CN102558189A - Refining method of methyhaaltrexone bromide - Google Patents
Refining method of methyhaaltrexone bromide Download PDFInfo
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Abstract
The invention provides a refining method of methyhaaltrexone bromide, belonging to the technical field of chemical drug synthesis. According to the refining method, the methyhaaltrexone bromide is separated and purified by inverse silica gel column chromatography, and the procedure of recrystallization on a methyhaaltrexone bromide product by a mixed solvent of methanol and water can be added before and after the inverse silica gel column chromatography. According to the refining method, the conditions are mild, the yield is high, the purity of refined products is high, and the generated product meet the requirement on purification of medical methyhaaltrexone bromide preparation, so that the method is applicable to industrialized mass production.
Description
Technical field
The present invention relates to the process for purification of methylnaltrexone bromide, belong to the chemicals synthesis technical field.
Background technology
Methylnaltrexone bromide (SC-37359, MNTX) is a kind of selectivity mu opioid receptor antagonists; As a kind of quaternary ammonium salt, limited the ability of methylnaltrexone bromide through hemato encephalic barrier, make the opiate receptor antagonist of methylnaltrexone bromide as a kind of peripheral action; Act on as in the stomach intestinal tissue; Therefore, methylnaltrexone bromide has reduced the constipation effect of opioid drug, and do not influence opioid drug to cns analgesic activity.
Methylnaltrexone bromide has following characteristics: 1) acting on the μ acceptor of periphery, do not activate the opiate receptor of cns, possibly be competitive antagonism; 2) safety, a series of tests do not find that all it has serious toxic side effect, and common adverse reactions is stomachache, diarrhoea, flatulence and dizzy; 3) effect is fast, gets final product onset in several minutes; 4) the treatment constipation is than logical purgatives of stool and tenderizer good effect; 5) action pathway is not unique, can be directly with gi tract on opiate receptor combine onset, also can combine with opiate receptor through the blood whole body that distributes.Therefore, methylnaltrexone bromide not only can be treated the gastrointestinal side-effect of opioid drug, also can treat the parenteral untoward reaction; 6) not through hemato encephalic barrier, do not weaken the central analgesia effect of opiate.
The compound name of methylnaltrexone bromide is called bromination-17-(cyclopropyl methyl)-4,5 α-epoxy-3,14-dihydroxyl-17-methyl-6-oxo morphinan, and its structural formula is following:
Methylnaltrexone bromide belongs to the verivate of morphine ketone; Preparation were established through to methylnaltrexone bromide carries out literature search and investigation; Find that the preparation methylnaltrexone bromide all is raw material with the Naltrexone Hydrochloride, alkalization obtains free alkali, and methylating obtains the finished product methylnaltrexone bromide again.Induction-arrangement goes out its synthetic route and is broadly divided into three:
Synthetic route one (referring to one Chinese patent application prospectus CN101516892A):
This route is the phenolic hydroxyl group of protection TREXUPONT earlier, again methyl, hydrogenation deprotection base, IX, the synthetic title product methylnaltrexone bromide of bromination reaction on methyl-sulfate.
Synthetic route two (referring to U.S. Pat 4176186):
This route is the phenolic hydroxyl group of protection TREXUPONT earlier, again methyl, hydrolysis deprotection base, IX, the synthetic title product methylnaltrexone bromide of bromination reaction on methyl iodide.
Synthetic route three (referring to U.S. Pat 4176186):
The free alkali that this prepared route is a Naltrexone Hydrochloride directly carries out the bromomethylation reaction with monobromethane, and one goes on foot and obtains the product methylnaltrexone bromide.
From top three methylnaltrexone bromide synthetic circuits, the reaction reagent toxicity that synthetic route one is adopted is bigger, and synthesis condition is comparatively harsh, carries out and gets up to have certain difficulty; Synthetic route two is similar with synthetic route one principle, and is not too harsh but synthetic route two requires, and relatively easily carries out; Synthetic route three steps are the shortest, and midbody is quality controllable, and just the by product in the finished product is difficult to remove, and therefore, adopt synthetic route three, for obtaining high-quality methylnaltrexone bromide product needed thick product made with extra care.
The method that is prepared as follows of methylnaltrexone bromide is specifically disclosed among the US4176186 embodiment 5: in reactor drum, add 50ml anhydrous propanone, 0.5ml N, mix, add 2.5g (7.35mmol) TREXUPONT alkali; Add 4.25g (44.8mmol) monobromethane, room temperature confined reaction 21 days is after reaction is accomplished; The concentrating under reduced pressure reaction solution; Add methanol crystallization, the methanol recrystallization gets the reaction product methylnaltrexone bromide.FF adopts in this method is the mode of traditional recrystallization, and shortcoming is: utilize the needed purity of high-quality methylnaltrexone bromide highly finished product that methylnaltrexone bromide product that this method obtains can not fulfilling medicinal.
Summary of the invention
The purpose of this invention is to provide a kind of new methylnaltrexone bromide process for purification.The process for purification mild condition of methylnaltrexone bromide of the present invention; Yield is high; Highly finished product purity is high, be fit to industrialized production, and the methylnaltrexone bromide product that utilizes the inventive method to obtain meets the medicinal needed purity of high-quality methylnaltrexone bromide highly finished product.
Technical scheme of the present invention is following:
A kind of process for purification of methylnaltrexone bromide adopts reversed-phase silica gel column chromatography separation and purification methylnaltrexone bromide.
Further, above-mentioned methylnaltrexone bromide process for purification is crossed the reverse phase silica gel post with the methylnaltrexone bromide aqueous solution of crude, earlier with 1% methanol aqueous solution (volumn concentration; Wash-out down together); With 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring is when the principal constituent spot appears in thin-layer chromatography again; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product.The developping agent of wherein said thin-layer chromatography is ETHYLE ACETATE-sherwood oil-methanol mixed solvent, and three's volume ratio is an ETHYLE ACETATE: sherwood oil: methyl alcohol=1: 1: 1.
The process for purification of above-mentioned methylnaltrexone bromide before carrying out reversed-phase silica gel column chromatography, can have a preposition purification step: use the mixed solvent of first alcohol and water that the methylnaltrexone bromide bullion is carried out recrystallization purifying.Common way is: the methylnaltrexone bromide bullion is added in the mixed solvent of first alcohol and water, stirring heating makes it dissolving, adds gac then and refluxes; Be cooled to room temperature again, separate out solid under stirring, filter; Filter cake is drained with methanol wash, and vacuum-drying gets white products.Wherein, said gac is preferably medicinal carbon, needle-use activated carbon more preferably, the methylnaltrexone bromide of pharmaceutically acceptable to prepare (particularly injection with).The volume ratio of first alcohol and water is preferably 3～5 in the mixed solvent of first alcohol and water: 1, and more preferably 4: 1.The consumption of gac adds the 5g gac with every 100mL solution and is advisable.Return time is preferably 30min.Vacuum drying temperature is preferably 80 ℃, and the time is preferably 6h.
Methylnaltrexone bromide process for purification provided by the present invention further, after reversed-phase silica gel column chromatography, has the purification step of a postposition: use the mixed solvent of first alcohol and water that methylnaltrexone bromide is carried out recrystallization purifying.Generally be that the methylnaltrexone bromide that obtains through reversed-phase silica gel column chromatography is added in the mixed solvent of first alcohol and water, stirring heating makes it dissolving, refluxes; Be cooled to room temperature then, separate out solid under stirring, filter; Filter cake is drained with methanol wash, and vacuum-drying gets purified product.Wherein, the volume ratio of first alcohol and water is preferably 3～5 in the mixed solvent of first alcohol and water: 1, and more preferably 4: 1; Return time is preferably 30min; Vacuum drying temperature is preferably 80 ℃, and the time is preferably 6h.
The most preferably scheme of methylnaltrexone bromide process for purification provided by the present invention comprises following three steps:
1) the methylnaltrexone bromide bullion being added methyl alcohol and water volume ratio is that stirring heating makes it dissolving in 4: 1 the mixed solvent, and cold slightly back adding consumption is the needle-use activated carbon of 5% (g/mL); Backflow 30min; Be cooled to stirring at room 4h then, filter, filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get white products (methylnaltrexone bromide highly finished product 1).
2) product that step 1) is obtained is crossed the reverse phase silica gel post with suitable quantity of water dissolving back; Earlier with 1% methanol aqueous solution wash-out; With 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring is when the principal constituent spot appears in thin-layer chromatography again; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product (methylnaltrexone bromide highly finished product 2).
3) with step 2) to add methyl alcohol and water volume ratio be that stirring heating is dissolved, backflow 30min in 4: 1 the mixed solvent for the methylnaltrexone bromide product that obtains; Be cooled to stirring at room 4h then, filter, filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get purified product.
Methylnaltrexone bromide bullion involved in the present invention can use any compound method of the prior art to obtain, and includes but not limited to following method: under the nitrogen protection, add 11.6g (34.0mmol) TREXUPONT alkali in the there-necked flask; The 175mL anhydrous propanone, 23.2mLDMF, 11.4mL (208mmol) monobromethane; Close nitrogen; 25 ℃ of confined reactions 21 days, TLC monitoring experiment process, developping agent is ETHYLE ACETATE-sherwood oil-methyl alcohol (volume ratio 1: 1: 1).The concentrating under reduced pressure reaction solution was to doing after reaction was accomplished, and suction filtration gets the methylnaltrexone bromide bullion behind the adding 150mL washing with acetone.80 ℃ of vacuum-drying 6h get the 13.4g product, yield 90.17%.
The advantage of methylnaltrexone bromide process for purification of the present invention is:
(1) mild condition.The process for purification of methylnaltrexone bromide of the present invention adopts the method for reversed-phase silica gel column chromatography and methanol-water recrystallization, does not need HTHP, mild condition.
(2) yield is high.Experiment proof (referring to the table 1-6 in the embodiment), the process for purification of methylnaltrexone bromide of the present invention is under the prerequisite of the purity that guarantees finished product, and yield is higher.
(3) be fit to industrialized production.The industrial equipment of reverse phase silica gel post is very ripe at present, and the process for purification of methylnaltrexone bromide of the present invention adopts reversed-phase silica gel column chromatography, and is simple to operate, is fit to industrialized production.
(4) highly finished product purity is high.Referring to the table 7 in the embodiment; The methylnaltrexone bromide finished product purity that process for purification of the present invention obtains is very high; Surpass the purity that the methylnaltrexone bromide process for purification can reach in the prior art, the purifying end product of methylnaltrexone bromide process for purification of the present invention is suitable as the raw material of medicinal methylnaltrexone bromide preparation.
Description of drawings
Fig. 1 is the HPLC collection of illustrative plates of embodiment 1 methylnaltrexone bromide end product purity detecting;
Fig. 2 is the HPLC collection of illustrative plates of embodiment 5 methylnaltrexone bromide end product purity detecting.
Embodiment
Preparation example 1: methylnaltrexone bromide synthetic
Under the nitrogen protection, add 11.6g (34.0mmol) TREXUPONT alkali in the there-necked flask, the 175mL anhydrous propanone; 23.2mL DMF, 11.4mL (208mmol) monobromethane is closed nitrogen; 25 ℃ of confined reactions 21 days, reaction are accomplished back concentrating under reduced pressure reaction solution to doing suction filtration behind the adding 150mL washing with acetone; Get 80 ℃ of vacuum-drying 6h of filter cake, get 13.4g methylnaltrexone bromide bullion, yield 90.17%.
Embodiment 1: methylnaltrexone bromide refining
Add 13.4g methylnaltrexone bromide bullion, 75mL methyl alcohol, 19mL pure water in the 250mL four-hole boiling flask, the stirring heating dissolving, cold slightly back adds the 0.7g needle-use activated carbon; Backflow 30min is cooled to stirring at room 4h, filters; Filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get white products (note is made " methylnaltrexone bromide highly finished product 1 ") 10.4g, yield 77.61%.
The reverse phase silica gel post is crossed in above-mentioned 10.4g methylnaltrexone bromide highly finished product 1 usefulness suitable quantity of water dissolving back; With 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) is monitored earlier; When the principal constituent spot appears in thin-layer chromatography; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product (note is made " methylnaltrexone bromide highly finished product 2 ") 7.15g, yield 68.75%.
Add 7.15g methylnaltrexone bromide highly finished product 2,42.0mL methyl alcohol, 10.5mL pure water in the 100mL four-hole boiling flask, stirring heating dissolving, backflow 30min; Be cooled to stirring at room 4h; Filter, filter cake is drained with methanol wash, 80 ℃ of vacuum-drying 6h; Get white products (note is made " methylnaltrexone bromide highly finished product 3 ") 5.86g, yield 81.96%.
1H-NMR (500MHz d
6-DMSO δ ppm) 9.48 (s, but 1H D
2The O exchange), 6.67 (s, 2H), 6.39 (s, but 1H D
2The O exchange), 4.91 (s, 2H), 4.03 (d, J=3.5Hz 1H), 3.90 (dd, J=3.5,13.5Hz 1H); 3.65 (s, 3H), 3.51 (d, J=20.5Hz1H), 3.32 (s, 1H), 3.05 (dd, J=4.5; 20.5Hz 1H), 2.97 (dt, J=4.5,13.5Hz 1H), 2.91 (dt, J=5.5,14.5Hz 1H), 2.75 (d; J=10.5Hz 1H), 2.08 (d, J=14.5Hz1H), 2.04 (d, J=14Hz 1H), 1.59 (d, J=10.5Hz 1H); (1.56 dt, J=3.5,14Hz 1H), 1.23～1.21 (m, 1H), 0.77～0.36 (m, 4H).
13C-NMR(125MHz?d
6-DMSOδppm)207.506，143.616，140.481，127.774，120.300，119.794，118.151，88.526，71.732，70.898，70.868，56.673，52.834，48.387，34.870，32.062，27.293，24.423，5.720，3.825，2.777。
Embodiment 2: methylnaltrexone bromide refining
Add 13.4g methylnaltrexone bromide bullion, 75mL methyl alcohol, 19mL pure water in the 250mL four-hole boiling flask, the stirring heating dissolving, cold slightly back adds the 0.7g needle-use activated carbon, and backflow 30min is cooled to stirring at room 4h.Filter, filter cake is drained with methanol wash, and 80 ℃ of vacuum-drying 6h get white products (note is made " methylnaltrexone bromide highly finished product 1 ") 10.2g.
The reverse phase silica gel post is crossed in above-mentioned 10.2g methylnaltrexone bromide highly finished product 1 usefulness suitable quantity of water dissolving back; Earlier with 1% methanol aqueous solution wash-out; With 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring is when the principal constituent spot appears in thin-layer chromatography again; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product (note is made " methylnaltrexone bromide highly finished product 2 ") 7.05g.
Embodiment 3: methylnaltrexone bromide refining
13.4g the methylnaltrexone bromide bullion is crossed the reverse phase silica gel post with suitable quantity of water dissolving back; Earlier with 1% methanol aqueous solution wash-out; With 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring is when the principal constituent spot appears in thin-layer chromatography again; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product 7.25g.
Embodiment 4: methylnaltrexone bromide refining
13.4g the methylnaltrexone bromide bullion is crossed the reverse phase silica gel post with suitable quantity of water dissolving back; Earlier with 1% methanol aqueous solution wash-out; With 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring is when the principal constituent spot appears in thin-layer chromatography again; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product 7.30g.
Add above-mentioned 7.30g methylnaltrexone bromide product, 42.0mL methyl alcohol, 10.5mL pure water in the 100mL four-hole boiling flask, stirring heating dissolving, backflow 30min; Be cooled to stirring at room 4h, filter, filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get white products 5.76g.
Embodiment 5: methylnaltrexone bromide refining
Add 90.7g methylnaltrexone bromide bullion, 508mL methyl alcohol, 127mL pure water in the reactor drum, the stirring heating dissolving, cold slightly back adds gac 5g; Backflow 30min is cooled to stirring at room 4h, filters; Filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get white products (note is made " methylnaltrexone bromide highly finished product 1 ") 71.9g, yield 79.3%.
71.9g the reverse phase silica gel post is crossed in methylnaltrexone bromide highly finished product 1 usefulness suitable quantity of water dissolving back; With 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) is monitored earlier; When the principal constituent spot appears in thin-layer chromatography; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product (note is made " methylnaltrexone bromide highly finished product 2 ") 48.84g, yield 67.95%.
Add 48.84g methylnaltrexone bromide highly finished product 2,273.6mL methyl alcohol, 68.4mL pure water in the reactor drum, stirring heating dissolving, backflow 30min; Be cooled to stirring at room 4h; Filter, filter cake is drained with methanol wash, 80 ℃ of vacuum-drying 6h; Get white products (note is made " methylnaltrexone bromide highly finished product 3 ") 40.15g, yield 82.21%.
Embodiment 6: methylnaltrexone bromide refining
Add 74.4g methylnaltrexone bromide bullion, 416mL methyl alcohol, 104mL pure water in the reactor drum, the stirring heating dissolving, cold slightly back adds gac 5g; Backflow 30min is cooled to stirring at room 4h, filters; Filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get white products (note is made " methylnaltrexone bromide highly finished product 1 ") 56.5g, yield 76.0%.
56.5g the reverse phase silica gel post is crossed in methylnaltrexone bromide highly finished product 1 usefulness suitable quantity of water dissolving back; With 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) is monitored earlier; When the principal constituent spot appears in thin-layer chromatography; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product (note is made " methylnaltrexone bromide highly finished product 2 ") 38.84g, yield 68.70%.
Add 38.84g methylnaltrexone bromide highly finished product 2,217.6mL methyl alcohol, 54.4mL pure water in the reactor drum, stirring heating dissolving, backflow 30min; Be cooled to stirring at room 4h; Filter, filter cake is drained with methanol wash, 80 ℃ of vacuum-drying 6h; Get white products (note is made " methylnaltrexone bromide highly finished product 3 ") 31.64g, yield 81.47%.
Embodiment 7: methylnaltrexone bromide refining
Add 481.04g methylnaltrexone bromide bullion, 2696mL methyl alcohol, 674mL pure water in the reactor drum, the stirring heating dissolving, cold slightly back adds needle-use activated carbon 5g; Backflow 30min is cooled to stirring at room 4h, filters; The filter cake methanol wash is drained; 80 ℃ of vacuum-drying 6h get white products (note is made " methylnaltrexone bromide highly finished product 1 ") 365.72g, yield 76.03%.
365.72g the reverse phase silica gel post is crossed in methylnaltrexone bromide highly finished product 1 usefulness suitable quantity of water dissolving back; With 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) is monitored earlier; When the principal constituent spot appears in thin-layer chromatography; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product (note is made " methylnaltrexone bromide highly finished product 2 ") 251.76g, yield 68.84%.
Add 251.76g methylnaltrexone bromide highly finished product 2,1408mL methyl alcohol, 352mL pure water in the reactor drum, stirring heating dissolving, backflow 30min; Be cooled to stirring at room 4h; Filter, filter cake is drained with methanol wash, 80 ℃ of vacuum-drying 6h; Get white products (note is made " methylnaltrexone bromide highly finished product 3 ") 204.74g, yield 81.32%.
Embodiment 8: methylnaltrexone bromide refining
Add 488.81g methylnaltrexone bromide bullion, 2736mL methyl alcohol, 684mL pure water in the reactor drum, the stirring heating dissolving, cold slightly back adds needle-use activated carbon 5g; Backflow 30min is cooled to stirring at room 4h, filters; Filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get white products (note is made " methylnaltrexone bromide highly finished product 1 ") 371.52g, yield 76.00%.
371.52g the reverse phase silica gel post is crossed in methylnaltrexone bromide highly finished product 1 usefulness suitable quantity of water dissolving back; With 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) is monitored earlier; When the principal constituent spot appears in thin-layer chromatography; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product (note is made " methylnaltrexone bromide highly finished product 2 ") 256.54g, yield 69.05%.
Add 256.54g methylnaltrexone bromide highly finished product 2,1440mL methyl alcohol, 360mL pure water in the reactor drum, stirring heating dissolving, backflow 30min; Be cooled to stirring at room 4h; Filter, filter cake is drained with methanol wash, 80 ℃ of vacuum-drying 6h; Get white products (note is made " methylnaltrexone bromide highly finished product 3 ") 207.21g, yield 80.77%.
Embodiment 9: methylnaltrexone bromide refining
Add 493.97g methylnaltrexone bromide bullion, 2768mL methyl alcohol, 692mL pure water in the reactor drum, the stirring heating dissolving, cold slightly back adds needle-use activated carbon 5g; Backflow 30min is cooled to stirring at room 4h, filters; Filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get white products (note is made " methylnaltrexone bromide highly finished product 1 ") 370.42g, yield 74.98%.
Product is crossed the reverse phase silica gel post with suitable quantity of water dissolving back; With 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) is monitored earlier; When the principal constituent spot appears in thin-layer chromatography; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product (note is made " methylnaltrexone bromide highly finished product 2 ") 256.09g, yield 69.14%.
Add 256.09g methylnaltrexone bromide bullion, 1432mL methyl alcohol, 358mL pure water in the reactor drum, stirring heating dissolving, backflow 30min; Be cooled to stirring at room 4h; Filter, filter cake is drained with methanol wash, 80 ℃ of vacuum-drying 6h; Get white products (note is made " methylnaltrexone bromide highly finished product 3 ") 206.63g, yield 80.68%.
Summarize with the result in the face of the data of the foregoing description down and analyze, verify the feasibility and the stability of process for refining of the present invention.
Three batches of product lab scale datas:
Table 1: the refining 1 (raw material: the methylnaltrexone bromide bullion) of finished product
Table 2: the refining 2 (raw materials: methylnaltrexone bromide highly finished product 1) of finished product
Table 3: the refining 3 (raw materials: methylnaltrexone bromide highly finished product 2) of finished product
Three batches of product amplification quantity datas:
Table 4: the refining 1 (raw material: the methylnaltrexone bromide bullion) of finished product
Table 5: the refining 2 (raw materials: methylnaltrexone bromide highly finished product 1) of finished product
Table 6: the refining 3 (raw materials: methylnaltrexone bromide highly finished product 2) of finished product
The quality control inspection of the purifying end product of methylnaltrexone bromide:
Proterties: colourless crystallization property powder
HPLC detects: performance liquid instrument model: Aqilent 1100 type high performance liquid chromatographs
Chromatographic condition: chromatographic column: Agela Akasil C
18, 5 μ m, 4.6 * 250mm
Moving phase: methyl alcohol: 0.15% trifluoroacetic acid aqueous solution=22: 78
Detect wavelength: 230nm
Flow velocity: 1.0mL/min
Sample size: 20 μ L
Column temperature: 30 ℃
Theoretical plate number: press methylnaltrexone bromide and calculate, should be not less than 3000.
HPLC method detected result is seen table 7.
Table 7: the quality control of the purifying end product of methylnaltrexone bromide reaches the comparison with the US4176186 recrystallization method:
Annotate: the US4176186 recrystallization method is: the methylnaltrexone bromide bullion is used methanol crystallization earlier, uses the methanol recrystallization again, gets the product methylnaltrexone bromide.
Can see through above data; The purifying end product content of methylnaltrexone bromide process for purification of the present invention and related substance (impurity) have all reached higher standard; Be suitable as the raw material of medicinal methylnaltrexone bromide preparation; And the purifying end product content of the methylnaltrexone bromide that the US4176186 recrystallization method obtains is lower, and related substance (impurity) is more, is not suitable for the raw material as medicinal methylnaltrexone bromide preparation.
The technology that three batches of lab scales (embodiment 1,5 and 6) are established is reappeared through three batches of pilot scales (embodiment 7,8 and 9), shows that this technology circulation ratio is good, the products obtained therefrom steady quality.The purity detecting HPLC collection of illustrative plates of embodiment 1 and embodiment 5 end products is seen Figure of description 1,2.
Claims (10)
1. the process for purification of a methylnaltrexone bromide adopts reversed-phase silica gel column chromatography separation and purification methylnaltrexone bromide.
2. process for purification as claimed in claim 1 is characterized in that, the methylnaltrexone bromide aqueous solution of crude is crossed the reverse phase silica gel post; Earlier with 1% methanol aqueous solution wash-out; With 5% methanol aqueous solution wash-out, the thin-layer chromatography monitoring is when the principal constituent spot appears in thin-layer chromatography again; Collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is obtained the methylnaltrexone bromide product.
3. process for purification as claimed in claim 2 is characterized in that, the developping agent of thin-layer chromatography is that volume ratio is ETHYLE ACETATE-sherwood oil-methanol mixed solvent of 1: 1: 1.
4. like claim 1 or 2 or 3 described process for purification, it is characterized in that, before carrying out reversed-phase silica gel column chromatography, the methylnaltrexone bromide bullion is carried out recrystallization purifying with the mixed solvent of first alcohol and water.
5. process for purification as claimed in claim 4 is characterized in that, the method for the methylnaltrexone bromide bullion being carried out recrystallization purifying is: it is in 3～5: 1 the mixed solvent that the methylnaltrexone bromide bullion is added methyl alcohol and water volume ratio; Stirring heating makes it dissolving, adds gac then and refluxes, and is cooled to room temperature again; Separate out solid under stirring; Filter, filter cake is drained with methanol wash, and vacuum-drying gets final product.
6. process for purification as claimed in claim 5 is characterized in that, in the mixed solvent of the used first alcohol and water of recrystallization, the volume ratio of first alcohol and water is 4: 1; Said gac is a needle-use activated carbon, and its consumption is that every 100mL solution adds the 5g gac.
7. like claim 1 or 2 or 3 described process for purification, it is characterized in that, after carrying out reversed-phase silica gel column chromatography, the methylnaltrexone bromide product is carried out recrystallization purifying with the mixed solvent of first alcohol and water.
8. process for purification as claimed in claim 7 is characterized in that, will add methyl alcohol and water volume ratio through methylnaltrexone bromide product that reversed-phase silica gel column chromatography obtains is in 3～5: 1 the mixed solvent; Stirring heating makes it dissolving, refluxes, and is cooled to room temperature then; Separate out solid under stirring, filter, filter cake is drained with methanol wash; Vacuum-drying gets purified product.
9. process for purification as claimed in claim 8 is characterized in that, in the mixed solvent of the used first alcohol and water of recrystallization, the volume ratio of first alcohol and water is 4: 1.
10. process for purification as claimed in claim 1 is characterized in that, comprises the steps:
1) the methylnaltrexone bromide bullion being added methyl alcohol and water volume ratio is that stirring heating makes it dissolving, every then 100mL solution adding 5g needle-use activated carbon in 4: 1 the mixed solvent; Backflow 30min; Be cooled to stirring at room 4h again, filter, filter cake is drained with methanol wash; 80 ℃ of vacuum-drying 6h get white products;
2) product that step 1) is obtained is crossed the reverse phase silica gel post after with water dissolution, earlier with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out; The thin-layer chromatography monitoring; When the principal constituent spot appears in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collecting is got product;
3) with step 2) to add methyl alcohol and water volume ratio be in 4: 1 the mixed solvent for the product that obtains, the stirring heating dissolving, backflow 30min is cooled to stirring at room 4h then, filters, and filter cake is drained with methanol wash, and 80 ℃ of vacuum-drying 6h get purified product.
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