CN106432017A - Synthesis method of valnemulin hydrochloride - Google Patents
Synthesis method of valnemulin hydrochloride Download PDFInfo
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- CN106432017A CN106432017A CN201610792861.7A CN201610792861A CN106432017A CN 106432017 A CN106432017 A CN 106432017A CN 201610792861 A CN201610792861 A CN 201610792861A CN 106432017 A CN106432017 A CN 106432017A
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- 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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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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Abstract
The invention discloses a synthesis method of valnemulin hydrochloride. The synthesis method comprises the following three steps: synthesis of dimethylcysteamine pleuromulin from pleuromulin, synthesis of D-valine dane salt from D-valine and synthesis of valnemulin hydrochloride from dimethylcysteamine pleuromulin and D-valine dane salt. The synthesis method has the advantages that lots of homogeneous reactions are adopted, the post-treatment method is simple, organic solvents can be recycled, the reaction yield and the product purity are high, safety and environment-friendliness are realized, the reaction is moderate, and thus, the method is very suitable for industrialized enlarged production; with the adoption of the method, the repeated washing step during D-valine hydrolysis and salt formation is omitted, the production operation is simplified, the labor intensity is reduced, the consumption of low-boiling-point ether solvents is greatly reduced, volatilization of the solvents is reduced, low pollution is caused, and the method is conducive to the health of workers and the safety of the environment.
Description
Technical field
The present invention relates to the synthetic method of a kind of diterpenoids antibiotic, particularly to the synthesis side of a kind of valnemulin hydrochloride
Method, belongs to technical field of medicine synthesis.
Background technology
Valnemulin hydrochloride (Valnemulin hydrochloride), belongs to pleuromulins (Valnemulin
Hydrochloride) semisynthetic antibiotics, its antimicrobial spectrum is relatively wide, antibacterial activity is very strong, to mycoplasma, bacterium and conveyor screw, as
Mycoplasma arthritidis, mycoplasma canis, MG, mycoplasma pneumoniae, streptococcus, Actinobacillus, Pasteurella, swine dysentery
Treponema and colon pili sample conveyor screw etc. all have good antibacterial activity, and have the spy that the off-drug period is short, toxicity is low
Point, is mainly used in the treatment of porcine mycoplasmal pneumonia, swine dysentery, hog middle inflammation and pig ileitis.1999, European Union ratified hydrochloric acid
Valnemulin is for prevention and treats the swine dysentery being caused by Brachyspira hyodysenteriae infection and is caused by mycoplasma pneumoniae infection
Porcine enzootic pneumonia, it is the medicine pre-mixing agent of first all Europe approval, and in January, 2004 is by European Union's approval prevention and controls
Treat the scorching ileitis with pig of hog middle.Valnemulin hydrochloride is initially utilized pleuromutilin by Sandoz company
(Pleuromutilin) being Material synthesis, Novartis Co., Ltd is made into pre-mixing agent, trade name thereafterExist
The listing of multiple countries, is widely used in veterinary clinic；Within 2008, Britain's veterinary drug allusion quotation has recorded valnemulin hydrochloride.
The chemical name of valnemulin hydrochloride is：[[2-[[(2R)-2-amino-3-methyl isophthalic acid-oxo butyl] amino]-1,
1-dimethyl ethyl] sulfenyl] acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-6-vinyl decahydro-5-hydroxyl-4,6,9,
10-tetramethyl-1-oxo-3a, 9-propyl alcohol-3aH-cyclopenta cyclo-octene-8-base ester hydrochloride, molecular formula is C31 hours 52N2O5S, molecular weight is 601.28, and proterties is white or yellowish amorphous powder, has strong hygroscopicity, is dissolved in water, ethanol,
In methyl tertiary butyl ether(MTBE) almost insoluble, fusing point is 174-177 DEG C.The chemical structural formula of valnemulin hydrochloride is：
The conventional synthesis process of valnemulin hydrochloride, is to use to carry out pleuromutilin and D-Val Deng's salt to joint
Becoming, its synthesis step mainly includes：(1) pleuromutilin is prepared dimethyl half light amine pleuromutilin, (2) D-Val Deng
The synthesis of salt, the synthesis of (3) valnemulin hydrochloride.Specifically, first with pleuromutilin as raw material, through paratoluensulfonyl chloride
Sulfonation is reacted with dimethyl cysteamine hydrochloride, generates dimethyl half light amine pleuromutilin, i.e. 14-O-[(1-amino-2-first
Base propane-2-base) mercapto acetyl group] nurse body woods；Dimethyl half light amine pleuromutilin is protected with amino again, carboxyl is activated
D-Val Deng's salt generation acylation reaction, after after hydrochloric acid deprotection generate valnemulin hydrochloride.
Chinese patent CN103382172A discloses the synthetic method of a kind of valnemulin hydrochloride, with pleuromutilin, two
Methyl cysteamine and D-Val are primary raw material, through amido protecting, pleuromutilin activation, hydrocarbylation, acylation and de-
Amido protectings etc. react, and finally prepare valnemulin hydrochloride.This synthetic method is suitable to industrialized production, is not necessarily in course of reaction
Crossing post to separate, solvent toxicity used is little and can recycle, and reaction condition is gentle, typically between 0～70 DEG C, and reaction
Total recovery is higher.But, it lower boiling t-butyl methyl ether is used for multiple times in this synthetic method as reaction dissolvent, especially step
In three (compound 21) last handling process, need to while hot the reactant after solvent evaporated be poured in lower boiling t-butyl methyl ether,
T-butyl methyl ether so can be caused seriously to volatilize, affect the healthy of operating personnel, also make the volatilization ether in operating environment
Content increases, and t-butyl methyl ether is not easily recycled applies mechanically, i.e. not environmentally, dangerous again.And, step 4 reaction is heterogeneous suspension
Reaction, the reaction time is long, and reaction is thorough not, thus causes the reaction yield of this step not high.
Content of the invention
The technical problem to be solved is the defect overcoming prior art, provides the conjunction of a kind of valnemulin hydrochloride
One-tenth method, the method step is simple, reaction is thorough, post processing uses callable low poison solvent, and yield significantly improves, green
Environmental protection.
Of the present invention technical problem is that with following technical proposals realize：
The synthetic method of a kind of valnemulin hydrochloride, comprises the following steps：
(1) synthesis of dimethyl half light amine pleuromutilin
Add pleuromutilin, oxolane and water in the flask equipped with dropping funel and condenser, the lower dropping of stirring
The tetrahydrofuran solution of paratoluensulfonyl chloride, drips the NaOH solution adding 10N after finishing；It is warming up to backflow, back flow reaction 1h, reaction
Liquid is that yellow is muddy, stops reaction；After filtration drying, obtain compound as white solid 12；
Compound the 12nd, dimethyl half light amine hydrochlorate and oxolane is added in flask, under 30 DEG C～40 DEG C stirrings,
The NaOH solution regulation pH value of addition benzyl tributyl ammonium chloride and 10N is 7～8, controls reaction temperature 40 ± 2 DEG C, acutely stirs
Mix；Then heat to 40 DEG C～45 DEG C to react 1 hour；It after reaction terminates, is diluted with water reactant liquor, then reactant liquor is cooled to 10
Filter after DEG C, be dried overnight after washing with the oxolane of water and 0～5 DEG C, obtain dimethyl half light amine pleuromutilin crude product；Two
Methyl half light amine pleuromutilin crude product Diethyl ether recrystallization；
(2) synthesis of D-Val Deng salt
Potassium hydroxide is dissolved in ethanol at 30～40 DEG C, then D-Val, methyl acetoacetate is added alcoholic lye
In, stir molten clear after in glassy yellow, be warming up to backflow, after back flow reaction 2h, the ethanol of 85%～95% be distilled off, obtain D-
The ethanol solution of valine Deng's salt；
(3) synthesis of valnemulin hydrochloride
Add oxolane in the ethanol solution of step 2 gained D-Val Deng's salt, after stirring and dissolving, add N-methyl
Morpholine, stirring borehole cooling is to less than 5 DEG C；Then the slow tetrahydrofuran solution instilling ethyl chloroformate in system, during instillation
System temperature is less than 5 DEG C, drips and finishes stirring 30min；The tetrahydrochysene furan of the dimethyl half light amine pleuromutilin that addition step 1 prepares
Muttering solution, continuing stirring reaction, reaction temperature is less than 20 DEG C；Use TLC monitoring reaction end after 2h, stop after reaction completely
Tetrahydrofuran solvent in reactant liquor is evaporated by stirring；
Add acetic acid ethyl dissolution to being evaporated in residue, molten clear rear addition distilled water；Under stirring at room temperature, 6N salt is instilled
Acid for adjusting pH to 1.0～1.2, then stratification, discard organic phase；Adding ethyl acetate in aqueous phase, quick stirring is lower to be used
10N sodium hydroxide solution regulates pH to 7, then uses 2N sodium hydroxide solution condition pH instead to 9.0～10.0, and stratification discards
Aqueous phase, washes organic phase, then adds distilled water and concentrated hydrochloric acid in organic phase, stand 30min, discarded after being stirred vigorously 2h
Machine phase, aqueous phase is freeze-dried, obtains the valnemulin hydrochloride of white powder.
When described step one prepares compound 12, pleuromutilin is 1 with the molar ratio of paratoluensulfonyl chloride：1.1,
The volume that feeds intake of oxolane is 1000mL/ every mol pleuromutilin, and the volume that feeds intake of water is that the every mol of 200mL/ truncates
Pleurin；In the tetrahydrofuran solution of described paratoluensulfonyl chloride, the addition volume of oxolane is that 400～500mL/ is every
Mol paratoluensulfonyl chloride；The NaOH solution addition of 10N is 200～250mL/ every mol pleuromutilin；
When described step one prepares dimethyl half light amine pleuromutilin, compound 12 and dimethyl half light amine hydrochlorate
Molar ratio is 1：1；The volume that feeds intake of oxolane is 1000～1200mL/ every mol compound 12, benzyl tributyl chlorine
The inventory changing ammonium is 25～30g/ every mol compound 12；Thinned water amount is 1.5 times of oxolane inventory.
In described step 2, D-Val, methyl acetoacetate, the molar ratio of potassium hydroxide are 1：0.8～1.2：
0.8～1.3, preferably 1：1.0～1.1：1.1～1.2；The volume inventory of ethanol is 30～40 times of potassium hydroxide quality,
It is preferably 32～36 times.
In described step 2, the moisture of ethanol used is not higher than 5%.
The raw material inventory of described step 3 with the D-Val Deng's salt content in the ethanol solution of D-Val Deng's salt is
Benchmark, D-Val Deng's salt content is converted according to conversion ratio 100% by step 2；Described D-Val Deng's salt and diformazan
The molar ratio of base half light amine pleuromutilin is 1：0.7～1.0；
The described oxolane volume adding in the ethanol solution of D-Val Deng's salt is 11～15mL/ every gD-figured silk fabrics
Propylhomoserin Deng；The volume that feeds intake of N-methylmorpholine is 0.4mL/ every gD-valine Deng's salt；The oxolane of described ethyl chloroformate
In solution, the volume that feeds intake of ethyl chloroformate is 0.5mL/ every gD-valine Deng's salt, and the volume that feeds intake of oxolane is chlorine
6～10 times of Ethyl formate volume；In the tetrahydrofuran solution of described dimethyl half light amine pleuromutilin, oxolane
The volume that feeds intake is 7～10mL/ every g dimethyl half light amine pleuromutilin.
In described step 3, the molar ratio of described D-Val Deng's salt and dimethyl half light amine pleuromutilin is 1：
0.7～0.8；For dissolving the ethyl acetate that the ethyl acetate volume of bottoms is residue quality 20～25 times, molten
The distilled water adding volume to be ethyl acetate volume half after clear；After separating through acid adjustment, add in aqueous phase and steam for the first time
The identical ethyl acetate of distilled water amount；After alkali tune separates, in organic phase, add the distilled water identical with the first distillation water yield.
First time acid adjustment process in described step 3, be first under room temperature quickly stirs with 6N hydrochloric acid adjust pH to 1.0～
1.2, it is then stirred vigorously 30min, repetition measurement pH；If pH rises, then adjust pH to 1.0～1.2 with 2N hydrochloric acid.
When becoming salt in described step 3, concentrated hydrochloric acid is 6N hydrochloric acid, and it adds mole is that dimethyl half light amine truncates and picks up the ears
Element feeds intake 1～1.2 times of mole.
The invention has the beneficial effects as follows：
The invention provides the synthetic method of a kind of novel valnemulin hydrochloride, make with pleuromutilin, D-Val
For primary raw material, concrete preparation process is optimized, final prepared high yield highly purified valnemulin hydrochloride product.Should
Synthetic method many employings homogeneous reaction, post-processing approach is simple, and organic solvent can realize that recycled, reaction yield and product are pure
Spend all very high, safety and environmental protection, it is especially suitable for industrial amplification production.Its advantage mainly includes：
(1) synthesis of D-Val Deng salt uses " one kettle way ", reaction dissolvent is replaced by ethanol, and has abandoned original
Topple over while hot, the low temperature post-processing approach such as crystallization for a long time, after reaction terminates, only go out major part ethanol by air-distillation, surplus
Remaining D-Val Deng's salt ethanol solution can carry out the next step directly as raw material；Course of reaction is back flow reaction, simply
Controlled, post processing uses air-distillation, industrial very easy realization.And, the ethanol distilling out can realize time use,
Decrease the usage amount of organic solvent, reduce production cost, decrease the generation amount of solvent slop, to more environment-friendly, more
The environmental protection adding.
(2) in the synthesis step of valnemulin hydrochloride, due to the addition of ethanol in D-Val Deng's salt ethanol solution, make
Reaction system is become homogeneous from heterogeneous, is greatly accelerated reaction speed, promotes that reaction is thoroughly carried out, thus when shortening reaction
Between, decrease the production of accessory substance, improve the yield of reaction and the quality of product.
(3) The present invention reduces D-Val hydrolysis and the cyclic washing step in salification process, simplify production operation,
Reduce labour intensity, shorten the production cycle.
(4) present invention greatly reduces the usage amount of low boiling ether solvent, reduces the volatilization of solvent, pollute little,
Be conducive to the health of workman and the safety of environment.
(5) the inventive method reaction condition is gentle, there is not excessive temperature and crosses the reaction of low temperature, and reaction temperature is easy
Control, energy consumption is low, and security is high.
(6) consersion unit of the present invention is conventional equipment, low cost, it is simple to safeguard and maintenance.
Brief description
Fig. 1 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 1 product.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail.
First, the synthesis of dimethyl half light amine pleuromutilin
Pleuromutilin (compound 11), oxolane and water is added in the flask equipped with dropping funel and condenser,
The lower tetrahydrofuran solution dripping paratoluensulfonyl chloride of stirring, drips the NaOH solution adding 10N after finishing；It is warming up to backflow, backflow
Stopping reaction after reacting 1 hour, reactant liquor is that yellow is muddy；After filtration drying, obtain white solid (compound 12).
Compound the 12nd, dimethyl half light amine hydrochlorate and oxolane is added in flask, under 30 DEG C～40 DEG C stirrings,
Add the NaOH solution of benzyl tributyl ammonium chloride and 10N, control reaction temperature 40 ± 2 DEG C, be stirred vigorously；Then heat to 40
DEG C～45 DEG C react 1 hour；After reaction terminates, be diluted with water reactant liquor, filter after then reactant liquor being cooled to 10 DEG C, with water and
It is dried overnight after the oxolane washing of 0～5 DEG C, obtain dimethyl half light amine pleuromutilin (intermediate I) crude product；By intermediate
I crude product ether recrystallizes, and obtains white dimethyl half light amine pleuromutilin finished product.
2nd, the synthesis of D-Val Deng salt
Potassium hydroxide is dissolved in ethanol under thermal condition, then by D-Val (compound 21), methyl acetoacetate
(compound 22) adds in alcoholic lye, stir molten clear after in glassy yellow, be warming up to backflow, after back flow reaction 2h, be distilled off absolutely
Major part ethanol, obtains the ethanol solution of D-Val Deng's salt (compound ii)；
3rd, the synthesis of valnemulin hydrochloride
Add oxolane in step 2 gained D-Val Deng's salt ethanol solution, after stirring and dissolving, add N-methyl
Quinoline, stirring borehole cooling is to less than 5 DEG C；Then the slow tetrahydrofuran solution instilling ethyl chloroformate in system, body during instillation
It is that temperature is less than 5 DEG C, drip and finish stirring 30min；The oxolane of the dimethylcysteamine pleuromutilin that addition step 1 prepares
Solution, continues stirring reaction, and reaction temperature is less than 20 DEG C；Use TLC monitoring reaction end after 2h, stop after reaction completely stirring
Mix, the tetrahydrofuran solvent in reactant liquor is evaporated；
Add acetic acid ethyl dissolution to being evaporated in residue, molten clear rear addition distilled water；Under room temperature quickly stirs, instill
6N salt acid for adjusting pH to 1.0～1.2, then stratification, discard organic phase；Add ethyl acetate in aqueous phase, quickly stir
Lower 10N sodium hydroxide solution regulates pH to 7, then uses 2N sodium hydroxide solution condition pH instead to 9.0～10.0, stratification,
Aqueous phase discarded, washes organic phase, then adds distilled water and concentrated hydrochloric acid in organic phase, stand 30min, abandon after being stirred vigorously 2h
Going organic phase, aqueous phase is freeze-dried, obtains the valnemulin hydrochloride (target product TM) of white powder.
In the examples below that, the raw material manufacturer being used and purity are as shown in the table, and remaining raw material is commercially available
Product.
In the examples below that, involved properties of product method of testing and test condition are as follows：
1st, the TLC detection method in step 3：
Solvent：Volume ratio is 7：The CHCl of 13/CH3OH mixed liquor；
Detection method：After extracting reaction solution, straight contact panel, observes after expansion under uviol lamp；Owing to intermediate I does not develops the color, when
On TLC plate, during immaculate, proved response is complete.
2nd, the content assaying method of valnemulin hydrochloride
1. chromatographic condition and system suitability test：With octadecylsilane check silica gel be filler (125mm ×
4.6mm, 3 μm), (take potassium dihydrogen phosphate 8.7g and disodium hydrogen phosphate 0.94g with acetonitrile-phosphate buffer (Ph=2.5), add
Water 1000mL makes dissolving, with phosphorus acid for adjusting pH value to 2.5) (43:57) for flowing phase；Column temperature 45 DEG C；Detection wavelength is 210nm,
Flow velocity is 1.2mL per minute, and number of theoretical plate is calculated by valnemulin hydrochloride peak and is not less than 3000.
2. assay method：Take this product appropriate, accurately weighed, dissolve and dilute to make with 50% acetonitrile solution and do not have in 1mL
The solution of hydrochloric valnemulin 0.8mg, precision measures 5 μ L and injects liquid chromatograph, and record chromatogram retains to principal component peak
3 times of time；Separately taking tartaric acid list hydrogen valnemulin reference substance appropriate, accurate Cheng Ding, is that solution dissolves and determines with 50% acetonitrile
The solution of the hydrogen of list containing tartaric acid valnemulin 1mg in every 1mL is made in amount dilution, is measured in the same method.Calculate peak area by external standard method, and
It is multiplied by 0.841, obtain C in test sample31H52N2O5The content of S HCl.
Embodiment 1
The synthetic method of a kind of valnemulin hydrochloride, specifically includes following steps：
(1) synthesis of dimethyl half light amine pleuromutilin
In the 500mL four-hole boiling flask equipped with agitator, thermometer, dropping funel and condenser, add compound 11
(75.7g, 0.2mol), 200mL oxolane, 40mL water, the tetrahydrofuran solution of the lower dropping paratoluensulfonyl chloride of stirring (will
The paratoluensulfonyl chloride of 42g, 0.22mol is dissolved in 100mL oxolane), drip the NaOH solution adding 50mL 10N after finishing；Will be anti-
Answering mixture to be heated to backflow, back flow reaction 1 hour, reactant liquor is that yellow is muddy, stops reaction；Filtering, filter cake is done in 75 DEG C
Dry, obtain white solid (compound 12) 96g, yield 90.1%.
In the 500mL there-necked flask equipped with agitator, add compound 12 (96g, 0.18mol), dimethyl half light amine salt
The tetrahydrofuran solution (25.5g, 0.18mol dimethyl half light amine hydrochlorate is dissolved in 200mL oxolane) of hydrochlorate, in 35 DEG C
Under stirring, add the NaOH solution of benzyl tributyl ammonium chloride 5g, 20mL 10N, adjust pH to be 7, be stirred vigorously at 40 DEG C；So
After be warming up to 40 DEG C～45 DEG C react 1 hour.After reaction terminates, add 300mL water dilute reaction solution, be subsequently cooled to 10 DEG C,
Stir 15 minutes at a temperature of this, filter, wash filter cake with water and cold oxolane (100mL × 2), be dried overnight in 55 DEG C,
Obtain 76g dimethyl half light amine pleuromutilin crude product, reaction yield 90.7%, fusing point 144.6 DEG C～146.7 DEG C.
Dimethyl half light amine pleuromutilin crude product Diethyl ether recrystallization, obtains 71.2g white solid, i.e. dimethyl half light amine
Pleuromutilin finished product, recrystallizes yield 85%, product fusing point 148.5 DEG C～149.5 DEG C.
(2) synthesis of D-Val Deng salt
36.6g (0.65mol) potassium hydroxide is dissolved at 30～40 DEG C 1250mL ethanol, then by 65g (0.55mol)
D-Val, 70.9g (0.61mol) methyl acetoacetate add in alcoholic lye, after stirring 10min molten clear after, in glassy yellow；Rise
Temperature, to backflow, after back flow reaction 2h, is distilled off 1100mL ethanol, and residue is the ethanol solution of D-Val Deng's salt.
Through conversion, the D-Val Deng's salt content in the ethanol solution of D-Val Deng's salt is 11.36g (44.79mmol).
(3) synthesis of valnemulin hydrochloride
Add 140mL oxolane in the ethanol solution of D-Val Deng's salt, after stirring and dissolving, add 4.8mL N-first
Base morpholine, stirring borehole cooling is to less than 5 DEG C；Then the slow tetrahydrofuran solution instilling ethyl chloroformate in system (will
5.6mL ethyl chloroformate is dissolved in 40mL oxolane), during instillation, system temperature is less than 5 DEG C, drips and finishes stirring 30min；Add step
The dimethylcysteamine of 16g, 34.37mmol (is cut by the tetrahydrofuran solution of the rapid 1 dimethylcysteamine pleuromutilin preparing
Short pleurin is dissolved in 120mL oxolane), continue stirring reaction, reaction temperature is less than 20 DEG C；Use TLC monitoring anti-after 2h
Answer terminal, stop stirring after reaction completely, the tetrahydrofuran solvent in reactant liquor is evaporated；
Add 500mL acetic acid ethyl dissolution to being evaporated in residue, molten clear rear addition 250mL distilled water；Quick in room temperature
Under stirring, instillation 6N salt acid for adjusting pH, to 1.0～1.2, consumes 6N hydrochloric acid 14mL altogether, is then stirred vigorously 30min, repetition measurement pH, use
A little 2N hydrochloric acid adjusts pH to 1.0～1.2；Stratification, discards organic phase, adds 250mL ethyl acetate, quickly stir in aqueous phase
Mix lower 10N sodium hydroxide solution regulation pH to 7, then use 2N sodium hydroxide solution condition pH instead to 9.0～10.0, stand point
Layer, aqueous phase discarded, by the water of 100mL*3 washing organic phase, then the organic phase after washing adds 250mL distilled water and
20mL concentrated hydrochloric acid, stands 30min after being stirred vigorously 2h, discards organic phase, and aqueous phase is freeze-dried, obtains the salt of white powder
Acid valnemulin 17.4g, yield 89.7%.
Through HPLC monitoring, the content of valnemulin hydrochloride product is 99.46%, and HPLC collection of illustrative plates is as shown in Figure 1.
Embodiment 2
The synthetic method of a kind of valnemulin hydrochloride, specifically includes following steps：
(1) synthesis of dimethyl half light amine pleuromutilin
In the 500mL four-hole boiling flask equipped with agitator, thermometer, dropping funel and condenser, add pleuromutilin
(133.5g, 0.3mol), 300mL oxolane, 60mL water, the tetrahydrofuran solution of the lower dropping paratoluensulfonyl chloride of stirring (will
The paratoluensulfonyl chloride of 63g, 0.33mol is dissolved in 150mL oxolane), it is subsequently adding the NaOH solution of 75mL 10N；Will reaction
Mixture is heated to reflux a hour, and reactant liquor is that yellow is muddy, stops reaction, filters, and filter cake, in 75 DEG C of dryings, obtains white solid
Body (compound 12) 145.0g, yield 90.7%.
In the 500mL there-necked flask equipped with agitator, add compound 12 (145.0g, 0.27mol), dimethyl half light amine
Hydrochloride (38.3g, 0.27mol) and 300mL oxolane, in 35 DEG C stirring under, add benzyl tributyl ammonium chloride 7.5g and
The NaOH solution of 30mL 10N, adjusts pH to be 8, controls reaction temperature 40 DEG C, be stirred vigorously；Then heat to 40 DEG C～45 DEG C, instead
Answer 1 hour.After reaction terminates, add 450mL water dilute reaction solution, reactant liquor be cooled to 10 DEG C, stir 15 minutes at this temperature,
Filtering, washing filter cake with water and cold oxolane (150mL × 2), 55 DEG C are dried overnight, and obtain 116g dimethyl half light amine and truncate
Pleurin crude product, reaction yield 92.3%, fusing point 144.6 DEG C～146.7 DEG C.
With ether, dimethyl half light amine pleuromutilin crude product is recrystallized, obtain 108.2g white solid, i.e. g diformazan
Base half light amine pleuromutilin finished product.Product fusing point 148.5 DEG C～149.5 DEG C, recrystallizes yield 86.1%.
(2) synthesis of D-Val Deng salt
33.6g (0.55mol) potassium hydroxide is dissolved in 1250mL ethanol at 30～40 DEG C, then by 70.1g
(0.60mol) D-Val, 63.9g (0.55mol) methyl acetoacetate add in alcoholic lye, after stirring 10min molten clear after, in
Glassy yellow；Being warming up to backflow, after back flow reaction 2h, 1100mL ethanol being distilled off, residue is the ethanol of D-Val Deng's salt
Solution；
Through conversion, the D-Val Deng's salt content in the ethanol solution of D-Val Deng's salt is 12.50g (49.25mmol).
(3) synthesis of valnemulin hydrochloride
Add 160mL oxolane in the ethanol solution of D-Val Deng's salt, after stirring and dissolving, add 5.0mL N-first
Base morpholine, stirring borehole cooling is to less than 5 DEG C；Then the slow tetrahydrofuran solution instilling ethyl chloroformate in system (will
6.3mL ethyl chloroformate is dissolved in 45mL oxolane), during instillation, system temperature is less than 5 DEG C, drips and finishes stirring 30min；Add step
The tetrahydrofuran solution of the rapid 1 dimethyl half light amine pleuromutilin preparing is (by the dimethyl half light amine of 17.5g, 37.60mmol
Pleuromutilin is dissolved in 120mL oxolane), continue stirring reaction, reaction temperature is less than 20 DEG C；TLC is used to monitor after 2h
Reaction end, stops stirring, is evaporated the tetrahydrofuran solvent in reactant liquor after reaction completely；
Add 600mL acetic acid ethyl dissolution to being evaporated in residue, molten clear rear addition 350mL distilled water；Quick in room temperature
Under stirring, instillation 6N salt acid for adjusting pH, to 1.0～1.2, consumes 6N hydrochloric acid 14.4mL altogether, is then stirred vigorously 30min, repetition measurement pH,
Adjust pH to 1.0～1.2 with a little 2N hydrochloric acid；Stratification, discards organic phase, adds 350mL ethyl acetate, quickly in aqueous phase
The lower 10N sodium hydroxide solution of stirring regulates pH to 7, then uses 2N sodium hydroxide solution condition pH instead to 9.0～10.0, stands point
Layer, aqueous phase discarded, by the water of 100mL*3 washing organic phase, then the organic phase after washing adds 350mL distilled water and
20mL concentrated hydrochloric acid, stands 30min after being stirred vigorously 2h, discards organic phase, and aqueous phase is freeze-dried, obtains the salt of white powder
Acid valnemulin 19.4g, yield 90.5%.
Through HPLC monitoring, the content of valnemulin hydrochloride product is 99.26%.
Embodiment 3
The synthetic method of a kind of valnemulin hydrochloride, specifically includes following steps：
(1) synthesis of dimethyl half light amine pleuromutilin
In the 500mL four-hole boiling flask equipped with agitator, thermometer, dropping funel and condenser, add pleuromutilin
(75.7g, 0.2mol), 200mL oxolane, 40mL water, the tetrahydrofuran solution of the lower dropping paratoluensulfonyl chloride of stirring (will
The paratoluensulfonyl chloride of 42g, 0.22mol is dissolved in 100mL oxolane), it is subsequently adding the NaOH solution of 50mL 10N；Will reaction
Mixture is heated to reflux a hour, and reactant liquor is that yellow is muddy, stops reaction, filters, and filter cake, in 75 DEG C of dryings, obtains white solid
Body (compound 12) 96g, yield 90.1%.
In the 500mL there-necked flask equipped with agitator, add compound 12 (96g, 0.18mol), dimethyl half light amine salt
Hydrochlorate (25.5g, 0.18mol) and 200mL oxolane, under 35 DEG C of stirrings, add benzyl tributyl ammonium chloride 5g and 20mL
The NaOH solution of 10N, adjusts pH to be 7.5, controls 40 DEG C, be stirred vigorously；Then heat to 40 DEG C～45 DEG C, react 1 hour.Reaction
After end, add 300mL water dilute reaction solution, be then cooled to 10 DEG C, stir 15 minutes at this temperature, filter, with water and cold
Oxolane (100mL × 2) washs filter cake, and 55 DEG C are dried overnight, and obtain 76g dimethyl half light amine pleuromutilin crude product, reaction
Yield 90.7%, crude product fusing point 144.6 DEG C～146.7 DEG C.
With ether, dimethyl half light amine pleuromutilin crude product is recrystallized, obtain 71.2g white solid, i.e. dimethyl
Half light amine pleuromutilin finished product.Finished product fusing point 148.5 DEG C～149.5 DEG C, recrystallizes yield 85%.
(2) synthesis of D-Val Deng salt
25.4g (0.45mol) potassium hydroxide is dissolved in 1000mL ethanol at 30～40 DEG C, then by 47.3g
(0.4mol) D-Val, 40.7g (0.35mol) methyl acetoacetate add in alcoholic lye, after stirring 10min molten clear after, in
Glassy yellow；Being warming up to backflow, after back flow reaction 2h, 900mL ethanol being distilled off, residue is that the ethanol of D-Val Deng's salt is molten
Liquid；
Through conversion, the D-Val Deng's salt content in the ethanol solution of D-Val Deng's salt is 8.26g (32.57mmol).
(3) synthesis of valnemulin hydrochloride
Add 120mL oxolane in the ethanol solution of D-Val Deng's salt, after stirring and dissolving, add 3.5mL N-first
Base morpholine, stirring borehole cooling is to less than 5 DEG C；Then the slow tetrahydrofuran solution instilling ethyl chloroformate in system (will
4.2mL ethyl chloroformate is dissolved in 40mL oxolane), during instillation, system temperature is less than 5 DEG C, drips and finishes stirring 30min；Add step
The tetrahydrofuran solution of the rapid 1 dimethyl half light amine pleuromutilin preparing is (by the dimethyl half light amine of 6.2g, 13.31mmol
Pleuromutilin is dissolved in 46.5mL oxolane), continue stirring reaction, reaction temperature is less than 20 DEG C；TLC is used to monitor after 2h
Reaction end, stops stirring, is evaporated the tetrahydrofuran solvent in reactant liquor after reaction completely；
Add 500mL acetic acid ethyl dissolution to being evaporated in residue, molten clear rear addition 250mL distilled water；Quick in room temperature
Under stirring, instillation 6N salt acid for adjusting pH, to 1.0～1.2, consumes 6N hydrochloric acid 9.7mL altogether, is then stirred vigorously 30min, repetition measurement pH, use
A little 2N hydrochloric acid adjusts pH to 1.0～1.2；Stratification, discards organic phase, adds 250mL ethyl acetate, quickly stir in aqueous phase
Mix lower 10N sodium hydroxide solution regulation pH to 7, then use 2N sodium hydroxide solution condition pH instead to 9.0～10.0, stand point
Layer, aqueous phase discarded, by the water of 100mL*3 washing organic phase, then the organic phase after washing adds 250mL distilled water and
14.2mL concentrated hydrochloric acid, stands 30min after being stirred vigorously 2h, discards organic phase, and aqueous phase is freeze-dried, obtains white powder
Valnemulin hydrochloride 12.5g, yield 88.6%.
Through HPLC monitoring, the content of valnemulin hydrochloride product is 99.28%.
Embodiment 4
The synthetic method of a kind of valnemulin hydrochloride, specifically includes following steps：
(1) synthesis of dimethyl half light amine pleuromutilin
In the 500mL four-hole boiling flask equipped with agitator, thermometer, dropping funel and condenser, add pleuromutilin
(75.7g, 0.2mol), 200mL oxolane, 40mL water, the tetrahydrofuran solution of the lower dropping paratoluensulfonyl chloride of stirring (will
42g, 0.22mol paratoluensulfonyl chloride is dissolved in 100mL oxolane), it is subsequently adding the NaOH solution of 50mL 10N.Reaction is mixed
Compound is heated to reflux a hour, and reactant liquor is that yellow is muddy, stops reaction, filters, and filter cake, in 75 DEG C of dryings, obtains white solid
(compound 12) 96g, yield 90.1%.
In the 500mL there-necked flask equipped with agitator, add compound 12 (96g, 0.18mol), dimethyl half light amine salt
Hydrochlorate (25.5g, 0.18mol) and 200mL oxolane, under 35 DEG C of stirrings, add benzyl tributyl ammonium chloride 5g and 20mL
The NaOH solution of 10N, adjusts pH to be 7, controls 40 DEG C and be stirred vigorously.Then heat to 40 DEG C～45 DEG C, react 1 hour.Reaction knot
Add 300mL water dilute reaction solution after bundle, be then cooled to 10 DEG C, stir 15 minutes at this temperature, filter, with water and cold tetrahydrochysene
Furans (100mL × 2) washs filter cake, and 55 DEG C are dried overnight, and obtain 76g dimethyl half light amine pleuromutilin crude product, reaction yield
90.7%, crude product fusing point 144.6 DEG C～146.7 DEG C.
With ether, dimethyl half light amine pleuromutilin crude product is recrystallized, obtain 71.2g white solid, i.e. dimethyl
Half light amine pleuromutilin finished product.Finished product fusing point 148.5 DEG C～149.5 DEG C, recrystallizes yield 85%.
(2) synthesis of D-Val Deng salt
35.4g (0.63mol) potassium hydroxide is dissolved in 1100mL ethanol at 30～40 DEG C, then by 82.7g
(0.7mol) D-Val, 84.5g (0.77mol) methyl acetoacetate add in alcoholic lye, after stirring 10min molten clear after, in
Glassy yellow；Being warming up to backflow, after back flow reaction 2h, 950mL ethanol being distilled off, residue is that the ethanol of D-Val Deng's salt is molten
Liquid；
Through conversion, the D-Val Deng's salt content in the ethanol solution of D-Val Deng's salt is 14.46g (57.00mmol).
(3) synthesis of valnemulin hydrochloride
Add 210mL oxolane in the ethanol solution of D-Val Deng's salt, after stirring and dissolving, add 5.8mL N-first
Base morpholine, stirring borehole cooling is to less than 5 DEG C；Then the slow tetrahydrofuran solution (7.2mL instilling ethyl chloroformate in system
Ethyl chloroformate+50mL oxolane), during instillation, system temperature is less than 5 DEG C, drips and finishes stirring 30min；Add dimethyl half light amine
The dimethyl half light amine pleuromutilin of 21.23g, 45.6mmol (is dissolved in 180mL tetra-by the tetrahydrofuran solution of pleuromutilin
Hydrogen furans), continue stirring reaction, reaction temperature is less than 20 DEG C；Use TLC monitoring reaction end after 2h, stop after reaction completely
Only the tetrahydrofuran solvent in reactant liquor is evaporated by stirring；
Add 750mL acetic acid ethyl dissolution to being evaporated in residue, molten clear rear addition 375mL distilled water；Quick in room temperature
Under stirring, instillation 6N salt acid for adjusting pH, to 1.0～1.2, consumes 6N hydrochloric acid 18mL altogether, is then stirred vigorously 30min, repetition measurement pH, use
A little 2N hydrochloric acid adjusts pH to 1.0～1.2；Stratification, discards organic phase, adds 375mL ethyl acetate, quickly stir in aqueous phase
Mix lower 10N sodium hydroxide solution regulation pH to 7, then use 2N sodium hydroxide solution condition pH instead to 9.0～10.0, stand point
Layer, aqueous phase discarded, by the water of 100mL*3 washing organic phase, then the organic phase after washing adds 375mL distilled water and
27mL concentrated hydrochloric acid, stands 30min after being stirred vigorously 2h, discards organic phase, and aqueous phase is freeze-dried, obtains the salt of white powder
Acid valnemulin 22.14g, yield 89.8%.
Through HPLC monitoring, the content of valnemulin hydrochloride product is 99.32%.
Embodiment 5
The present embodiment is that embodiment applied mechanically by the ethanol in step 2.
The ethanol distilling out in step 2 is overlapped repeatedly and is used for step 2, the receipts of monitoring ethanol moisture and D-Val Deng's salt
Rate and quality.Selecting with a batch of raw material, inventory is all similar with the step 2 in embodiment 1 with reaction method, its district
It is not：After back flow reaction terminates, reactant liquor is evaporated, obtains D-Val Deng's salt of solid-state；And D-Val Deng's salt is produced
Product carry out weighing and content detection.Gained D-Val Deng's product salt carries out valnemulin hydrochloride (TM) after the dissolving of quantitative ethanol
Synthesis, to monitor ethanol moisture, the quality of follow-up workshop section product is affected；Inventory and reaction method all with in embodiment 1
Step 3 is identical；The dimethyl half light amine pleuromutilin using during synthetic hydrochloric acid valnemulin is same batch products.
Experimental data is as shown in the table.
By data in upper table it can be seen that as the increase of number of times applied mechanically by ethanol, in ethanol, moisture is gradually increased；Work as second
After in alcohol, moisture is more than 5%, the yield of finished product valnemulin hydrochloride starts substantially to reduce.Time is with rear D-Val Deng
Though salt sample size has decline, but inconspicuous, but the color of D-Val Deng's salt sample has started to change.When in ethanol, moisture is big
After 5%, the yield of finished product valnemulin hydrochloride starts to reduce, and product content is decreased obviously.For ensureing that product hydrochloric acid is irrigated
The quality of the wonderful woods of Buddhist nun, ethanol is after time, and moisture is not higher than 5% and is advisable.The ethanol warp no longer applied mechanically after time
Reach after recycling after ethanol quality standard as new ethanol for production.
Claims (9)
1. the synthetic method of a valnemulin hydrochloride, it is characterised in that comprise the following steps：
(1) synthesis of dimethyl half light amine pleuromutilin
Adding pleuromutilin, oxolane and water in the flask equipped with dropping funel and condenser, the lower dropping of stirring is to first
The tetrahydrofuran solution of benzene sulfonyl chloride, drips the NaOH solution adding 10N after finishing；Be warming up to backflow, back flow reaction 1h, reactant liquor in
Yellow is muddy, stops reaction；After filtration drying, obtain compound as white solid 12；
Add compound the 12nd, dimethyl half light amine hydrochlorate and oxolane in flask, under 30 DEG C～40 DEG C stirrings, add
The NaOH solution regulation pH value of benzyl tributyl ammonium chloride and 10N is 7～8, controls reaction temperature 40 ± 2 DEG C, is stirred vigorously；So
After be warming up to 40 DEG C～45 DEG C react 1 hour；It after reaction terminates, is diluted with water reactant liquor, after then reactant liquor being cooled to 10 DEG C
Filter, be dried overnight after washing with the oxolane of water and 0～5 DEG C, obtain dimethyl half light amine pleuromutilin crude product；Dimethyl
Half light amine pleuromutilin crude product Diethyl ether recrystallization；
(2) synthesis of D-Val Deng salt
Potassium hydroxide is dissolved in ethanol at 30～40 DEG C, then adds D-Val, methyl acetoacetate in alcoholic lye, stir
Mix molten clear after in glassy yellow, be warming up to backflow, after back flow reaction 2h, the ethanol of 85%～95% be distilled off, obtain D-figured silk fabrics ammonia
The ethanol solution of acid Deng's salt；
(3) synthesis of valnemulin hydrochloride
Add oxolane in the ethanol solution of step 2 gained D-Val Deng's salt, after stirring and dissolving, add N-methylmorpholine,
Stirring borehole cooling is to less than 5 DEG C；Then the slow tetrahydrofuran solution instilling ethyl chloroformate in system, system temperature during instillation
Degree is less than 5 DEG C, drips and finishes stirring 30min；The oxolane of the dimethyl half light amine pleuromutilin that addition step 1 prepares is molten
Liquid, continues stirring reaction, and reaction temperature is less than 20 DEG C；Use TLC monitoring reaction end after 2h, stop after reaction completely stirring
Mix, the tetrahydrofuran solvent in reactant liquor is evaporated；
Add acetic acid ethyl dissolution to being evaporated in residue, molten clear rear addition distilled water；Under stirring at room temperature, instill 6N hydrochloric acid to adjust
Joint pH to 1.0～1.2, then stratification, discard organic phase；Adding ethyl acetate in aqueous phase, quick stirring is lower uses 10N hydrogen
Sodium hydroxide solution regulates pH to 7, then uses 2N sodium hydroxide solution condition pH instead to 9.0～10.0, stratification, aqueous phase discarded,
Washing organic phase, then adds distilled water and concentrated hydrochloric acid in organic phase, stands 30min, discard organic phase after being stirred vigorously 2h,
Aqueous phase is freeze-dried, obtains the valnemulin hydrochloride of white powder.
2. the synthetic method of a kind of valnemulin hydrochloride according to claim 1, it is characterised in that prepared by described step one
During compound 12, pleuromutilin is 1 with the molar ratio of paratoluensulfonyl chloride：1.1, the volume that feeds intake of oxolane is
1000mL/ every mol pleuromutilin, the volume that feeds intake of water is 200mL/ every mol pleuromutilin；Described paratoluensulfonyl chloride
Tetrahydrofuran solution in, the addition volume of oxolane is 400～500mL/ every mol paratoluensulfonyl chloride；The NaOH of 10N
Solution addition is 200～250mL/ every mol pleuromutilin；
When described step one prepares dimethyl half light amine pleuromutilin, compound 12 feeds intake with dimethyl half light amine hydrochlorate
Mol ratio is 1：1；The volume that feeds intake of oxolane is 1000～1200mL/ every mol compound 12, benzyl tributyl ammonium chloride
Inventory be 25～30g/ every mol compound 12；Thinned water amount is 1.5 times of oxolane inventory.
3. the synthetic method of a kind of valnemulin hydrochloride according to claim 1, it is characterised in that in described step 2,
D-Val, methyl acetoacetate, the molar ratio of potassium hydroxide are 1：0.8～1.2：0.8～1.3, the volume of ethanol is thrown
Doses is 30～40 times of potassium hydroxide quality.
4. the synthetic method of a kind of valnemulin hydrochloride according to claim 3, it is characterised in that described D-Val,
Methyl acetoacetate, the molar ratio of potassium hydroxide are 1：1.0～1.1：1.1～1.2；The volume inventory of ethanol is hydrogen-oxygen
Change potassium quality 32～36 times.
5. the synthetic method of a kind of valnemulin hydrochloride according to claim 1, it is characterised in that institute in described step 2
It is not higher than 5% by the moisture of ethanol.
6. the synthetic method according to a kind of valnemulin hydrochloride described in claim 1, it is characterised in that the raw material of described step 3
On the basis of D-Val Deng's salt content in the ethanol solution of D-Val Deng's salt for the inventory, D-Val Deng's salt content passes through
Step 2 is converted according to conversion ratio 100%；Feeding intake of described D-Val Deng's salt and dimethyl half light amine pleuromutilin
Mol ratio is 1：0.7～1.0；
The described oxolane volume adding in the ethanol solution of D-Val Deng's salt is 11～15mL/ every gD-valine
Deng；The volume that feeds intake of N-methylmorpholine is 0.4mL/ every gD-valine Deng's salt；The tetrahydrofuran solution of described ethyl chloroformate
In, the volume that feeds intake of ethyl chloroformate is 0.5mL/ every gD-valine Deng's salt, and the volume that feeds intake of oxolane is chloro-carbonic acid
6～10 times of ethyl ester volume；In the tetrahydrofuran solution of described dimethyl half light amine pleuromutilin, feeding intake of oxolane
Volume is 7～10mL/ every g dimethyl half light amine pleuromutilin.
7. the synthetic method of a kind of valnemulin hydrochloride according to claim 6, it is characterised in that in described step 3,
The molar ratio of described D-Val Deng's salt and dimethyl half light amine pleuromutilin is 1：0.7～0.8；For dissolving distillation
The ethyl acetate volume of residue is the ethyl acetate of residue quality 20～25 times, and molten clear rear addition volume is ethyl acetate
The distilled water of volume half；After separating through acid adjustment, in aqueous phase, add the ethyl acetate identical with the distillation water yield for the first time；Adjust
After alkali separates, in organic phase, add the distilled water identical with the first distillation water yield.
8. the synthetic method of a kind of valnemulin hydrochloride according to claim 1, it is characterised in that in described step 3
Acid adjustment process for the first time, is first to adjust pH to 1.0～1.2 with 6N hydrochloric acid under room temperature quickly stirs, is then stirred vigorously 30min,
Repetition measurement pH；If pH rises, then adjust pH to 1.0～1.2 with 2N hydrochloric acid.
9. the synthetic method of a kind of valnemulin hydrochloride according to claim 1, it is characterised in that become in described step 3
During salt, concentrated hydrochloric acid is 6N hydrochloric acid, and it adds mole is that dimethyl half light amine pleuromutilin feeds intake 1～1.2 times of mole.
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| CN101597248A (en) * | 2009-07-10 | 2009-12-09 | 河北远征药业有限公司 | The preparation method of valnemulin and hydrochloride thereof |
| CN101735123A (en) * | 2009-12-22 | 2010-06-16 | 山东胜利股份有限公司 | Method for synthesizing valnemulin hydrochloride |
| CN102675173A (en) * | 2012-04-28 | 2012-09-19 | 湖北启达药业有限公司 | Chemical synthesis method of valnemulin hydrochloride |
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| CN101597248A (en) * | 2009-07-10 | 2009-12-09 | 河北远征药业有限公司 | The preparation method of valnemulin and hydrochloride thereof |
| CN101735123A (en) * | 2009-12-22 | 2010-06-16 | 山东胜利股份有限公司 | Method for synthesizing valnemulin hydrochloride |
| CN102675173A (en) * | 2012-04-28 | 2012-09-19 | 湖北启达药业有限公司 | Chemical synthesis method of valnemulin hydrochloride |
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