methylene chloride of 160Kg is added, the active carbon of 1Kg is then added thereto again, stirring 30min is filtered, and filtrate is pale yellow Color concentrates the filtrate to substantially without fraction again, the acetone of 65Kg is added, 120Kg is added dropwise originally thereto in stirring and dissolving Water is cooled to 0~10 DEG C, filters, and filter cake elutes (acetone: water=2:3) with mixed solution.

Filter cake oven-dried weight 15.2Kg.The crude product of 15.2Kg TA08 and the acetone of 25Kg are added into 300L reaction kettle, Stirring, is heated to 50~60 DEG C, thereto the normal heptane of dropwise addition 62Kg, and 50~60 DEG C of temperature control；Drop finishes, at this temperature, stirring 0.5~1h is cooled to 0~10 DEG C of suction filtration, and it is primary that filter cake continues mashing.The mashing that TA08 is added into 300L reaction kettle is primary Crude product and 23Kg acetone, stirring, be heated to 50~60 DEG C, thereto be added dropwise 58Kg normal heptane, 50~60 DEG C of temperature control； Drop finishes, and at this temperature, stirs 0.5~1h, is cooled to 0~10 DEG C of suction filtration, weight 12.6Kg after filter cake drying.

The total recovery of step 4 and step 5 is 77%

12KgTA08 and 48Kg isopropanol and 23Kg n-propylamine are added into 300L reaction kettle.System is warming up to 55~ 60℃.24~30h of heat preservation reflection.It is complete that HPLC detects raw material conversion.Reaction mixture is transferred in single port bottle, base is concentrated into The dehydrated alcohol of 16Kg is added thereto, continues to be concentrated into no fraction without fraction for this, and 96Kg ethyl alcohol is added thereto, and The phosphoric acid of 3.6Kg and the solution of 48Kg ethyl alcohol is added dropwise in the tap water of 10Kg, stirring and dissolving thereto, there is solid during being added dropwise It is precipitated.After completion of dropwise addition, continue to stir 0.5h.System is filtered, filter cake dries to obtain 9.8KgTA-PA.By the solid of drying, throw Enter, in 300L reaction kettle, 120Kg methylene chloride and the solution of potassium carbonate of 90Kg6% is added thereto, stirs 0.5h, point 15Kg*1 is extracted with dichloromethane in liquid, water phase, and organic phase is washed with water, and 30Kg*1 is organic to be added to desiccant dryness.It filters dense It is reduced to residue about 25Kg or so, the normal heptane of 55Kg is added thereto, continues to be concentrated, until system residue about 25Kg or so, by body 50~60 DEG C are warming up under system's stirring, mashing, 0.5~1h, mashing terminates, and system is cooled to 10 DEG C or so, is filtered, filter cake is used Normal heptane elution, solid filter cake drying, weight 7Kg, HPLC largest single impurity 1.6%, direct crystallization effect is unobvious, again at salt.

It is added above-mentioned solid into 300L reaction kettle, the ethyl alcohol of 65Kg, the water of 70Kg, stirring and dissolving is added thereto The solution of the ethyl alcohol of the phosphoric acid and 40Kg of 2.5Kg, solid is precipitated during dropwise addition, after completion of dropwise addition, continues to stir 0.5h.By body System filters, and filter cake ethanol rinse dries to obtain 8KgTA-PA.8KgTA-PA and 80Kg dichloro is added into 300L reaction kettle The solution of potassium carbonate of methane and 60Kg6%.0.5h, liquid separation are stirred, the water phase methylene chloride of 15Kg extracts primary.Merge organic Phase, then it is primary with 30Kg water washing.Desiccant is added in organic phase, dry, filters, is concentrated into substantially without fraction, is added thereto The acetone of 25Kg is concentrated into residue about 15Kg or so, and the normal heptane of 28Kg is added thereto, continues to be concentrated, until system residue is about System is stirred down and is warming up to 50~60 DEG C by 15Kg or so, and mashing, 0.5~1h, mashing terminates, and system is cooled to 10 DEG C of left sides The right side filters, and filter cake is eluted with normal heptane, solid filter cake drying, weight 5.4Kg.HPLC purity 98.5%, largest single impurity < 0.2%.

The total recovery of step 6 and step 7 is 41.7%

Using TA04 as starting material, the total recovery that finished product Tulathromycin is made is 25.3%

Embodiment 2 (present invention process)

40kgTA04 is put into 1000L reaction kettle, 100kg toluene stirs 20~30min, and 55 DEG C are concentrated into no fraction. 25 DEG C or so are cooled under nitrogen protection, vacuum is pumped into 900Kg methylene chloride, opens stirring, system cools down under nitrogen protection To -5~5 DEG C, the solution of 22kg benzyl chloroformate and 66Kg methylene chloride is added dropwise into system.About 1.5h is added dropwise altogether, drips Finish.0~5 DEG C, 2~3h of heat preservation, raw material conversion finish.(HPLC monitors raw material conversion) temperature control T≤35 DEG C, by reaction mixture It is concentrated to dryness in oily, 0~10 DEG C of low temperature preservation.

Above-mentioned TA05,260kgDMSO are added into 500L reaction kettle, opens and stirs, after dissolved clarification, is added portionwise thereto 18KgIBX, 20~30 DEG C are reacted 2~3 hours, and HPLC detection raw material conversion finishes.Reaction system is poured into 150Kg ice water, 250Kg methylene chloride is added, stirs 10 minutes, there is solid precipitation, filters, filtrate layered, water layer is stripped with 100Kg methylene chloride Once, merge organic phase, 5% sodium bicarbonate aqueous solution tune PH8~9 100Kg are layered, and organic phase uses saturated sodium-chloride water-soluble again Liquid washed once, 100Kg*1, and the drying of 10Kg anhydrous sodium sulfate is added, filters, and filter cake elution, filtrate merges concentration, is concentrated into nothing Fraction, is added 160Kg isopropanol thereto, and the 40Kg isopropanol of 9.8kg oxalic acid is added dropwise in 50~55 DEG C of stirring dissolved clarifications thereto A large amount of solids are precipitated in solution, system are carried out to be cooled to 5~10 DEG C, centrifugation.Solid is dried in vacuum drying oven, obtains 50Kg's White solid TA06-OX.50KgTA06-OX is added in the enamel still of 300L；106Kg methylene chloride, the carbonic acid of 45Kg10% Potassium solution stirs 20~30min, liquid separation, and water phase 26Kg methylene chloride extracts once, and merging organic phase washing is primary, 20Kg*1.The dry system of 5Kg anhydrous sodium sulfate is added, filters, elution, is concentrated into substantially without fraction, 80kg normal heptane is added, stirs It mixes, the solid was filtered TA06 42.1kg.

The total recovery of step 1, step 2 and step 3 is 89.2%

12.4KgTA06 and 106Kg methylene chloride is added in the enamel still of 300L, stirs 20~30min, is pumped into and is added dropwise Tank is stand-by.Into 300L ultralow temperature kettle, 4.67Kg trimethyl sulfur bromide (with the toluene band water of 26Kg), 30Kg tetrahydro furan is added It mutters, is cooled to -20~-15 DEG C, 6.78Kg potassium tert-butoxide is added portionwise, and about 0.5h is finished in stirring；Heat preservation -, 20~-15 DEG C, instead 2h is answered, system is down to -75~-65 DEG C.The dichloromethane solution of above-mentioned TA06 is added dropwise to system (about 3h), temperature control to -70 ~-60 DEG C, the conversion of insulation reaction 2~3h, HPLC raw material finishes.Reaction system is poured slowly into the chlorine equipped with 100Kg 10% In the container for changing ammonium salt solution, stirring terminates reaction.Stirring mixture is risen again to 15~25 DEG C, and liquid separation, water phase is extracted with methylene chloride Primary, 26Kg*1 is taken, organic phase merging washed once with 10% ammonium chloride solution, and 20Kg*1. is washed with water once, The dry organic phase of 5Kg anhydrous sodium sulfate is added in 20Kg*1., filters, is concentrated into no fraction, then twice with acetone band, and oil pump, which is drawn, to be done, TA07 crude product 12.5Kg is obtained, wait throw in next step.

The crude product and 80L ethyl alcohol of 12.5KgTA07 are added into the hydriding reactor of 200L, under stirring, is added thereto The palladium carbon (aqueous 68%, give money as a gift 1Kg) of 3.12Kg 10% seals reaction flask, is replaced 3 times with nitrogen；It is replaced 3 times with hydrogen； Logical hydrogen synthesis under normal pressure 19h, HPLC starting material left 7%, mending hydrogen, the reaction was continued, and the conversion of HPLC raw material is complete.System is directly taken out Filter, filter cake ethanol rinse, filtrate is brown, adds 2% active carbon decoloring, pads suction filtered through kieselguhr, filtrate be it is light yellow, will filter Liquid is concentrated into substantially without fraction, the ethyl alcohol of 29Kg is added, the tap water of 54Kg, drop is added dropwise in 50~55 DEG C of stirring and dissolvings thereto Temperature is filtered to 10~15 DEG C, and filter cake elutes (ethyl alcohol: water=1:3) with mixed solution.Filter cake oven-dried weight 9.4Kg.

The crude product of 9.4KgTA08 is added into the reaction kettle of 100L and the ethyl alcohol of 16.8Kg, stirring are heated to 50~55 DEG C, dissolved clarification, thereto be added dropwise 32Kg water, 50~55 DEG C of temperature control；Drop finishes, and at this temperature, stirs 0.5h, is cooled to 10~15 DEG C filter, filter cake drying after weight 8.2Kg.

The total recovery of step 4 and step 5 is 76.7%

7KgTA08 and 28Kg isopropanol and 13.5Kg n-propylamine are added into the reaction kettle of 100L.System is warming up to 60~65 DEG C.24~30h of heat preservation reflection.It is complete that HPLC detects raw material conversion.Reaction is concentrated into substantially without fraction, thereto plus The isopropanol for entering 28Kg is warming up to 50~55 DEG C, and the solution of 1.6Kg oxalic acid and 4Kg isopropanol is added dropwise thereto, and process is added dropwise In have solid precipitation.After completion of dropwise addition, continue to stir 0.5h.System is cooled to 10~15 DEG C, is filtered, filter cake is dried 7.5KgTA-OX。

The solution of potassium carbonate of 7.5KgTA-OX and 53Kg methylene chloride and 20Kg10% is added into the reaction kettle of 100L. 0.5h, liquid separation are stirred, the water phase methylene chloride of 13Kg extracts primary.Merge organic phase, then primary with 15Kg water washing.It is organic Desiccant is added in phase, dry, filters, filtrate, which is transferred in the reaction kettle of 50L, to be concentrated into substantially without fraction, and 10Kg is added thereto Normal heptane, continue to be concentrated into starchiness, thereto be added 6.8Kg normal heptane, system is stirred down and is warming up to 50~60 DEG C, Mashing, 0.5~1h, mashing terminate, and system is cooled to 10 DEG C or so, is filtered, and filter cake is eluted with normal heptane, and solid filter cake dries It is dry, weight 5.5Kg.2Kg acetone is added, 9Kg normal heptane, 50~55 DEG C are concentrated into starchiness, and 4.5Kg is being added just thereto System is stirred down and is warming up to 50~60 DEG C by heptane, and mashing, 0.5~1h, mashing terminates, and system is cooled to 10 DEG C or so, is taken out Filter, filter cake are eluted with normal heptane, solid filter cake drying, weight 5.1Kg, HPLC purity 99.0%, largest single impurity < 0.2%.

The total recovery of step 6 and step 7 is 67.6%

Using TA04 as starting material, the total recovery that finished product Tulathromycin is made is 46.2%.

Claims (4)

1.TA06 oxalates TA06-OX:

2. it is as described in claim 1 TA06-OX's the preparation method comprises the following steps:

(1) intermediate TA04 is reacted with hydroxyl protection base reagent, obtains TA05；

(2) TA05 aoxidizes to obtain TA06；

(3) TA06 reacts to obtain TA06-OX with oxalic acid；

Wherein, step (2) oxidation system is DMSO and IBX, is reacted at 20-30 DEG C.

3. method according to claim 2, the hydroxyl protection base reagent in step (1) is benzyl chloroformate.

4. application of the TA06-OX as described in claim 1 in the method for preparing Tulathromycin.