CN107235971B - A kind of new method preparing Retapamulin - Google Patents
A kind of new method preparing Retapamulin Download PDFInfo
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- CN107235971B CN107235971B CN201710642787.5A CN201710642787A CN107235971B CN 107235971 B CN107235971 B CN 107235971B CN 201710642787 A CN201710642787 A CN 201710642787A CN 107235971 B CN107235971 B CN 107235971B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract
The present invention provides a kind of new method for preparing externally used antimicrobial medicine Retapamulin, this method obtains Retapamulin using Tiamulin as starting material, by the chemical reaction of 5 step entities plus subtractive process.This law starting material is quality controllable, is suitable for new drug development and declares；This law technological operation is simple, and condition is controllable, and preparation cost is low, is convenient for industrial production, is the great innovation to Retapamulin synthetic method.
Description
Technical field
The present invention relates to the preparation methods of a kind of important topical antibiotic drug, in particular to chemical combination name
Referred to as [[(outside 3-) -8- methyl -8- azabicyclic [3.2.1] octane] -3- sulfydryl] -, (3aS, 4R, 5S, 6S, 8R, 9R, 9aR,
10R) the decahydronaphthalene penta cyclooctane -8- of -1- oxo -3a, 9- propane -3aH- ring of -4,6,9,10- tetramethyl -5- hydroxyl -6- vinyl
The preparation method of acetic acid esters.
Background technique
Retapamulin, chemical entitled [[(outside 3-) -8- methyl -8- azabicyclic [3.2.1] octane] -3- sulfydryl] -,
(3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R) -4,6,9,10- tetramethyl -5- decahydronaphthalene -1- oxo -3a of hydroxyl -6- vinyl,
Penta cyclooctane -8- acetic acid esters of 9- propane -3aH- ring is a semi-synthetic truncation pleurotin class antibiotic, its energy and bacterium
Ribosomes 50S subunit on unique site combine, block the region ribosomes P, interference peptidy transeferace activity, to select
The synthesis for inhibiting to property bacterioprotein, reaches antibacterial effect.The quotient that FDA had approved SmithKline company and declare on April 17th, 2007
The name of an article is listing containing 1% Retapamulin emulsifiable paste in the U.S. for Altabax, and indication is 9 months or more children and adults because of gold
Blister sore caused by staphylococcus aureus and micrococcus scarlatinae.
For the compound, have been reported preparation method (US20090149655, WO2005023257A1,
WO2010056855A1) be using pleuromutilin as raw material, by hydroxyl protection, with hydrochloric acid outside-tropine -3- mercaptan takes
Generation reaction obtains the crude product of target product, and for crude product using Retapamulin finished product is refining to obtain, specific route is as follows:
About the preparation method of Retapamulin, starting material used in existing method is pleuromutilin, pleuromutilin
For bacterial fermentation product, be easy to be controlled by monopolization, furthermore because tunning impurity spectrum is complicated and uncontrollable, influence it is auspicious he
Not forest products quality, Ye Shi pharmaceutical production producer's impurity are studied increased difficulty and are increased, while being unfavorable for new drug registration and declaring.
Summary of the invention
In view of the deficiencies of the prior art, the object of the present invention is to provide a kind of completely new Retapamulin preparation method, the systems
Preparation Method is using a kind of new bulk pharmaceutical chemicals, bulk pharmaceutical chemicals system easy to control the quality.
It is to synthesize a kind of important intermediate as the key that starting material prepares Retapamulin using the bulk pharmaceutical chemicals, therefore, this
Invention is to provide a kind of intermediate and preparation method thereof for synthesizing Retapamulin first.
In order to solve the above technical problems, the present invention adopts the following technical scheme that:
A kind of intermediate synthesizing Retapamulin, structural formula is as shown in formula II:
The preparation method of intermediate shown in formula II is occurred to change shown in rearrangement reaction production II as Tiamulin or its salt
Object is closed, Tiamulin structural formula is as shown in formula I；
Tiamulin or its salt are starting material, and the salt includes acylate and inorganic salts, and acylate such as prolongs recklessly
Rope hydrochlorate, maleate, Eurya plant lemon hydrochlorate, acetate, tosilate, benzene sulfonate etc.；Inorganic salts such as hydrochloride, sulfuric acid
Salt, phosphate etc..
Further, the preparation method, the rearrangement reaction solvent for use are methanol, ethyl alcohol, methylene chloride, methyl- tert
One of butyl ether, 1,4- dioxane and tetrahydrofuran are a variety of.It is preferred that methanol.
Further, the preparation method, the rearrangement reaction carries out under trimethyl orthoformate and inorganic acid effect, safe
The molar ratio of wonderful rhzomorph or its salt and orthoformate is 1:5-10.
Preferably, the inorganic acid is inorganic acid.
Preferably, inorganic acid is one of sulfuric acid, hydrochloric acid and phosphoric acid or a variety of.Preferably sulfuric acid.
Further, the preparation method, the rearrangement reaction carry out under the conditions of temperature range is 20-60 DEG C.It is preferred that
Temperature range is 40-50 DEG C.
Further, the present invention provides the methods for preparing Retapamulin using prepared intermediate.
In order to solve the above technical problems, the present invention adopts the following technical scheme that:
Based on the method that the intermediate prepares Retapamulin, include the steps that carrying out as follows:
(1) II compound represented of formula generation hydrolysis obtains III compound represented of formula；
(2) IV compound represented of substitution reaction production occurs for III compound represented of formula and chloracetyl chloride:
(3) IV compound represented of formula and hydrochloric acid it is outer-the anti-raw substitution reaction production V of tropine -3- mercaptan shown in chemical combination
Object:
(4) VI compound represented of rearrangement reaction production, the chemical combination as shown in formula VI occur for V compound represented of formula
Object is by being refining to obtain Retapamulin finished product:
Further, the method for preparing Retapamulin, in step (1), hydrolysis water under alkaline condition
Solution.
Preferably, alkaline condition is inorganic base.
Preferably, the inorganic base is inorganic strong alkali, such as sodium hydroxide, potassium hydroxide, lithium hydroxide.It is preferred that hydroxide
Sodium.
Further, the method for preparing Retapamulin, in step (1), the hydrolysis is 20- in temperature range
It is carried out under the conditions of 60 DEG C.Preferable temperature is 40-50 DEG C.
Further, the method for preparing Retapamulin, in step (2), the substitution reaction under organic base catalytic,
In a solvent, at a certain temperature, esterification occurs for III compound of formula and chloracetyl chloride.
Preferably, the organic base is in triethylamine, tri-n-butylamine, 4-dimethylaminopyridine, pyridine and diisopropylethylamine
It is one or more.It is preferred that pyridine.
Preferably, III compound represented of formula and the molar ratio of organic base are 1:3-5.
Further, the method for preparing Retapamulin, in step (2), III compound represented of formula and chloracetyl chloride
Molar ratio be 1:1.5-2.5.
Further, the method for preparing Retapamulin, in step (2), the substitution reaction solvent for use is selected from first
Base tertbutyl ether, isopropyl ether, ether, tetrahydrofuran, methyl iso-butyl ketone (MIBK), toluene, methylene chloride, ethyl acetate, butyl acetate
With one of isopropyl acetate or a variety of.It is preferred that methyl tertiary butyl ether(MTBE).
Further, the method for preparing Retapamulin, in step (2), the substitution reaction temperature is (- 50 DEG C)-
(30℃).Preferable reaction temperature is -0 DEG C of (- 20).
Further, the method for preparing Retapamulin, in step (3), the substitution reaction under inorganic base effect,
It is carried out under phase transfer catalyst effect.
Preferably, the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, benzyl
Triethylammonium bromide, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, trimethyl
One of ammonium chloride and tetradecyl trimethyl ammonium chloride are a variety of.It is preferred that tetrabutylammonium bromide.
Preferably, the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide.It is preferred that sodium hydroxide.
Preferably, the inorganic base is configured to aqueous solution, concentration 15-30%.Preferred concentration is 20%.
Preferably, IV compound represented of formula and the molar ratio of inorganic base aqueous solution are 1:3-7.Change shown in preferred formula IV
The molar ratio for closing object and inorganic base aqueous solution is 1:5.
Further, the method for preparing Retapamulin, in step (3), the substitution reaction solvent for use is selected from first
In base tertbutyl ether, isopropyl ether, ether, methyl iso-butyl ketone (MIBK), methylene chloride, ethyl acetate, butyl acetate and isopropyl acetate
It is one or more.It is preferred that methyl tertiary butyl ether(MTBE).
Further, the method for preparing Retapamulin, in step (3), the substitution reaction temperature is 0-60 DEG C.It is excellent
Choosing for reaction temperature is 20-30 DEG C.
Further, the method for preparing Retapamulin, in step (3), IV compound represented of formula and hydrochloric acid it is outer-support
Product -3- mercaptan molar ratio is 1:1.5-2.0.
Further, the method for preparing Retapamulin, in step (4), the rearrangement reaction under strongly acidic conditions,
It is carried out under Louis acid catalysis effect.
Preferably, the lewis acid is in alchlor, ferric trichloride, zinc chloride, antimony trifluoride and titanium tetrachloride
It is one or more.
Preferably, V compound represented of formula and lewis acidic molar ratio are 1:2-5, preferred molar ratio 1:3.
Preferably, the strong acid is selected from concentrated hydrochloric acid, the concentrated sulfuric acid, concentrated nitric acid, preferably concentrated hydrochloric acid.V compound represented of formula
It is 1:2-5 (mass volume ratio kg/L), optimum ratio 1:3 with strong acid proportion.
Further, the method for preparing Retapamulin, in step (4), the rearrangement reaction solvent for use is selected from 1,
One of 4- dioxane, methanol, ethyl alcohol, acetonitrile, acetone and glycol monoethyl ether are a variety of.It is preferred that solvent for use is 1,4-
Dioxane.
Further, the method for preparing Retapamulin, in step (4), the rearrangement reaction temperature range is selected from 0-
60℃.It is preferred that rearrangement reaction temperature is 20-30 DEG C.
Further, the method for preparing Retapamulin, in step (4), VI compound represented of formula is pure by solvent
It re-refines to obtain Retapamulin finished product after change.
Preferably, the solvent is ethyl acetate, isopropyl acetate, butyl acetate, n-hexane, normal heptane, methanol, second
One of alcohol, isopropanol, methanol aqueous solution, ethanol water and isopropanol water solution are a variety of.Every time using shown in Formula IV
Compound and solvent proportion at 1:1-6 (mass volume ratio kg/L).
Preferably, the purification process may include that the collocation of one or more mixed solvent systems uses.
The beneficial effects of the present invention are:
1) starting material selected by the present invention is semi-synthetic class veterinary medicine, has stringent quality standard (such as European Pharmacopoeia mark
It is quasi-), and impurity spectrum is clear, therefore the starting material is quality controllable.Retapamulin is prepared with the starting material, is convenient for pharmaceutical production
Enterprise carries out the quality research of Retapamulin product, declares conducive to new drug.
2) the present invention provides a kind of completely new preparation method, integrated artistic is simple, and reaction temperature is moderate, no ultralow temperature or
Pyroreaction is convenient for industrialized production.
3) preparation method agents useful for same of the invention is cheap and easy to get, and charging is convenient, and transport storage is simple, and preparation cost is low.
Specific embodiment
Below with reference to specific embodiment, the present invention will be further described in detail.Illustrated embodiment is in order to preferably
The contents of the present invention are illustrated, but are not that the contents of the present invention are only limitted to illustrated embodiment.So being familiar with this field
Technical staff carries out nonessential modifications and adaptations to embodiment according to foregoing invention content, still falls within protection model of the invention
It encloses.
The preparation of 1 important intermediate of embodiment (III compound represented of formula)
III compound represented chemical name of formula is (3aS, 4R, 6S, 8R, 9R, 9aR, 10R) -4,6,9,10- tetramethyl eight
Penta cyclooctane-5- ketone of hydrogen-8--6-vinyl of hydroxyl-1-methoxy-3a, 9- propane-3aH- ring.
1.21kg type I compound and 7.5L anhydrous methanol are added in 50L double-layer glass reaction kettle, nitrogen protection, stirring
Trimethyl orthoformate 1.175kg, cooling are added after lower dissolved clarification；0-10 DEG C starts that the concentrated sulfuric acid is added dropwise, and keeps the temperature < 15 DEG C, about 1.0-1.5
Hour drop finishes, the total 602.7g concentrated sulfuric acid；It is warming up to 45-50 DEG C of interior temperature reaction, about 6.0-7.0 end of reaction stops heating, cooling
Degree starts to instill 50% sodium hydrate aqueous solution, temperature control < 30 DEG C, drop finishes within about 1.0 hours, instills altogether to 10-20 DEG C
2.164kg 50% sodium hydrate aqueous solution；It is warming up to 55-65 DEG C of interior temperature reaction, end of reaction after about 4.0-5.0 hours is stopped
It only heats, is cooled to 20-30 DEG C, 25L drinking water is added, ethyl acetate extraction (is extracted twice, each ethyl acetate dosage
5.0L), merge organic phase, washing (washing three times, uses water 6.0L every time) is added anhydrous sodium sulfate 1.0kg and stirs lower drying
1.0-2.0 hour；50.0-60.0 DEG C is concentrated under reduced pressure into cutout, is added after 1.5L normal heptane is evaporated under reduced pressure to cutout and 820mL is added
Normal heptane is heated to 45-50 DEG C of stirring dissolved clarification；It is cooled to 20-30 DEG C, rear ice bath crystallization (0-10 DEG C) 1.0-1.5 hours；It takes out
Filter, filter cake are eluted with about 50-100mL normal heptane, and vacuum drying (55-65 DEG C, -0.08 to -0.09MPa) 4-6 hours obtains
672.3g white-yellowish solid (III compound represented of formula), yield 81.7%, purity 98.9%.
The preparation of 2 formula of embodiment, IV compound
The chemical name of IV compound of formula is (3aS, 4R, 6S, 8R, 9R, 9aR, 10R) -4,6,9,10- tetramethyl octahydro -
Penta cyclooctane-5- ketone-8- chloracetate of 8--6-vinyl of hydroxyl-1-methoxy-3a, 9- propane-3aH- ring.
4.8L methyl tertiary butyl ether(MTBE), III compound of 418.2g formula are added in 10L double-layer glass reaction kettle, dissolved clarification is stirred,
200-300 revs/min of speed of agitator；The cooling of high/low temperature circulator, temperature control is in -10 to -15 DEG C of dropwise addition pyridines (total 445.0g), about
It is added dropwise within 15-20 minutes；The mixing of chloracetyl chloride and 1.5L methyl tertiary butyl ether(MTBE) is added dropwise at -20~-25 DEG C for cooling, temperature control
Liquid has in reaction kettle a large amount of white-yellowish solids to generate, is added dropwise within about 2.5-3.5 hours；It is warming up to -10~-15 DEG C of reactions
Reaction was completed within 1.0-1.5 hours, is layered after the stirring of 3.0L drinking water is added, and organic phase drinks washing once with 3.0L, discards water
Layer；Organic phase is stirred 1.0-2.0 hours dry with 0.5kg anhydrous sodium sulfate；45.0-55.0 DEG C is concentrated under reduced pressure into cutout, then plus
Enter 45.0-55.0 DEG C of 200mL n-hexane and is concentrated under reduced pressure into cutout；1280mL n-hexane is added, it is molten to be warming up to 40-50 DEG C of stirring
Clearly, rear to stop heating, Temperature fall；Ice bath cooling crystallization at 20-30 DEG C of interior temperature；0-10 DEG C crystallization 1.0-2.0 hours；It filters,
Filter cake is eluted with about 30-50mL n-hexane, vacuum drying (55-65 DEG C, -0.08~-0.09MPa) 4-6 hours, obtains 345.0g Huang
White solid (IV compound of formula), yield 67.1%, purity 98.0%.
The preparation of 3 formula of embodiment, V compound
The chemical name of V compound of formula is [[(outside 3-) -8- methyl -8- azabicyclic [3.2.1] octane] -3- sulfydryl] -
(3aS, 4R, 6S, 8R, 9R, 9aR, 10R) -4,6,9,10- tetramethyl -1- decahydronaphthalene -1- oxo -3a of methoxyl group -6- vinyl,
Penta cyclooctane -5- ketone -8- acetic acid esters of 9- propane -3aH- ring
It is added IV compound 205.5g of formula into 10L reaction kettle, methyl tertiary butyl ether(MTBE) 2.05L, 116.2g hydrochloric acid is outer-support
Product -3- mercaptan, 20.5g TBAB, speed of agitator control 10-20 DEG C of instillation sodium hydroxide water of temperature control under 300-400 revs/min
Solution (100g sodium hydroxide is dissolved in 400mL water), is added dropwise for about 1.0-1.5 hours, after be warming up to 20-30 DEG C of reaction 1.0-
Reaction was completed after 1.5 hours, and 2.0L drinking water, liquid separation after stirring is added, and organic layer is washed with 10% aqueous ammonium chloride solution of 2.0L
1 time, then washing 1 time is drunk with 2.0L, organic phase stirs 2.0-4.0 hours dry, 45.0-55.0 with 0.5kg anhydrous sodium sulfate
It DEG C is concentrated under reduced pressure into after oily solid (V compound of formula) to be directly used in and react in next step.
In following embodiment, the purity of Formula IV compound and Retapamulin highly finished product uses high performance liquid chromatography (HPLC)
Measurement, chromatographic condition are as follows:
Chromatographic column: Kromasil Eternity-C18 4.6*250mm, 5 μm
Mobile phase: buffer salt: acetonitrile: water=30:21:49
Buffer salt configuration method: it weighs 10g ammonium carbonate and is slowly added to after the dissolution of 800mL purified water is added in 1L volumetric flask
22mL perchloric acid is diluted to scale after not generating bubble, adjusts pH value to 10.0 with ammonium hydroxide；
Detection wavelength: 212nm
Column temperature: 30 DEG C
Flow velocity: 1.0ml/min
Sample volume: 20 μ l
Sample concentration: 10.0mg/ml (acetonitrile as solvents)
The preparation of 4 formula of embodiment, VI compound
The chemical name of VI compound of formula is [[(outside 3-) -8- methyl -8- azabicyclic [3.2.1] octane] -3- mercapto
Base] -, (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R) -4,6,9, the 10- decahydronaphthalene -1- oxygen of tetramethyl -5- hydroxyl -6- vinyl
Generation -3a, penta cyclooctane -8- acetic acid esters of 9- propane -3aH- ring.
Gained oily solid (V compound of formula) in embodiment 3 and 1.33L 1,4- dioxane are added in 5L reaction flask
Stirring and dissolving, cooling, heat preservation 15 DEG C or less is added dropwise to the concentrated hydrochloric acid solution of zinc chloride, and (204g zinc chloride is dissolved in 797mL concentrated hydrochloric acid
In), it is added dropwise within about 1.5-2.0 hours, then be warming up to 20.0-30.0 DEG C of reaction 1.0-1.5 hours, reaction was completed, is added
2.0L drinking water, stirring to reaction solution are clarified；Methylene chloride is extracted twice, and merges dichloromethane extract, 0.5kg anhydrous slufuric acid
Sodium stirring is lower 2.0-4.0 hours dry；50.0-60.0 DEG C is concentrated under reduced pressure into cutout, be added 100mL ethyl acetate be evaporated under reduced pressure to
260mL ethyl acetate, 50.0-60.0 DEG C of heating stirring dissolved clarification are added after cutout, heat preservation instills n-hexane (total 780mL), about
It is added dropwise within 1.5-2.0 hours；It is naturally cooling to 20.0-30.0 DEG C, then to be cooled to 0-10.0 DEG C of crystallization 1.0-1.5 small for ice bath
When, it filters, filter cake is eluted with 50mL n-hexane；Obtained solid and 260mL ethyl acetate are added in tri- mouthfuls of vials of 2.0L,
50.0-60.0 DEG C of heating stirring dissolved clarification, heat preservation instill n-hexane (total 760mL), are added dropwise within about 1.5-2.0 hours；Naturally it drops
Temperature has a large amount of white-yellowish solids to be precipitated to 20.0-30.0 DEG C, and ice bath is cooled to 0-10.0 DEG C of crystallization 1.0-1.5 hours, filters,
Filter cake is eluted with 50mL n-hexane；Filter cake and 520mL methanol are added in tri- mouthfuls of vials of 2.0L, dissolved clarification is stirred at room temperature, it is rear to drip
Enter drinking water (total 520mL), is added dropwise within about 2.0-3.0 hours, a large amount of off-white powders are precipitated；It is naturally cooling to 20.0-
After 30.0 DEG C, ice bath is cooled to 0-10.0 DEG C of crystallization 1.0-1.5 hours, filters, and filter cake is eluted with 50-100mL drinking water, vacuum
Dry (55-65 DEG C, -0.08~-0.09MPa) 6-8 hours, obtaining 124.8g white-yellowish solid, (Formula IV compound, Retapamulin are thick
Product), HPLC purity 99.9%, from formula IV compound so far yield 48.2%.
The preparation of 5 Retapamulin highly finished product of embodiment
Formula IV compound 100.0g is dissolved in 700mL acetone, after solution is instilled at room temperature in 4.0L purified water, about 1-2
Hour drop finishes, after be cooled to 0-10 DEG C, cooling crystallization 1-2 hour, filter, 100mL purifies water washing filter cake, and filter cake is dried in vacuo
(55-65 DEG C, -0.08~-0.09MPa) 6-8 hours obtains Retapamulin highly finished product 94.5g, refines yield 94.5%, HPLC is pure
Degree 99.9%.
6 Retapamulin structural identification data of embodiment
(1) mass spectrometric data:
Instrument: the source the API3000 of AB company, ESI, positive ion mode, [M+H+]+=518.7, with Retapamulin theory point
Son amount is consistent；
(2) single crystal X-ray diffraction result:
Instrument: Japanese Rigaku MicroMax 002+ single crystal diffractometer
By single crystal X-ray diffraction examining report, result is analyzed are as follows: final to determine that asymmetry unit stoichiometric equation is
C30H47NO4S, calculating molecular weight is 517.77, this is completely the same with the data that CAS is 224452-66-8 compound.Molecule is absolute
Configuration is as follows:
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the scope of the claims of invention.
Claims (8)
1. a kind of method for synthesizing Retapamulin, which is characterized in that include the steps that carrying out as follows:
1) II compound represented of formula generation hydrolysis obtains III compound represented of formula:
2) IV compound represented of substitution reaction production occurs for III compound represented of formula and chloracetyl chloride:
3) IV compound represented of formula and hydrochloric acid it is outer-V compound represented of substitution reaction production occurs for tropine -3- mercaptan:
4) VI compound represented of rearrangement reaction production occurs for V compound represented of formula, is passed through by VI compound represented of formula
It is refining to obtain Retapamulin finished product:
2. the method according to claim 1, wherein by Tiamulin or its salt weight occurs for the Formula II compound
Row's reaction generates, and Tiamulin structural formula is as shown in formula I
The rearrangement reaction carries out under trimethyl orthoformate and inorganic acid effect, and Tiamulin or its salt and orthoformate rub
You are than being 1:5-10.
3. according to the method described in claim 2, it is characterized in that, the rearrangement reaction solvent for use is methanol, ethyl alcohol, dichloro
One of methane, methyl tertiary butyl ether(MTBE), 1,4- dioxane and tetrahydrofuran are a variety of.
4. the method according to claim 1, wherein in step (1), hydrolysis water under alkaline condition
Solution.
5. the method according to claim 1, wherein the substitution reaction is in the presence of an organic base in step (2)
It carries out, the organic base is one of triethylamine, tri-n-butylamine, 4-dimethylaminopyridine, pyridine and diisopropylethylamine or more
Kind, reaction solvent for use is selected from methyl tertiary butyl ether(MTBE), isopropyl ether, ether, tetrahydrofuran, methyl iso-butyl ketone (MIBK), toluene, dichloromethane
One of alkane, ethyl acetate, butyl acetate and isopropyl acetate are a variety of.
6. the method according to claim 1, wherein the substitution reaction exists in inorganic base in step (3)
Under, it is carried out under phase transfer catalyst effect, the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium iodide, four fourths
Ammonium chloride, benzyl triethyl ammonium bromide, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, ten
One of dialkyl group trimethyl ammonium chloride and tetradecyl trimethyl ammonium chloride are a variety of, and reaction solvent for use is selected from methyl- tert
One in butyl ether, isopropyl ether, ether, methyl iso-butyl ketone (MIBK), methylene chloride, ethyl acetate, butyl acetate and isopropyl acetate
Kind is a variety of.
7. the method according to claim 1, wherein the rearrangement reaction is in strong acidic condition in step (4)
Under, Louis acid catalysis effect under carry out, the lewis acid be alchlor, ferric trichloride, zinc chloride, antimony trifluoride and
One of titanium tetrachloride is a variety of, and reaction solvent for use is selected from Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol, acetonitrile, acetone and second two
One of alcohol monomethyl ether is a variety of.
8. the method according to claim 1, wherein VI compound represented of formula is pure by solvent in step (4)
It re-refines to obtain Retapamulin finished product after change, the solvent is ethyl acetate, isopropyl acetate, butyl acetate, n-hexane, positive heptan
One of alkane, methanol, ethyl alcohol, isopropanol, methanol aqueous solution, ethanol water and isopropanol water solution are a variety of.
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