CN107235971A - A kind of new method for preparing Retapamulin - Google Patents

A kind of new method for preparing Retapamulin Download PDF

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Publication number
CN107235971A
CN107235971A CN201710642787.5A CN201710642787A CN107235971A CN 107235971 A CN107235971 A CN 107235971A CN 201710642787 A CN201710642787 A CN 201710642787A CN 107235971 A CN107235971 A CN 107235971A
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retapamulin
formula
compound
preparing
ether
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CN107235971B (en
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王帆
占肖
何志红
王绍辉
陈小舟
杨玉金
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Chongqing Huapont Pharm Co Ltd
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Chongqing Huapont Pharm Co Ltd
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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
    • 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
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a kind of new method for preparing externally used antimicrobial medicine Retapamulin, this method obtains Retapamulin using Tiamulin as initiation material by 5 step entities chemical reaction plus subtractive process.This law initiation 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 easy to industrial production, is the great innovation to Retapamulin synthetic method.

Description

A kind of new method for preparing Retapamulin
Technical field
It is to be related to chemical combination name specifically the present invention relates to the preparation method of the important topical antibiotic medicine of a class Referred to as [[(outside 3-) -8- methyl -8- azabicyclics [3.2.1] octane] -3- sulfydryls] -, (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R) decahydronaphthalene cyclooctane-the 8- of -1- oxos -3a, 9- propane -3aH- rings penta of -4,6,9,10- tetramethyls -5- hydroxyls -6- vinyl The preparation method of acetic acid esters.
Background technology
Retapamulin, chemical entitled [[(outside 3-) -8- methyl -8- azabicyclics [3.2.1] octane] -3- sulfydryls] -, (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R) -4,6,9,10- tetramethyl -5- decahydronaphthalene -1- oxos -3a of hydroxyl -6- vinyl, Cyclooctane -8- the acetic acid esters of 9- propane -3aH- rings penta, be one it is semi-synthetic block pleurotin class antibiotic, it can and bacterium Ribosomes 50S subunits on unique site combine, block ribosomes P regions, interference peptidy transeferace activity, so as to select Suppress to property the synthesis of bacterioprotein, reach antibacterial effect.FDA have approved the business that SmithKline company declares on April 17th, 2007 The name of an article lists for Altabax containing 1% Retapamulin emulsifiable paste in the U.S., and its indication is more than 9 months children and adults because of gold Blister sore caused by staphylococcus aureus and micrococcus scarlatinae.
For the compound, have been reported its 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 crude product is again by being refining to obtain Retapamulin finished product, and specific route is as follows：
On the preparation method of Retapamulin, initiation material used in existing method is pleuromutilin, pleuromutilin For bacterial fermentation product, easily by monopolization control, furthermore because tunning impurity is composed complicated and is difficult to control to, influence it is auspicious he Forest products quality, the increased difficulty increasing of Ye Shi pharmaceutical production producer impurity research, are not declared while being unfavorable for new drug registration.
The content of the invention
In view of the shortcomings of the prior art, it is an object of the invention to provide a kind of brand-new Retapamulin preparation method, the system Preparation Method uses a kind of new bulk drug, bulk drug system easy to control the quality.
The key that Retapamulin is prepared by starting material of the bulk drug is a kind of important intermediate of synthesis, therefore, this Invention is to provide a kind of intermediate for synthesizing Retapamulin and preparation method thereof first.
To solve above technical problem, the present invention is adopted the following technical scheme that：
A kind of intermediate for synthesizing Retapamulin, its structural formula is as shown in formula II：
The preparation method of intermediate shown in formula II, the change shown in rearrangement reaction production II is occurred as Tiamulin or its salt Compound, Tiamulin structural formula is as shown in formula I；
Tiamulin or its salt are initiation material, and described 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, described preparation method, the rearrangement reaction solvent for use is methanol, ethanol, dichloromethane, methyl- tert One or more in butyl ether, 1,4- dioxane and tetrahydrofuran.It is preferred that methanol.
Further, described preparation method, the rearrangement reaction is carried out under trimethyl orthoformate and inorganic acid effect, safe The mol ratio of wonderful rhzomorph or its salt and orthoformate is 1：5-10.
It is preferred that, the inorganic acid is inorganic acid.
It is preferred that, inorganic acid is the one or more in sulfuric acid, hydrochloric acid and phosphoric acid.Preferably sulfuric acid.
Further, described preparation method, the rearrangement reaction is carried 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 invention provides the method that Retapamulin is prepared using prepared intermediate.
To solve above technical problem, the present invention is adopted the following technical scheme that：
The step of method of Retapamulin is prepared based on described intermediate, including is carried out as follows：
(1) the compound generation hydrolysis shown in formula II obtains the compound shown in formula III；
(2) compound shown in substitution reaction production IV occurs with chloracetyl chloride for the compound shown in formula III：
(3) compound shown in formula IV and hydrochloric acid it is outer-tropine -3- mercaptan instead gives birth to chemical combination shown in substitution reaction production V Thing：
(4) compound shown in rearrangement reaction production VI occurs for the compound shown in formula V, as the chemical combination shown in formula VI Thing is by being refining to obtain Retapamulin finished product：
Further, in the described method for preparing Retapamulin, step (1), hydrolysis water in the basic conditions Solution.
It is preferred that, alkalescence condition is inorganic base.
It is preferred that, the inorganic base is inorganic strong alkali, such as sodium hydroxide, potassium hydroxide, lithium hydroxide.It is preferred that hydroxide Sodium.
Further, in the described method for preparing Retapamulin, step (1), the hydrolysis is 20- in temperature range Carried out under the conditions of 60 DEG C.Preferable temperature is 40-50 DEG C.
Further, in the described method for preparing Retapamulin, step (2), the substitution reaction under organic base catalytic, With chloracetyl chloride in a solvent, at a certain temperature, esterification occurs for the compound of formula III.
It is preferred that, the organic base is in triethylamine, tri-n-butylamine, DMAP, pyridine and diisopropylethylamine One or more.It is preferred that pyridine.
It is preferred that, the mol ratio of compound and organic base shown in formula III is 1：3-5.
Further, in the described method for preparing Retapamulin, step (2), compound and chloracetyl chloride shown in formula III Mol ratio be 1：1.5-2.5.
Further, in the described method for preparing Retapamulin, 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, dichloromethane, ethyl acetate, butyl acetate With the one or more in isopropyl acetate.It is preferred that methyl tertiary butyl ether(MTBE).
Further, in the described method for preparing Retapamulin, step (2), the substitution reaction temperature be (- 50 DEG C)- (30℃).Preferable reaction temperature is -0 DEG C of (- 20).
Further, in the described method for preparing Retapamulin, step (3), the substitution reaction inorganic base effect under, Carried out under phase transfer catalyst effect.
It is preferred that, the phase transfer catalyst is TBAB, tetrabutylammonium iodide, tetrabutylammonium chloride, benzyl Triethylammonium bromide, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, trimethyl One or more in ammonium chloride and tetradecyl trimethyl ammonium chloride.It is preferred that TBAB.
It is preferred that, the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide.It is preferred that sodium hydroxide.
It is preferred that, the inorganic base is configured to the aqueous solution, and concentration is 15-30%.Preferred concentration is 20%.
It is preferred that, the mol ratio of compound and inorganic base aqueous solution shown in formula IV is 1：3-7.Change shown in preferred formula IV The mol ratio of compound and inorganic base aqueous solution is 1：5.
Further, in the described method for preparing Retapamulin, step (3), the substitution reaction solvent for use is selected from first In base tertbutyl ether, isopropyl ether, ether, methyl iso-butyl ketone (MIBK), dichloromethane, ethyl acetate, butyl acetate and isopropyl acetate One or more.It is preferred that methyl tertiary butyl ether(MTBE).
Further, in the described method for preparing Retapamulin, step (3), the substitution reaction temperature is 0-60 DEG C.It is excellent It is 20-30 DEG C to choose for reaction temperature.
Further, in the described method for preparing Retapamulin, step (3), outside the compound and hydrochloric acid shown in formula IV-support Product -3- mercaptan mol ratio is 1：1.5-2.0.
Further, in the described method for preparing Retapamulin, step (4), the rearrangement reaction under strongly acidic conditions, Carried out under Louis acid catalysis effect.
It is preferred that, the lewis acid is in alchlor, ferric trichloride, zinc chloride, antimony trifluoride and titanium tetrachloride It is one or more.
It is preferred that, compound and lewis acidic mol ratio shown in formula V are 1：2-5, preferred molar ratio is 1：3.
It is preferred that, the strong acid is selected from concentrated hydrochloric acid, the concentrated sulfuric acid, concentrated nitric acid, preferably concentrated hydrochloric acid.Compound shown in formula V It is 1 with strong acid proportioning：2-5 (mass volume ratio kg/L), optimum ratio is 1：3.
Further, in the described method for preparing Retapamulin, step (4), the rearrangement reaction solvent for use is selected from 1, One or more in 4- dioxane, methanol, ethanol, acetonitrile, acetone and glycol monoethyl ether.It is preferred that solvent for use is 1,4- Dioxane.
Further, in the described method for preparing Retapamulin, 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, in the described method for preparing Retapamulin, step (4), the compound shown in formula VI is pure by solvent Re-refined after change and obtain Retapamulin finished product.
It is preferred that, the solvent is ethyl acetate, isopropyl acetate, butyl acetate, n-hexane, normal heptane, methanol, second One or more in alcohol, isopropanol, methanol aqueous solution, ethanol water and isopropanol water solution.Every time using shown in Formula IV Compound and solvent proportioning 1：1-6 (mass volume ratio kg/L).
It is preferred that, the purge process may include that the collocation of one or more mixed solvent systems is used.
The beneficial effects of the present invention are：
1) the selected initiation material of the present invention is semi-synthetic class veterinary medicine, with strict quality standard (such as European Pharmacopoeia mark It is accurate), and impurity spectrum is clear, therefore the initiation material is quality controllable.Retapamulin is prepared with the initiation material, is easy to pharmaceutical production Enterprise carries out the quality research of Retapamulin product, is declared beneficial to new drug.
2) the invention provides a kind of brand-new preparation method, integrated artistic is simple, and reaction temperature is moderate, no ultralow temperature or Pyroreaction, is easy to industrialized production.
3) preparation method agents useful for same of the invention is cheap and easy to get, and charging is convenient, and shipping storage is simple, prepares cost low.
Embodiment
With reference to specific embodiment, the present invention will be further described in detail.Illustrated embodiment is in order to preferably Present disclosure is illustrated, but is not that present disclosure is only limitted to illustrated embodiment.So being familiar with this area Technical staff carries out nonessential modifications and adaptations according to foregoing invention content to embodiment, still falls within the protection model of the present invention Enclose.
The preparation of the important intermediate of embodiment 1 (compound shown in formula III)
Compound chemical name shown in formula III is (3aS, 4R, 6S, 8R, 9R, 9aR, 10R) -4,6,9,10- tetramethyls eight Cyclooctane-5- the ketone of hydrogen-8--6-vinyl of hydroxyl-1-methoxy-3a, 9- propane-3aH- rings penta.
1.21kg type I compounds and 7.5L absolute methanols are added in 50L double-layer glass reaction kettles, nitrogen protection, stirring Trimethyl orthoformate 1.175kg, cooling are added after lower dissolved clarification；0-10 DEG C starts that the concentrated sulfuric acid, insulation is added dropwise<15 DEG C, about 1.0-1.5 Hour drop finishes, the common 602.7g concentrated sulfuric acids；Interior 45-50 DEG C of reaction of temperature is warming up to, about 6.0-7.0 reactions are finished, and stop heating, cooling Degree starts to instill 50% sodium hydrate aqueous solution, temperature control to 10-20 DEG C<30 DEG C, drop finishes within about 1.0 hours, instills altogether 2.164kg 50% sodium hydrate aqueous solution；Interior 55-65 DEG C of reaction of temperature is warming up to, reacts and finishes after about 4.0-5.0 hours, stop Only heat, be cooled to 20-30 DEG C, add 25L drinking water, ethyl acetate extraction (is extracted twice, each ethyl acetate consumption 5.0L), organic phase is merged, washing (washing three times, use water 6.0L every time) adds the lower drying of anhydrous sodium sulfate 1.0kg stirrings 1.0-2.0 hour；50.0-60.0 DEG C is concentrated under reduced pressure into cutout, adds the vacuum distillation of 1.5L normal heptanes and adds 820mL to after stopping 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；Take out Filter, filter cake is eluted with about 50-100mL normal heptanes, vacuum drying (55-65 DEG C, -0.08 to -0.09MPa) 4-6 hours, is obtained 672.3g white-yellowish solids (compound shown in formula III), yield 81.7%, purity 98.9%.
The preparation of the compound of 2 formula of embodiment IV
The chemical name of the compound of formula IV be (3aS, 4R, 6S, 8R, 9R, 9aR, 10R) -4,6,9,10- tetramethyls octahydro - Cyclooctane-5- ketone-8- the chloracetates of 8--6-vinyl of hydroxyl-1-methoxy-3a, 9- propane-3aH- rings penta.
4.8L methyl tertiary butyl ether(MTBE)s, the compound of 418.2g formulas III are added in 10L double-layer glass reaction kettles, dissolved clarification is stirred, 200-300 revs/min of speed of agitator；High/low temperature circulator cools, and pyridine (common 445.0g) is added dropwise at -10 to -15 DEG C in temperature control, about 15-20 minutes completion of dropping；The mixing of chloracetyl chloride and 1.5L methyl tertiary butyl ether(MTBE)s is added dropwise at -20~-25 DEG C for cooling, temperature control There are a large amount of white-yellowish solids to generate in liquid, reactor, about 2.5-3.5 hours completion of dropping；It is warming up to -10~-15 DEG C of reactions Terminate reaction within 1.0-1.5 hours, be layered after adding the stirring of 3.0L drinking water, organic phase drinks washing with 3.0L once, discards water Layer；Organic phase is stirred with 0.5kg anhydrous sodium sulfates and dried 1.0-2.0 hours；45.0-55.0 DEG C is concentrated under reduced pressure into cutout, then adds Enter 45.0-55.0 DEG C of 200mL n-hexanes and be concentrated under reduced pressure into cutout；1280mL n-hexanes are added, 40-50 DEG C of stirring are warming up to molten Clearly, it is rear to stop heating, Temperature fall；Ice bath cooling crystallization during 20-30 DEG C of interior temperature；0-10 DEG C of crystallization 1.0-2.0 hours；Suction filtration, Filter cake is eluted with about 30-50mL n-hexanes, vacuum drying (55-65 DEG C, -0.08~-0.09MPa) 4-6 hours, obtains 345.0g yellow White solid (compound of formula IV), yield 67.1%, purity 98.0%.
The preparation of the compound of 3 formula of embodiment V
The chemical name of the compound of formula V be [[(outside 3-) -8- methyl -8- azabicyclics [3.2.1] octane] -3- sulfydryls] - (3aS, 4R, 6S, 8R, 9R, 9aR, 10R) -4,6,9,10- tetramethyl -1- decahydronaphthalene -1- oxos -3a of methoxyl group -6- vinyl, Cyclooctane -5- ketone -8- the acetic acid esters of 9- propane -3aH- rings penta
- support is added outside formula IV compound 205.5g, methyl tertiary butyl ether(MTBE) 2.05L, 116.2g hydrochloric acid into 10L reactors Product -3- mercaptan, 20.5g TBAB, speed of agitator is controlled under 300-400 revs/min, 10-20 DEG C of instillation sodium hydroxide water of temperature control Solution (100g sodium hydroxides are dissolved in 400mL water), about 1.0-1.5 hours completion of dropping, after be warming up to 20-30 DEG C reaction 1.0- Terminate reaction after 1.5 hours, add 2.0L drinking water, point liquid after stirring, organic layer is washed with the aqueous ammonium chloride solutions of 2.0L 10% 1 time, then washing 1 time is drunk with 2.0L, organic phase is stirred with 0.5kg anhydrous sodium sulfates and dried 2.0-4.0 hours, 45.0-55.0 DEG C it is concentrated under reduced pressure into after oily solid (compound of formula V) and is directly used in next step reaction.
In following examples, the purity of Formula IV compound and Retapamulin highly finished product uses high performance liquid chromatography (HPLC) Determine, chromatographic condition is as follows：
Chromatographic column：Kromasil Eternity-C18 4.6*250mm, 5 μm
Mobile phase：Buffer salt：Acetonitrile：Water=30:21:49
Buffer salt collocation method：10g ammonium carbonates are weighed in 1L volumetric flasks, adds after the dissolving of 800mL purified waters, is slowly added to 22mL perchloric acid, after bubble is not produced, is diluted to scale, and pH value is adjusted to 10.0 with ammoniacal liquor；
Detection wavelength：212nm
Column temperature：30℃
Flow velocity：1.0ml/min
Sample size：20μl
Sample concentration：10.0mg/ml (acetonitrile as solvents)
The preparation of the compound of 4 formula of embodiment VI
The chemical name of the compound of formula VI is [[(outside 3-) -8- methyl -8- azabicyclics [3.2.1] octane] -3- mercaptos 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, the cyclooctane -8- acetic acid esters of 9- propane -3aH- rings penta.
Gained oily solid (compound of formula V) in embodiment 3 and 1.33L 1,4- dioxane are added in 5L reaction bulbs Stirring and dissolving, cooling, (204g zinc chloride are dissolved in 797mL concentrated hydrochloric acids to the concentrated hydrochloric acid solution that less than 15 DEG C of insulation is added dropwise to zinc chloride In), about 1.5-2.0 hours completion of dropping, then be warming up to 20.0-30.0 DEG C react 1.0-1.5 hour, terminate reaction, addition 2.0L drinking water, stirring to reaction solution clarification；Dichloromethane is extracted twice, combined dichloromethane extract, 0.5kg anhydrous slufuric acids Sodium stirring is lower to be dried 2.0-4.0 hours；50.0-60.0 DEG C is concentrated under reduced pressure into cutout, adds the vacuum distillation of 100mL ethyl acetate extremely 260mL ethyl acetate is added after cutout, 50.0-60.0 DEG C of heating stirring dissolved clarification, insulation instills n-hexane (common 780mL), about 1.5-2.0 hours completion of dropping；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, suction filtration, filter cake is eluted with 50mL n-hexanes；Gained 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, insulation instills n-hexane (common 760mL), about 1.5-2.0 hours completion of dropping；Naturally drop Temperature has a large amount of white-yellowish solids to separate out 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, suction filtration, Filter cake is eluted with 50mL n-hexanes；Filter cake and 520mL methanol are added in tri- mouthfuls of vials of 2.0L, dissolved clarification is stirred at room temperature, rear drop Enter drinking water (common 520mL), about 2.0-3.0 hours completion of dropping separates out a large amount of off-white powders；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, and suction filtration, filter cake drinks water wash, vacuum with 50-100mL Dry (55-65 DEG C, -0.08~-0.09MPa) 6-8 hours, obtaining 124.8g white-yellowish solids, (Formula IV compound, Retapamulin is thick Product), HPLC purity 99.9%, from formula IV compound so far yield 48.2%.
The preparation of the Retapamulin highly finished product of embodiment 5
Formula IV compound 100.0g is dissolved in 700mL acetone, after solution is instilled in 4.0L purified waters at room temperature, about 1-2 Hour drop finishes, after be cooled to 0-10 DEG C, cooling crystallization 1-2 hour, suction filtration, 100mL purifying water washing filter cakes, 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%.
The Retapamulin structural identification data of embodiment 6
(1) mass spectrometric data：
Instrument：The API3000 of AB companies, ESI source, 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 diffractometers
By single crystal X-ray diffraction examining report, its analysis result is：It is final to determine that asymmetry unit stoichiometric equation is C30H47NO4S, it is 517.77 to calculate molecular weight, and this is completely the same for the data of 224452-66-8 compounds with CAS.Molecule is absolute Configuration is as follows：
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with The present invention is described in detail good embodiment, it will be understood by those within the art that, can be to skill of the invention Art scheme is modified or equivalent substitution, and without departing from the objective and scope of technical solution of the present invention, it all should cover at this Among the right of invention.

Claims (10)

1. a kind of intermediate for synthesizing Retapamulin, its structural formula is as shown in formula II：
2. the preparation method of intermediate described in claim 1, it is characterised in that occur rearrangement reaction life by Tiamulin or its salt Compound shown in an accepted way of doing sth II, Tiamulin structural formula is as shown in formula I；
3. preparation method according to claim 2, it is characterised in that the rearrangement reaction solvent for use be methanol, ethanol, One or more in dichloromethane, methyl tertiary butyl ether(MTBE), 1,4- dioxane and tetrahydrofuran.
4. the preparation method according to Claims 2 or 3, it is characterised in that the rearrangement reaction in trimethyl orthoformate and Inorganic acid effect is lower to be carried out, and the mol ratio of Tiamulin or its salt and orthoformate is 1:5-10.
5. the method for Retapamulin is prepared based on the intermediate described in claim 1, it is characterised in that including the step being carried out as follows Suddenly：
(1) the compound generation hydrolysis shown in formula II obtains the compound shown in formula III；
(2) compound shown in substitution reaction production IV occurs with chloracetyl chloride for the compound shown in formula III：
(3) compound shown in formula IV and hydrochloric acid it is outer-tropine -3- mercaptan instead gives birth to compound shown in substitution reaction production V：
(4) compound shown in rearrangement reaction production VI occurs for the compound shown in formula V, as the compound warp shown in formula VI Cross and be refining to obtain Retapamulin finished product：
6. the method according to claim 5 for preparing Retapamulin, it is characterised in that in step (1), the hydrolysis Hydrolyze in the basic conditions.
7. the method according to claim 5 for preparing Retapamulin, it is characterised in that in step (2), the substitution reaction Carry out in the presence of an organic base, the organic base is triethylamine, tri-n-butylamine, DMAP, pyridine and diisopropyl second One or more in amine, reaction solvent for use is selected from methyl tertiary butyl ether(MTBE), isopropyl ether, ether, tetrahydrofuran, methyl-isobutyl One or more in ketone, toluene, dichloromethane, ethyl acetate, butyl acetate and isopropyl acetate.
8. the method according to claim 5 for preparing Retapamulin, it is characterised in that in step (3), the substitution reaction In the presence of an inorganic base, carried out under phase transfer catalyst effect, the phase transfer catalyst is TBAB, the tetrabutyl Ammonium iodide, tetrabutylammonium chloride, benzyl triethyl ammonium bromide, benzyltriethylammoinium chloride, 4-butyl ammonium hydrogen sulfate, trioctylphosphine first One or more in ammonium chloride, DTAC and tetradecyl trimethyl ammonium chloride, reaction is used molten Agent is selected from methyl tertiary butyl ether(MTBE), isopropyl ether, ether, methyl iso-butyl ketone (MIBK), dichloromethane, ethyl acetate, butyl acetate and acetic acid One or more in isopropyl ester.
9. the method according to claim 5 for preparing Retapamulin, it is characterised in that in step (4), the rearrangement reaction Under strongly acidic conditions, carried out under Louis acid catalysis effect, the lewis acid is alchlor, ferric trichloride, chlorination One or more in zinc, antimony trifluoride and titanium tetrachloride, reaction solvent for use is selected from Isosorbide-5-Nitrae-dioxane, methanol, ethanol, second One or more in nitrile, acetone and glycol monoethyl ether.
10. the method according to claim 5 for preparing Retapamulin, it is characterised in that in step (4), shown in formula VI Compound is re-refined after solvent purification obtains Retapamulin finished product, and the solvent is ethyl acetate, isopropyl acetate, acetic acid One in butyl ester, n-hexane, normal heptane, methanol, ethanol, isopropanol, methanol aqueous solution, ethanol water and isopropanol water solution Plant or a variety of.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107860838A (en) * 2017-11-02 2018-03-30 重庆华邦胜凯制药有限公司 The method of HPLC method separation determination Retapamulins and its related substances

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007062332A2 (en) * 2005-11-18 2007-05-31 Glaxo Group Limited Novel intermediates and their use
JP2008280297A (en) * 2007-05-11 2008-11-20 Kyorin Pharmaceut Co Ltd 12-position heterosubstituted mutilin derivative
JP2009040709A (en) * 2007-08-08 2009-02-26 Kyorin Pharmaceut Co Ltd 12-substituted mutilin derivative
CN105916499A (en) * 2014-01-22 2016-08-31 纳布里瓦治疗股份公司 12-epi-pleuromutilins

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007062332A2 (en) * 2005-11-18 2007-05-31 Glaxo Group Limited Novel intermediates and their use
WO2007062332A3 (en) * 2005-11-18 2007-11-29 Glaxo Group Ltd Novel intermediates and their use
JP2008280297A (en) * 2007-05-11 2008-11-20 Kyorin Pharmaceut Co Ltd 12-position heterosubstituted mutilin derivative
JP2009040709A (en) * 2007-08-08 2009-02-26 Kyorin Pharmaceut Co Ltd 12-substituted mutilin derivative
CN105916499A (en) * 2014-01-22 2016-08-31 纳布里瓦治疗股份公司 12-epi-pleuromutilins

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
肖立: "瑞他妙林的合成", 《中国医药工业杂志》 *
黄火明: "瑞他莫林的合成", 《中国医药工业杂志》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107860838A (en) * 2017-11-02 2018-03-30 重庆华邦胜凯制药有限公司 The method of HPLC method separation determination Retapamulins and its related substances
CN107860838B (en) * 2017-11-02 2020-07-28 重庆华邦胜凯制药有限公司 Method for separating and measuring Retapamulin and related substances by HP L C method

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