CN103382172A - Synthesis method for valnemulin hydrochloride - Google Patents
Synthesis method for valnemulin hydrochloride Download PDFInfo
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Abstract
The invention discloses a synthesis method for valnemulin hydrochloride. The synthesis method comprises the steps: with pleuromutilin, dimethyl cysteamine and D-valine as main raw materials, carrying out amino protection, pleuromutilin activation, hydrocarbylation, acylation and deamination protection reactions, and ultimately preparing to obtain valnemulin hydrochloride. The synthesis method is suitable for industrialized production, and has the main advantages that: 1, during the reaction process and without need of column separation, valnemulin hydrochloride with higher content is obtained; 2, a used solvent has small toxicity, can also be recycled, does not pollute the environment, and is suitable for industrialized production; 3, a reaction condition is mild and is generally between 0-70 DEG C, and higher temperature and lower temperature reactions does not exist; and 4, the total yield is higher and reaches 50% or more.
Description
Technical field
The present invention relates to a kind of synthetic method of valnemulin hydrochloride, belong to the organic synthesis field.
Background technology
Valnemulin hydrochloride (Valnemulin Hydrochloride, tie loose formula as follows) belong to the s-generation pleuromulins of animal specific, at first developed by Sandoz company in 1984, its antimicrobial spectrum is wider, to mycoplasma and multiple gram-positive microorganism, as suis, golden Portugal bacterium, actinobacillus etc. have good anti-microbial activity, In Vitro Bacteriostasis effect be safe second rhzomorph 10-100 doubly, and bioavailability is near 100%.1999, the hydrochloride of fertile Buddhist nun woods second was ratified by the European Community, was used for prevention or treated swine dysentery Brachyspira (Brachyspira hyodysenteriae) and infect the swine dysentery that causes and the porcine enzootic pneumonia that is caused by mycoplasma pneumoniae infection.It is the veterinary drug pre-mixture of first all Europe approval, is listed in prescription drugs for animals.Be used for the treatment of diarrhea of pigs and enteritis in Poland, Hungary's listing in 2000.This medicine is widely used in the whole world at present, and is recommended as by the expert that raises pigs the choice drug of controlling the porcine mycoplasmal infection.Be approved as prevention by the European Community in January, 2004 and infected the hog middle spirochetosis that causes by colon pili sample Brachyspira.Nearest studies show that, the chronic acute gastritis that fertile Buddhist nun woods second causes helicobacter pylori (Helicobacter pylori), peptide ulceration, gland cancer, cystic polyp etc. also have therapeutic action preferably, can be used for the medicine of above disease treatment or prepayment.In addition, nearest correlative study shows, irrigates Buddhist nun woods second and can effectively treat the mycoplasma infection with antibiotics resistance that the immunocompromised sufferer occurs.
The valnemulin hydrochloride molecular structural formula
The synthetic general step of valnemulin hydrochloride is mainly: at first with the hydroxyl tosylation of pleuromutilin C22; be easy to leave away when making the hydrochloride of itself and dimethyl cysteamine carry out nucleophilic reaction; thereby generate important intermediate-14-O-[(1-amino-2-methyl propane-2-yl) the mercapto ethanoyl] nurse body woods; then this compound and amido protecting D-Val through acylation reaction, finally by generating valnemulin hydrochloride after the hydrochloric acid deprotection.Synthetic valnemulin hydrochloride infared spectrum, 1H and 13CNMR collection of illustrative plates are seen respectively shown in accompanying drawing 1, accompanying drawing 2 and accompanying drawing 3.
Most pleuromulins compounds synthetic is all to carry out tosic acid in the C22 position, carries out the synthetic of next step after forming good leavings group again, therefore reports more to this step reaction both at home and abroad.(Y. 2012 for Wang, X. Ling according to domestic related journals (Feng Dexin, Li Xinle etc., 2010) and external patent or periodical report; Zhang Y. Y., Xu K. P., 2010; US 7612103B2) generally the reaction times is longer, and condition is comparatively harsh.
Summary of the invention
The technical problem to be solved in the present invention is to overcome existing defective, provides a kind of.
Purpose of the present invention is come specific implementation by the following technical programs:
A kind of synthetic method of valnemulin hydrochloride specifically comprises the steps,
Step 1: at t-butyl methyl ether and the H of pleuromutilin
2In the O mixture, add the Tosyl chloride with the pleuromutilin equimolar amount, then dripping concentration is the NaOH solution of 30-50wt%, under refluxad vigorous stirring, react 20-80min, generates a large amount of white solid matter, after filtration, the product that generates is cooled under room temperature, washs respectively with large water gaging and t-butyl methyl ether, get the 22-O-(4-tosyl group) oxygen ethanoyl nurse body woods;
Step 2: the dimethyl cysteamine hydrochloride that adds in the ethanolic soln of 1-2 wt % sodium ethylate, react 30-90min under room temperature, reaction system is cooled to 2-5
oAfter C, add by the synthetic 14-O-[(1-amino-2-methyl propane of step 1-2-yl) the mercapto ethanoyl] nurse body woods, stir 2-3h, decompression steams ethanol, adds ethyl acetate and distilled water, washing, separation, organic phase adds saturated NH again
4The Cl solution washing after separating two-phase, the most of ethyl acetate of underpressure distillation, gets 14-O-[(1-amino-2-methyl propane-2-yl) the mercapto ethanoyl] nurse body woods;
Step 3: solid KOH, D-Val, methyl acetoacetate are mixed, added benzene or refluxing toluene 3-4 hour, after reaction with the benzene evaporate to dryness, the solid matter of gained is poured in t-butyl methyl ether, stir 1-1.5h, filter, also use the t-butyl methyl ether flush cake, namely get the D-Val potassium methide.
step 4: the D-Val potassium methide of step 3 gained is suspended in methylene dichloride, add N-methylmorpholine, be cooled to 0 ℃ of left and right with ice cube, slowly drip the methylene dichloride that contains isobutyl chlorocarbonate, stir the 14-O-[(1-amino-2-methyl propane that adds again the step 2 gained after 30min-2-yl) the mercapto ethanoyl] nurse body woods, after reaction 1h, the evaporate to dryness methylene dichloride, add t-butyl methyl ether and distilled water, drip HCl under the condition that stirs again and transfer pH to 2, then continue approximately 4-5h of stirring at room, separate, water washs with t-butyl methyl ether, and then add t-butyl methyl ether, transfer pH to 8-9 with NaOH, stir 20min, then separate two-phase, organic phase is washed 2 times with distilled water, add again distilled water, drip HCl and transfer pH to 2-3, stir 15min, after separating two-phase, water namely gets valnemulin hydrochloride with the vacuum drying oven evaporate to dryness.
Preferably, in described step 1, described pleuromutilin: t-butyl methyl ether: NaOH solution is 1mmol:0.8-2mL:0.15-0.25mL:0.25-0.5mL, and the best is 1mmol:1mL:0.2mL:0.3mL.
The concentration of described NaOH solution is preferably 40wt%.
Preferably; in described step 2; described dimethyl cysteamine hydrochloride: the ethanolic soln of sodium ethylate: 14-O-[(1-amino-2-methyl propane-2-yl) mercapto ethanoyl] nurse body woods is 1mmol: 8-10mL:1-1.1 mmol, the best is 1mmol:10mL:1.1mmol.
Preferably, in described step 3, described D-Val: KOH: methyl acetoacetate: benzene or toluene are 1mmol: 65-70mg:1.1-1.3mL:1.5-2mL, and the best is 1mmol:65mg:1.2mmol:1.8mL.
Preferably, in described step 4, described D-Val: methylene dichloride: N-methylmorpholine: isobutyl chlorocarbonate (being dissolved in a small amount of dichloromethane solution): 14-O-[(1-amino-2-methyl propane-2-yl) mercapto ethanoyl] nurse body woods is 1mmol: 10-15mL:1-1.5mmoL:1-1.5mmoL:0.8-1mmol, the best is 1mmol:15mL:1.2mmol:1.2mmol:1mmol, the each consumption of described t-butyl methyl ether (consumption when comprising washing) is the t-butyl methyl ether of every mmole D-Val with 15-20mL, preferred 20mL;
The concentration of the dichloromethane solution of described isobutyl chlorocarbonate is 20-25mg/mL.
Preferably, in described step 2, described ethyl acetate consumption is every mmole dimethyl cysteamine hydrochloride 5-8mL ethyl acetate.
The synthetic method of valnemulin hydrochloride provided by the present invention; take pleuromutilin, dimethyl cysteamine and D-Val as main raw material; through reactions such as amido protecting, pleuromutilin activation, hydrocarbylation, acylations and deaminizating protections, finally prepare valnemulin hydrochloride.This synthetic method is suitable for suitability for industrialized production, and its advantage mainly contains:
Need not post in reaction process and separated, namely obtain the higher valnemulin hydrochloride of content;
It is clear and definite that valnemulin has Antibacterial Mechanism, anti-microbial activity is extremely strong, toxicity is little, without three cause, residual low, on immunity system without advantages such as impacts, be the efficient novel animal specific microbiotic of a kind of sensitivity of the diseases such as control chronic respiratory disease, mycoplasma pneumonia of swine, actinomycetes property pleuropneumonia, swine dysentery, hog middle inflammation, pig Proliferative Enteritis, have broad application prospects in veterinary clinic at home.Therefore, the present invention will have very high using value.
Synthetic methyl tertiary butyl ether and the NaOH solution of utilizing of pleuromulins compound of the present invention just reacts complete at 40-50 ℃ of reaction 20min, and condition is convenient, and yield is higher, reaches 97.8%.
In the valnemulin hydrochloride building-up reactions, the single step reaction of most critical is 14-O-[(1-amino-2-methyl propane-2-yl) the mercapto ethanoyl] nurse body woods and amido protecting D-Val form amido linkage.Amido linkage be formed with multi-method, wherein mixed anhydride method is the most economical, and yield is higher, but has the shortcoming of easy racemization.According to document (US, 5164526 etc.) solvent that utilizes is t-butyl methyl ether, utilizes Vinyl chloroformate to be raw material, has that yield is lower, the problem of easy racemization, the present invention utilize methylene dichloride for solvent, utilize isobutyl chlorocarbonate to be raw material, make reaction yield improve significantly to 82% left and right.In addition; utilize the time of HCl hydrolysis to be generally 2h in prior art; by the qualitative detection of tlc (TLC) to synthetic product; the hydrolysising condition of finding prior art is enough to synthetic intermediate is hydrolyzed to valnemulin hydrochloride far from, and the present invention can be fully complete with the protecting group hydrolysis of methyl acetoacetate.
Description of drawings
Accompanying drawing is used to provide a further understanding of the present invention, and consists of the part of specification sheets, is used for together with embodiments of the present invention explaining the present invention, is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is the infared spectrum of the valnemulin hydrochloride that the preparation method synthesized in background technology of the present invention;
Fig. 2 is the 1HNMR collection of illustrative plates of the valnemulin hydrochloride that in background technology, the preparation method synthesized;
Fig. 3 is the 13CNMR collection of illustrative plates of the valnemulin hydrochloride that in background technology, the preparation method synthesized.
Embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, is not intended to limit the present invention.
A kind of synthetic method of valnemulin hydrochloride specifically comprises the steps,
One, 22-O-(4-tosyl group) oxygen ethanoyl nurse body woods is synthetic
Embodiment 1:
With 75.7g(0.2mol) the Tosyl chloride of pleuromutilin, 42g (0.22mol) be dissolved in the mixing solutions of the methyl tertiary butyl ether of 200ml and 40mL distilled water, mixture slowly stirs and splashes into the NaOH solution 50ml that concentration is 0.01mol/ml.Then be heated to reflux, vigorous stirring, have a large amount of white masses to generate, then stir 20min after 20min simultaneously.The white solid of gained is filtered with Büchner funnel, use simultaneously methyl tertiary butyl ether and distilled water flushing, obtain the white powder product after seasoning, yield 97.8%.
Embodiment 2:
With 37.9g(0.1mol) the Tosyl chloride of pleuromutilin, 22.9g (0.12mol) be dissolved in the mixing solutions of the methyl tertiary butyl ether of 80ml and 20mL distilled water, mixture slowly stirs and splashes into the NaOH solution 30ml that concentration is 0.01mol/ml.Then be heated to reflux, vigorous stirring, have a large amount of white masses to generate, then stir 20min after 30min simultaneously.The white solid of gained is filtered with Büchner funnel, use simultaneously methyl tertiary butyl ether and distilled water flushing, obtain the white powder product after seasoning, yield 97.1%.
Embodiment 3:
With 37.9g(0.1mol) the Tosyl chloride of pleuromutilin, 20.9g (0.11mol) be dissolved in the mixing solutions of the methyl tertiary butyl ether of 100ml and 25mL distilled water, mixture slowly stirs and splashes into the NaOH solution 30ml that concentration is 0.01mol/ml.Then be heated to reflux, vigorous stirring, have a large amount of white masses to generate, then stir 20min after 30min simultaneously.The white solid of gained is filtered with Büchner funnel, use simultaneously methyl tertiary butyl ether and distilled water flushing, obtain the white powder product after seasoning, yield 96.8%.
mp?147～148?oC;?IR?(KBr):?3446,?2924,?2863,?1732,?1633,?1597,?1456,?1371,?1297,?1233,?1117,?1035,?832,?664,?560?cm-1;?1H?NMR?(400?MHz,?CDCl3)?δ?0.63?(d,?3H,?J?=?6.8?Hz),?0.87?(d,?3H,?J?=?6.8Hz),?1.11–1.15?(m,?1H),?1.22-1.26?(s,?5H),?1.33–1.36?(m,?1H),?1.41–1.44?(m,?1H),?1.46-1.50?(m,?5H),?1.63-1.65?(dd,?2H,J1=10Hz,J2=7.2?Hz),?2.01–2.08(m,?3H),?2.21–2.29?(m,?3H),?2.45(s,?3H),?3.34?(d,?1H,?J?=?6.4?Hz),?4.48?(s,?2H),?5.17-5.21?(d,?1H,?J?=?8.8?Hz),?5.31-5.34?(d,?1H,?J?=?6.4?Hz),?5.75-5.78?(d,?1H,?J?=?4.2?Hz),?6.43(q,?1H,?J?=?17.2?Hz,?10.8?Hz);?7.35-7.37?(d,?2H,?J?=?4.0?Hz),?7.80-7.82?(d,?2H,?J?=?4.0?Hz);?13C?NMR(100?MHz,?CDCl3)?δ?216.7,?164.8,?145.2,?138.6,?132.5,?129.9,?127.9,?117.2,?74.4,?70.2,?64.9,?57.9,?45.3,?44.4,?43.9,?41.7,?36.4,?35.9,?34.3,?30.2,?26.7,?26.3,?24.7,?21.6,?16.4,?14.6,?11.4.
Two, 14-O-[(1-amino-2-methyl propane-2-yl) mercapto ethanoyl] nurse body woods synthetic
Embodiment 1:
Join in the dehydrated alcohol of 150ml 0.63g sodium Metal 99.5 is cut into small pieces, filter out impurity after reaction, add dimethyl half Guang of 1.89g (13.5mmol) to press hydrochloride, at room temperature stir about 1h.Be cooled to below 0 oC; add the 22-O-(4-tosyl group) oxygen ethanoyl nurse body woods 7.2g (13.5mmol); stir 2.5h in ice bath; the most of ethanol of underpressure distillation after reaction; add ethyl acetate extraction, and with the unreacted dimethyl cysteamine hydrochloride of distilled water wash with generate tosilate.After organic phase is separated, direct recrystallization obtains target compound 3.7g, and yield is 68%.
Embodiment 2:
3.15g(0.14mol) sodium Metal 99.5 is cut into small pieces and joins in the dehydrated alcohol of 700ml, filters out impurity after reaction, adds dimethyl half Guang of 9.45g (0.066mol) to press hydrochloride, at room temperature stir about 1h.Be cooled to 0
oThe C left and right; add the 22-O-(4-tosyl group) oxygen ethanoyl nurse body woods 36g (0.068mol); stir 3h in ice bath; the most of ethanol of underpressure distillation after reaction; add ethyl acetate extraction, and with the unreacted dimethyl cysteamine hydrochloride of distilled water wash with generate tosilate.After organic phase is separated, direct recrystallization obtains target compound and obtains target compound 19.97g, and yield is 65%.
Embodiment 3:
3.34g(0.15mol) sodium Metal 99.5 is cut into small pieces and joins in the dehydrated alcohol of 750ml, filters out impurity after reaction, adds dimethyl half Guang of 9.92g (0.070mol) to press hydrochloride, at room temperature stir about 1h.Be cooled to 0
oThe C left and right; add the 22-O-(4-tosyl group) oxygen ethanoyl nurse body woods 37.8g (0.071mol); stir 3h in ice bath; the most of ethanol of underpressure distillation after reaction; add ethyl acetate extraction, and with the unreacted dimethyl cysteamine hydrochloride of distilled water wash with generate tosilate.After organic phase is separated, direct recrystallization obtains target compound and obtains target compound 20.5g, and yield is 63%.
mp?154-155oC;?IR?(free?base,?KBr):?3351,?2956,?2864,?1734,?1721,?1634,?1456,?1373,?1274,?1209,?1112,?1033,?982,?955,?941,?916?cm-1;?1H?NMR?(400?MHz,?CDCl3)?δ?0.73?(d,?3H,?J?=?7.2?Hz),?0.87?(d,?3H,?J?=?7.2?Hz),?1.09–1.16?(m,?1H),?1.23?(s,?6H),?1.30–1.38?(m,?2H),?1.45?(s,?1H),?1.52–1.53?(m,?7H),?1.55–1.60?(m,?1H),?1.63–1.69?(m,?2H),?1.74-1.78(q,?1H,?J=0.8?Hz),?2.04–2.10?(q,?2H),?2.18-2.25(m,?2H),?2.32-2.59?(q,?1H,?J=6.8?Hz),?3.09?(s,?2H),?3.13-3.17?(t,?2H,?J=1.6?Hz),?3.35?(d,?1H,?J=6.4?Hz),?5.17-5.22?(q,?1H,?J=1.6?Hz),?5.31-5.34?(q,?1H,?J?=?1.2?Hz),?5.74(d,?1H,?J?=?8.4),?6.43-5.51?(q,?1H,?J1?=?11.2?Hz,?J2?=?10.8?Hz);?13C?NMR(100?MHz,?CDCl3)?δ?216.9,?169.4,?139.0,?117.1,?74.6,?69.3,?58.2,?51.7,?48.5,?45.4,?44.7,?43.9,?41.8,?36.7,?35.9,?34.4,?31.2,?30.4,?26.8,?26.3,?26.2,?24.8,?16.8,?14.9,?11.4.
Three, the preparation of D-Val methyl sylvite
Example 1:
The methyl acetoacetate (0.3mol) of the solid KOH of 18.3g, the D-Val of 32.5g (0.27mol), 33ml and the benzene of 350ml are placed in 500ml with the round-bottomed flask of division box, backflow 3-4 hour, after reaction with the benzene evaporate to dryness.The solid matter of gained is poured in t-butyl methyl ether, stirs 1-1.5h under the condition of ice block cooling, filters, also uses the methyl tertiary butyl ether flush cake, namely gets D-Val methyl sylvite 48.57g, yield 71%.
Example 2:
The methyl acetoacetate (0.15mol) of the solid KOH of 9.15g, the D-Val of 16.25g (0.14mol), 16ml and the toluene of 250ml are placed in 500ml with the round-bottomed flask of division box, reflux after 2 hours, directly with the toluene evaporate to dryness.The solid matter of gained is poured in t-butyl methyl ether, stirs 1-1.5h under the condition of ice block cooling, filters, also uses the methyl tertiary butyl ether flush cake, namely gets D-Val methyl sylvite 25.65g, yield 75%.
Example 3:
The methyl acetoacetate (0.20mol) of the solid KOH of 24.4g, the D-Val of 44g (0.17mol), 22ml and the toluene of 300ml are placed in 500ml with the round-bottomed flask of division box, reflux after 2 hours, directly with the toluene evaporate to dryness.The solid matter of gained is poured in t-butyl methyl ether, stirs 1-1.5h under the condition of ice block cooling, filters, also uses the methyl tertiary butyl ether flush cake, namely gets D-Val methyl sylvite 31.9g, yield 74%.
Four, valnemulin hydrochloride is synthetic
Example 1:
The D-Val methyl sylvite 0.94g (3.7mmol) of above-mentioned gained is suspended in the methylene dichloride of 50ml; add NMM0.38g (3.5mmol); be cooled to 0 ℃ of left and right with ice cube; slowly drip the methylene dichloride 20ml that is dissolved in 0.48g isobutyl chlorocarbonate (3.5mmol), add again 1.63g14-O-[(1-amino-2-methyl propane-2-yl after stirring 30min) the mercapto ethanoyl] nurse body woods (3.5mmol).After reaction 1h, the evaporate to dryness methylene dichloride adds t-butyl methyl ether 60ml dissolving, then adds the distilled water of 80ml, then drips HCl accent pH to 2 left and right of 6N under the condition that stirs, and then continues approximately 4-5h of stirring at room.Then separate two, water is washed 2 times with methyl tertiary butyl ether, each 40ml.The t-butyl methyl ether that adds again 60ml, the NaOH accent pH to 8-9 with 2N stirs 20min, then separates two-phase.Organic phase is washed 2 times with distilled water, then adds distilled water,, the HCl that drips 3N transfers pH to 2-3, stirs 15min, and after the separation two-phase, water namely gets valnemulin hydrochloride 1.68g with the vacuum drying oven evaporate to dryness.Yield 80.2%.
Example 2:
The D-Val methyl sylvite 0.76g (3.0mmol) of above-mentioned gained is suspended in the methylene dichloride of 45ml; add NMM0.36g (3.6mmol); be cooled to 0 ℃ of left and right with ice cube; slowly drip the methylene dichloride 20ml that is dissolved in 0.39g isobutyl chlorocarbonate (3.6mmol), add again 1.39g14-O-[(1-amino-2-methyl propane-2-yl after stirring 30min) the mercapto ethanoyl] nurse body woods (3.0mmol).After reaction 1h, the evaporate to dryness methylene dichloride adds t-butyl methyl ether 50ml dissolving, then adds the distilled water of 70ml, then drips HCl accent pH to 2 left and right of 6N under the condition that stirs, and then continues approximately 4-5h of stirring at room.Then separate two, water is washed 2 times with methyl tertiary butyl ether, each 40ml.The t-butyl methyl ether that adds again 50ml, the NaOH accent pH to 8-9 with 2N stirs 20min, then separates two-phase.Organic phase is washed 2 times with distilled water, then adds distilled water,, the HCl that drips 3N transfers pH to 2-3, stirs 15min, and after the separation two-phase, water namely gets valnemulin hydrochloride 1.48g with the vacuum drying oven evaporate to dryness.Yield 82.1%.
Example 3:
The D-Val methyl sylvite 0.76g (3.0mmol) of above-mentioned gained is suspended in the methylene dichloride of 40ml; add NMM0.33g (3.3mmol); be cooled to 0 ℃ of left and right with ice cube; slowly drip the methylene dichloride 20ml that is dissolved in 0.39g isobutyl chlorocarbonate (3.6mmol), add again 1.16g14-O-[(1-amino-2-methyl propane-2-yl after stirring 30min) the mercapto ethanoyl] nurse body woods (2.5mmol).After reaction 1h, the evaporate to dryness methylene dichloride adds t-butyl methyl ether 50ml dissolving, then adds the distilled water of 60ml, then drips HCl accent pH to 2 left and right of 6N under the condition that stirs, and then continues approximately 4-5h of stirring at room.Then separate two, water is washed 2 times with methyl tertiary butyl ether, each 30ml.The t-butyl methyl ether that adds again 50ml, the NaOH accent pH to 8-9 with 2N stirs 20min, then separates two-phase.Organic phase is washed 2 times with distilled water, then adds distilled water,, the HCl that drips 3N transfers pH to 2-3, stirs 15min, and after the separation two-phase, water namely gets valnemulin hydrochloride 1.22g with the vacuum drying oven evaporate to dryness.Yield 81.5%.
mp?154-155oC;?IR?(free?base,?KBr):?3425,?2962,?2933,?1728,?1681,?1557,?1463,?1285,?1117,?1016,?982,?955,?938,?918?cm-1;?1H?NMR?(400?MHz,?CDCl3)?δ?0.76?(d,?3H,?J?=?7.2?Hz),?0.99?(d,?3H,?J?=?7.2?Hz),?1.13–1.21?(m,?10H),?1.34?(s,?8H),?1.49–1.61?(m,?6H),?1.76–1.86?(d,?2H),?2.25-2.45(m,?6H),?3.19-3.23?(d,?1H,?J=1.6?Hz),?3.36?(s,?2H),?3.61-3.64?(d,?2H,?J=1.2?Hz),?3.93-3.95?(d,?1H,?J=0.8?Hz),?5.21-5.30?(q,?2H),?5.73(s,?1H),?6.32-6.39?(t,?1H,?J1?=?16.4?Hz,?J2?=?12.0?Hz);?13C?NMR(100?MHz,?CDCl3)?δ170.1,?169.0,?139.5,?116.5,?74.4,?70.4,?58.6,?58.2,?48.2,?46.8,?45.6,?43.8,?41.8,?36.9,?35.9,?31.5,?30.1,?26.9,?26.4,?26.1,?24.7,?17.9,?17.4,?16.7,?14.9,?11.4。
The above is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment, the present invention is had been described in detail, for a person skilled in the art, it still can be modified to the technical scheme that aforementioned each embodiment puts down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. the synthetic method of a valnemulin hydrochloride is characterized in that: specifically comprises the steps,
Step 1: at t-butyl methyl ether and the H of pleuromutilin
2In the O mixture, add the Tosyl chloride with the pleuromutilin equimolar amount, then dripping concentration is the NaOH solution of 30-50wt%, under refluxad vigorous stirring, react 20-80min, generates a large amount of white solid matter, after filtration, the product that generates is cooled under room temperature, washs respectively with large water gaging and t-butyl methyl ether, get the 22-O-(4-tosyl group) oxygen ethanoyl nurse body woods;
Step 2: the dimethyl cysteamine hydrochloride that adds in the ethanolic soln of 1-2 wt % sodium ethylate, react 30-90min under room temperature, reaction system is cooled to 2-5
oAfter C, add by the synthetic 14-O-[(1-amino-2-methyl propane of step 1-2-yl) the mercapto ethanoyl] nurse body woods, stir 2-3h, decompression steams ethanol, adds ethyl acetate and distilled water, washing, separation, organic phase adds saturated NH again
4The Cl solution washing after separating two-phase, the most of ethyl acetate of underpressure distillation, gets 14-O-[(1-amino-2-methyl propane-2-yl) the mercapto ethanoyl] nurse body woods;
Step 3: solid KOH, D-Val, methyl acetoacetate are mixed, added benzene or refluxing toluene 3-4 hour, after reaction with the benzene evaporate to dryness, the solid matter of gained is poured in t-butyl methyl ether, stir 1-1.5h, filter, also use the t-butyl methyl ether flush cake, namely get the D-Val potassium methide;
step 4: the D-Val potassium methide of step 3 gained is suspended in methylene dichloride, add N-methylmorpholine, be cooled to 0 ℃ of left and right with ice cube, slowly drip isobutyl chlorocarbonate (being dissolved in a small amount of methylene dichloride), stir the 14-O-[(1-amino-2-methyl propane that adds again the step 2 gained after 30min-2-yl) the mercapto ethanoyl] nurse body woods, after reaction 1h, the evaporate to dryness methylene dichloride, add t-butyl methyl ether and distilled water, drip HCl under the condition that stirs again and transfer pH to 2, then continue approximately 4-5h of stirring at room, separate, water washs with t-butyl methyl ether, and then add t-butyl methyl ether, transfer pH to 8-9 with NaOH, stir 20min, then separate two-phase, organic phase is washed 2 times with distilled water, add again distilled water, drip HCl and transfer pH to 2-3, stir 15min, after separating two-phase, water namely gets valnemulin hydrochloride with the vacuum drying oven evaporate to dryness.
2. the synthetic method of valnemulin hydrochloride in the step 1 of above-mentioned method for making according to claim 1 is characterized in that: in described step 1,
Described pleuromutilin: t-butyl methyl ether: water: 30-50wt%NaOH solution is 1mmol:0.8-2mL:0.15-0.25mL:0.25-0.5mL.
3. the synthetic method of valnemulin hydrochloride in the step 1 of above-mentioned method for making according to claim 2, it is characterized in that: in described step 1, the concentration of described NaOH solution is 40wt%, described pleuromutilin: t-butyl methyl ether: water: 40wt%NaOH solution is 1mmol:1mL:0.2mL:0.3mL.
4. the synthetic method of valnemulin hydrochloride in the step 1 of above-mentioned method for making according to claim 1; it is characterized in that: in described step 2, described dimethyl cysteamine hydrochloride: the ethanolic soln of sodium ethylate: 14-O-[(1-amino-2-methyl propane-2-yl) mercapto ethanoyl] nurse body woods is 1mmol: 8-12mL:1-1.2 mmol.
5. the synthetic method of valnemulin hydrochloride in the step 1 of above-mentioned method for making according to claim 4; it is characterized in that: in described step 2, described dimethyl cysteamine hydrochloride: the ethanolic soln of sodium ethylate: 14-O-[(1-amino-2-methyl propane-2-yl) mercapto ethanoyl] nurse body woods is 1mmol:10mL:1.1mmol.
6. the synthetic method of valnemulin hydrochloride in the step 1 of above-mentioned method for making according to claim 1, it is characterized in that: in described step 3, described D-Val: KOH: methyl acetoacetate: benzene or toluene are 1mmol: 65-70mg:1.1-1.3mL:1.5-2mL.
7. the synthetic method of valnemulin hydrochloride in the step 1 of above-mentioned method for making according to claim 6, it is characterized in that: in described step 3, described D-Val: KOH: methyl acetoacetate: benzene or toluene are 1mmol:65mg:1.2mmol:1.8mL.
8. the synthetic method of valnemulin hydrochloride in the step 1 of above-mentioned method for making according to claim 1, it is characterized in that: in described step 4, described D-Val: methylene dichloride: N-methylmorpholine: isobutyl chlorocarbonate (being dissolved in a small amount of methylene dichloride): 14-O-[(1-amino-2-methyl propane-2-yl) mercapto ethanoyl] nurse body woods is 1mmol: 10-15mL:1-1.5mmoL:1-1.5mmoL:0.8-1mmol, the each consumption of described t-butyl methyl ether (consumption when comprising washing) is the t-butyl methyl ether of every mmole D-Val with 15-20mL.
9. the synthetic method of valnemulin hydrochloride in the step 1 of above-mentioned method for making according to claim 8, it is characterized in that: in described step 4, described D-Val: methylene dichloride: N-methylmorpholine: isobutyl chlorocarbonate (being dissolved in a small amount of methylene dichloride): 14-O-[(1-amino-2-methyl propane-2-yl) mercapto ethanoyl] nurse body woods is 1mmol:15mL:1.2mmol:1.2mmol:1mmol, the concentration of the dichloromethane solution of described isobutyl chlorocarbonate is 20-25mg/mL, the each consumption of described t-butyl methyl ether (consumption when comprising washing) is the t-butyl methyl ether of every mmole D-Val with 20mL.
10. the synthetic method of valnemulin hydrochloride in the step 1 of the described above-mentioned method for making of according to claim 1 to 9 any one, it is characterized in that: in described step 2, described ethyl acetate consumption is every mmole dimethyl cysteamine hydrochloride 5-8mL ethyl acetate.
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