CN106434797A - Technology for enzymatic synthesis of tulathromycin - Google Patents
Technology for enzymatic synthesis of tulathromycin Download PDFInfo
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- CN106434797A CN106434797A CN201610719426.1A CN201610719426A CN106434797A CN 106434797 A CN106434797 A CN 106434797A CN 201610719426 A CN201610719426 A CN 201610719426A CN 106434797 A CN106434797 A CN 106434797A
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Abstract
The invention relates to a method for synthesizing a veterinary medicine, and in particular, relates to a method for enzymatic synthesis of tulathromycin. A compound II and a immobilized esterase are added to water, after each-time reaction, a mother liquor and the immobilized lipase only require to be filtered and separated, and the immobilized esterase only requires to be washed with deionized water and can be reused; the synthesis process has the advantages of simple technology, convenience in operation, short reaction time, high production efficiency, low cost and less pollution.
Description
Technical field：
The present invention designs a kind of synthetic method of veterinary drug, a kind of specifically side of enzymatic clarification Tulathromycin
Method.
Background technology：
In animal husbandry, the respiratory tract infection of domestic animal is generally multiple infection, and paathogenic factor is many, and the state of an illness is complicated, is seeking biology
While preventing and treating and environment block, Drug therapy and prevention are current main paths.Therefore find a kind of to this infection safety,
Effectively, the novel antibacterial medicine of low-residual is extremely urgent.
Pfizer's Pharmaceutical released Tulathromycin in 2002, and various countries have carried out substantial amounts of internal and external pharmacology, toxicology
Related experiment, be also carried out substantial amounts of clinical trial proves that Tulathromycin has that antibacterial activity is strong, has a broad antifungal spectrum, partly declines simultaneously
The many merits such as phase length, become treatment pig and star's medicine of bovine respiratory infection.European drug evaluation administration in 2002 approval is safe
Draw mycin with Draxxin injection in European market, U.S.'s approval Tulathromycin is controlled for animal breath systemic disease within 2005
Treat, China's approval Tulathromycin uses in continent within 2008.
Synthetic method report with regard to Tulathromycin is relatively more both at home and abroad
Method one：Patent CN103073603A, with Azithromycin A as raw material, aoxidizes through acetic anhydride protection, sodium dichromate, with
Cyanogran. addition, reduction and condensation etc. five step synthesizes Tulathromycin
Method two:Patent CN102260306A, CN102786569A and document Boorg Med Chem Lett.12
(2002), 1771-2774 is with Azithromycin A as raw material, through acetic anhydride/Boc2O protects, swern oxidation, epoxidation, alkaline alcohol
Solution or palladium carbon deprotection, amination decylization synthesis Tulathromycin.
Method three:Patent US6472371B1, US6420536B1 etc., with Azithromycin A as raw material, is protected through Bian oxygen dicarbonyl chloride
Shield, swern aoxidizes, sulfur ylide epoxidation palladium carbon catalysis deprotection, ring opening synthesis Tulathromycin.
Method four:Patent CN102295672, EP1253153A1 discloses a kind of preparation method, with demethyl Azithromycin
For raw material, select 4 hydroxyls of protection with CbzCl, then carry out Swern oxidation, epoxidation is being carried out by sulfur ylide, afterwards
Carry out the removing of protection group with palladium carbon hydrogenation, finally carry out aminating reaction and obtain Tulathromycin.
In sum, in the course of reaction of synthesis Tulathromycin, or using the alkali such as Cyanogran. of severe toxicity, or handy
Make catalyst to expensive palladium carbon, carry out deprotection base, and when with palladium carbon, need high-pressure hydrogenation, special hazard.
It is an object of the invention to provide a kind of easy method is produced come the key intermediate epoxidation to synthesize Tulathromycin
Thing, this method adopts enzymatic clarification, says that improved esterase (Esterase) is adsorbed on LKZ518 carrier, forms immobilized ester
Enzyme, with water as reaction dissolvent, 15 DEG C of reaction temperature, complete the removing of benzyloxycarbonyl group under the conditions of pH7.5.This method adopts water as instead
Answer solvent, reaction condition is gentle, and removal efficiency is high, and immobilization esterase can reuse, and decrease environmental pollution, significantly drop
Low production cost.
Content of the invention：
In technique for existing chemosynthesis Tulathromycin, the removing of the protection group on 4 hydroxyls needs to use costliness
And the palladium carbon of danger carries out hydrogenation and removing, complex production process, operational hazards, seriously polluted, with high costs asking under high pressure
Topic, the present invention provides a kind of new technology of enzymatic clarification Tulathromycin, and reaction scheme is as follows：
A kind of technique of enzymatic clarification Tulathromycin, comprises the following steps that：
(1) demethyl Azithromycin, chloro-carbonic acid Bian ester are added in dichloromethane, after 0～5 DEG C of reaction 1～2h, add two
Methyl sulfoxide, after being cooled to -70～-80 DEG C, adds trifluoroacetic acid anhydride reactant 10～30min, add triethylamine react 10～
30min, reaction end is quenched with water and extracts organic faciess, after organic faciess concentrating under reduced pressure, obtains compound one；
(2) trimethyl bromination thioether, potassium tert-butoxide are added to -8 in THF～-16 DEG C of reaction 1.5～2.5h obtain sulfur leaf and stand
Moral solution, the compound one in step (1) is dissolved in dichloromethane, instills in sulfur ylide solution and reacts 1～3h, has reacted
Finish and reactant liquor is poured into extraction split-phase in saturated ammonium chloride solution, after organic faciess concentrating under reduced pressure, obtain compound two；
(3) adopt LKZ518 to be carrier, esterase is adopted covalent immobilization, being fixed esterase；
(4) compound two in step (2) is added water, and adjust addition after the dissolving of pH6.8～7.2 with the dilute hydrochloric acid of 1mol/L
The immobilization esterase of step (3) gained, adjusts pH7.3～7.7 with 1mol/L dilute hydrochloric acid and 1mol/L sodium hydroxide solution, controls
10～20 DEG C of reaction temperature, reacts 60～120min, uses screen filtration after the completion of reaction；Feed liquid adds q. s. methylene chloride and uses
1mol/L sodium hydroxide adjusts pH9.5～10.5 and extracts 10～15min, after organic faciess concentrating under reduced pressure, plus n-propylamine and isopropanol,
55～70 DEG C of reaction 24h, after reaction completes feed liquid concentrating under reduced pressure, afterwards plus acetone solution, Deca elutriation is brilliant, growing the grain sucking filtration get Tai La
Mycin.
In described step (4), the amount of addition water is 10-20 times of compound two mass；
N-propylamine-compound two equivalent proportion adding in described step (4) is 15-25, isopropanol-compound two mass
15-20 times；
In described step (4), screen cloth is 60～120 mesh；
The reaction mechanism that the application prepares Tulathromycin using enzyme process is as follows：
Benzyl chloroformate, due to halogen and the phenyl ring Liang Ge electrophilic group of ining succession on carbonyl, considerably increases Digestive Enzyme and sloughs
The difficulty of benzyl chloroformate, therefore increase the hydrophobic active center of esterase, the first makes it more firm with carrier immobilized, and it two
It is to increase the enzyme activity of zymophore after immobilization.
LKZ518 carrier is good for (Chinese) biological medicine company limited by Amy section and is provided, and LKZ518 carrier is styrene and two
Ethenylbenzene crosslinking net porous polymer, its sufficiently large aperture (average pore size 10～20nm) allows enzyme to enter in duct, passes through
And polymer specific surface (specific surface is between 100～500m2/g) occur physisorption (mainly hydrophobic adsorption) and
Crosslinked action (mainly valeral crosslinked action) is fixed together, and LKZ518 carrier has suitable pore volume and ensures that it is enough
Carry enzyme amount.
Immobilization process：With LKZ518 as carrier, glutaraldehyde as cross linker carries out enzyme immobilization.In suitable pH buffer
Giving uniform temperature, stirring, response time load enzyme amount on demand in system adds protease to complete immobilization process, then
The impurity such as post-treated cross-linking agent washing away on zymophore residual.
, more than 99.5%, total moles yield is more than 57% for the purity of described product Tulathromycin.
Tulathromycin synzyme of the present invention is good for (Chinese) Pharmaceuticals Ltd by Amy section and is provided, in this application
Tulathromycin synzyme is also known as immobilization esterase or esterase.
Compound two and immobilization esterase are added in water the present invention, only need to filter to isolate mother solution and consolidate after every secondary response
Surely change esterase, immobilization esterase only need deionized water rinse i.e. repeat use again, this building-up process process is simple, operation side
Just, the response time is short, production efficiency is high, low cost, pollution are few.
The innovative point of the present invention：
(1) immobilization esterase is used to replace palladium carbon and hydrogen deprotection safety non-pollution.
(2) immobilization esterase can recycle and reuse, and effectively reduces production cost.
(3) use immobilized ester enzymatic synthesiss Tulathromycin side reaction few, high income, product purity is high.
Specific embodiment:
With reference to specific embodiment, the present invention is expanded on further it should be appreciated that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.In addition, it is to be understood that after having read the content of present invention instruction, people in the art
Member makes various changes or modifications to the present invention, and these equivalent form of values equally fall within the model that claims appended by the application are limited
Enclose.
Embodiment one：
140ml dichloromethane, 17g (23.1mmol) demethyl Azithromycin, 4.6g is added in reaction flask
(27.6mmol) chloro-carbonic acid Bian ester, 0～5 DEG C of reaction 1h of temperature control, it is cooled to -80 DEG C, add dimethyl sulfoxide 32g
(409.5mol), Deca trifluoroacetic anhydride 16.2g (77.0mmol), drips Bi Fanying 30min, Deca triethylamine 17.2g
(170.0mmol) react 30min, reaction finishes and adds the extraction of 100ml water in system, obtains compound after organic faciess concentrating under reduced pressure
One 23.8g.
130mlTHF, 20.8g (132mmol) trimethyl bromination thioether, 19.6g (175mmol) uncle is added in reaction bulb
Butanol potassium, -10～15 DEG C carry out sulfur ylide reaction, and reaction 1.5h is cooled to -80 DEG C, compound dual-purpose 50ml dichloromethane
After dissolving, add in sulfur ylide solution, -75～-85 reaction 2.5h, reaction finishes pours 200ml saturation chlorination into reactant liquor
Extract split-phase in ammonium salt solution, after organic faciess concentrating under reduced pressure, obtain compound two 17g.
Add 17g compound two in reaction bulb, 240ml water, with 1mol/L dilute hydrochloric acid adjust pH6.8～7.2 molten clear after, plus
Enter the immobilization esterase of 2500u, with 1mol/L dilute hydrochloric acid and 1mol/L sodium hydroxide solution regulation system pH7.5, keep reaction
15 DEG C of reaction 1h of temperature, by reactant liquor and immobilization esterase filtration separation, immobilization esterase deionized water flush cycle utilizes,
Filtrate adds 100ml dichloromethane, adjusts pH9.5～10.5, extraction with 1mol/L sodium hydroxide, is changed after organic faciess concentrating under reduced pressure
Compound three.Add 20g (339mmol) n-propylamine, 65～70 DEG C of reaction 12h of 110ml isopropanol, after concentrating under reduced pressure, add 40ml
Acetone solution, Deca 120ml purification water crystallization, growing the grain 1h sucking filtration, be dried to obtain Tulathromycin 12.3g (15.5mmol) (mole
Yield 65%, purity 99.8%).
Embodiment two：
140ml dichloromethane, 17g (23.1mmol) demethyl Azithromycin, 4.6g is added in reaction flask
(27.6mmol) chloro-carbonic acid Bian ester, 0-5 DEG C of reaction 1h of temperature control, it is cooled to -80 DEG C, add dimethyl sulfoxide 32g (409.5mol),
Deca trifluoroacetic anhydride 16.2g (77.0mmol), drips Bi Fanying 30min, and Deca triethylamine 17.2g (170.0mmol) is reacted
30min, reaction finishes and adds the extraction of 100ml water in system, obtains compound one 23.5g after organic faciess concentrating under reduced pressure.
130mlTHF, 20.8g (132mmol) trimethyl bromination thioether, 19.6g (175mmol) uncle is added in reaction bulb
Butanol potassium, -10～15 DEG C carry out sulfur ylide reaction, and reaction 1.5h is cooled to -80 DEG C, and compound is molten with 50ml dichloromethane
Add after solution in sulfur ylide solution, -75～-85 reaction 2.5h, reaction finishes that reactant liquor is poured into 200ml saturated ammonium chloride is molten
Extract split-phase in liquid, after organic faciess concentrating under reduced pressure, obtain compound two 16.5g.
Add 16.5g compound two in reaction bulb, 240ml water, with 1mol/L dilute hydrochloric acid adjust pH6.8～7.2 molten clear after,
Add the immobilization esterase of 3000u, with 1mol/L dilute hydrochloric acid and 1mol/L sodium hydroxide solution regulation system pH7.3, keep anti-
Answer 15 DEG C of reaction 1h of temperature, by reactant liquor and immobilization esterase filtration separation, immobilization esterase deionized water flush cycle profit
With filtrate adds 100ml dichloromethane, adjusts pH9.5～10.5, extraction with 1mol/L sodium hydroxide, obtains after organic faciess concentrating under reduced pressure
To compound three.Add 20g (339mmol) n-propylamine, 65～70 DEG C of 110ml isopropanol reacts 12h, after concentrating under reduced pressure, plus
40ml acetone solution Deca 120ml purification water crystallization, growing the grain 1h sucking filtration, are dried to obtain Tulathromycin 12.0g (14.6mmol) and (rub
That yield 63.2%, purity 99.6%).
Embodiment three：
140ml dichloromethane, 17g (23.1mmol) demethyl Azithromycin, 4.6g is added in reaction flask
(27.6mmol) chloro-carbonic acid Bian ester, 0-5 DEG C of reaction 1h of temperature control, it is cooled to -80 DEG C, add dimethyl sulfoxide 32g (409.5mol),
Deca trifluoroacetic anhydride 16.2g (77.0mmol), drips Bi Fanying 30min, and Deca triethylamine 17.2g (170.0mmol) is reacted
30min, reaction finishes and adds the extraction of 100ml water in system, after organic faciess concentrating under reduced pressure, obtains compound 1.
130mlTHF, 20.8g (132mmol) trimethyl bromination thioether, 19.6g (175mmol) uncle is added in reaction bulb
Butanol potassium, -10～15 DEG C carry out sulfur ylide reaction, and reaction 1.5h is cooled to -80 DEG C, compound one 50ml dichloromethane
Add after dissolving in sulfur ylide solution, -75～-85 reaction 2.5h, reaction finishes pours 200ml saturated ammonium chloride into reactant liquor
Extract split-phase in solution, after organic faciess concentrating under reduced pressure, obtain compound two 17.5g.
Add 17g compound two in reaction bulb, 240ml water, with 1mol/L dilute hydrochloric acid adjust pH6.8～7.2 molten clear after, plus
Enter the immobilization esterase of 3500u, with 1mol/L dilute hydrochloric acid and 1mol/L sodium hydroxide solution regulation system pH7.7, keep reaction
15 DEG C of reaction 1h of temperature, by reactant liquor and immobilization esterase filtration separation, immobilization esterase deionized water flush cycle utilizes,
Filtrate adds 100ml dichloromethane, adjusts pH9.5～10.5, extraction with 1mol/L sodium hydroxide, is changed after organic faciess concentrating under reduced pressure
Compound three.Add 20g (339mmol) n-propylamine, 65～70 DEG C of 110ml isopropanol reacts 12h, after concentrating under reduced pressure, plus 40ml third
Ketone dissolves, Deca 120ml purification water crystallization, growing the grain 1h sucking filtration, is dried to obtain Tulathromycin 11.8g (14.3mmol) (mole receipts
Rate 61.9%, purity 99.5%).
Example IV：
140ml dichloromethane, 17g (23.1mmol) demethyl Azithromycin, 4.6g is added in reaction flask
(27.6mmol) chloro-carbonic acid Bian ester, 0-5 DEG C of reaction 1h of temperature control, it is cooled to -80 DEG C, add dimethyl sulfoxide 32g (409.5mol),
Deca trifluoroacetic anhydride 16.2g (77.0mmol), drips Bi Fanying 30min, and Deca triethylamine 17.2g (170.0mmol) is reacted
30min, reaction finishes and adds the extraction of 100ml water in system, obtains compound one 23.8g after organic faciess concentrating under reduced pressure.
130mlTHF, 20.8g (132mmol) trimethyl bromination thioether, 19.6g (175mmol) uncle is added in reaction bulb
Butanol potassium, -10～15 DEG C carry out sulfur ylide reaction, and reaction 1.5h is cooled to -80 DEG C, compound one 50ml dichloromethane
Add after dissolving in sulfur ylide solution, -75～-85 reaction 2.5h, reaction finishes pours 200ml saturated ammonium chloride into reactant liquor
Extract split-phase in solution, after organic faciess concentrating under reduced pressure, obtain compound two 17g.
Add 17g compound two in reaction bulb, 240ml water, with 1mol/L dilute hydrochloric acid adjust pH6.8～7.2 molten clear after, plus
Enter the immobilization esterase of 2500u, with 1mol/L dilute hydrochloric acid and 1mol/L sodium hydroxide solution regulation system pH7.5, keep reaction
20 DEG C of reaction 1h of temperature, by reactant liquor and immobilization esterase filtration separation, immobilization esterase deionized water flush cycle utilizes,
Filtrate adds 100ml dichloromethane, adjusts pH9.5～10.5, extraction with 1mol/L sodium hydroxide, is changed after organic faciess concentrating under reduced pressure
Compound three, adds 20g (339mmol) n-propylamine, 65～70 DEG C of 110ml isopropanol reacts 12h, after concentrating under reduced pressure, plus 40ml third
Ketone dissolving Deca 120ml purification water crystallization, growing the grain 1h sucking filtration, are dried to obtain Tulathromycin 11.0g (13.3mmol) (molar yield
57.6%, purity 99.4%).
Claims (5)
1. a kind of technique of enzymatic clarification Tulathromycin is it is characterised in that comprise the following steps that：
(1) demethyl Azithromycin, chloro-carbonic acid Bian ester are added in dichloromethane, after 0～5 DEG C of reaction 1～2h, add dimethyl
Sulfoxide, after being cooled to -70～-80 DEG C, adds trifluoroacetic acid anhydride reactant 10～30min, add triethylamine react 10～
30min, reaction end is quenched with water and extracts organic faciess, after organic faciess concentrating under reduced pressure, obtains compound one；
(2) trimethyl bromination thioether, potassium tert-butoxide are added to -8 in THF～that -16 DEG C of reaction 1.5～2.5h obtain sulfur ylide is molten
Liquid, the compound one in step (1) is dissolved in dichloromethane, instills and reacts 1～3h in sulfur ylide solution, and reaction finishes handle
Reactant liquor pours extraction split-phase in saturated ammonium chloride solution into, after organic faciess concentrating under reduced pressure, obtains compound two；
(3) adopt LKZ518 to be carrier, esterase is adopted covalent immobilization, being fixed esterase；
(4) compound two in step (2) is added water, and adjust addition step after the dissolving of pH6.8～7.2 with the dilute hydrochloric acid of 1mol/L
(3) the immobilization esterase of gained, adjusts pH7.3～7.7 with 1mol/L dilute hydrochloric acid and 1mol/L sodium hydroxide solution, controls reaction
10～20 DEG C of temperature, reacts 60～120min, uses screen filtration after the completion of reaction；Feed liquid adds q. s. methylene chloride, and uses 1mol/
L sodium hydroxide adjusts pH9.5～10.5 and extracts 10～15min, after organic faciess concentrating under reduced pressure, plus n-propylamine and isopropanol, 55～
70 DEG C of reaction 24h, after reaction completes feed liquid concentrating under reduced pressure, afterwards plus acetone solution, Deca elutriation is brilliant, sucking filtration get Tai La is mould for growing the grain
Element.
2. the technique of enzymatic clarification Tulathromycin as claimed in claim 1 is it is characterised in that add in described step (4)
N-propylamine-compound two equivalent proportion be 15-25,15-20 times of isopropanol-compound two mass.
3. the technique of enzymatic clarification Tulathromycin as claimed in claim 1 is it is characterised in that add in described step (4)
The amount of water is 10-20 times of compound two mass.
4. the technique of enzymatic clarification Tulathromycin as claimed in claim 1 is it is characterised in that screen cloth in described step (4)
For 60～120 mesh.
5. the technique of enzymatic clarification Tulathromycin as claimed in claim 1 is it is characterised in that described step (3) gained
The enzyme activity of immobilization esterase is 2500～3500u.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501364A (en) * | 2017-08-29 | 2017-12-22 | 博瑞生物医药（苏州）股份有限公司 | The salt of tulathromycin intermediate |
| CN113881741A (en) * | 2021-10-27 | 2022-01-04 | 吕彩烨 | Preparation process of veterinary tulathromycin |
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| CN1484695A (en) * | 2001-01-04 | 2004-03-24 | ����˹�ж�-����˹˹������˾ | Enzymatic deprotection of amines and hydroxides |
| CN1503804A (en) * | 2001-04-27 | 2004-06-09 | �Ʒ� | Process for preparing 4''-substituted-9-deoxo-9A-AZA-9A-homoerythromycin a derivatives |
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- 2016-08-25 CN CN201610719426.1A patent/CN106434797A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1484695A (en) * | 2001-01-04 | 2004-03-24 | ����˹�ж�-����˹˹������˾ | Enzymatic deprotection of amines and hydroxides |
| CN1503804A (en) * | 2001-04-27 | 2004-06-09 | �Ʒ� | Process for preparing 4''-substituted-9-deoxo-9A-AZA-9A-homoerythromycin a derivatives |
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| 焦云鹏: "《酶制剂生产与应用》", 31 August 2015, 中国轻工业出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107501364A (en) * | 2017-08-29 | 2017-12-22 | 博瑞生物医药（苏州）股份有限公司 | The salt of tulathromycin intermediate |
| CN113881741A (en) * | 2021-10-27 | 2022-01-04 | 吕彩烨 | Preparation process of veterinary tulathromycin |
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