CN102558189B - 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 chemicals synthesis technical field.
Background technology
Methylnaltrexone bromide (methyl naltrexone, MNTX) is a kind of selectivity mu opioid receptor antagonists, as a kind of quaternary ammonium salt, limit methylnaltrexone bromide by the ability of hemato encephalic barrier, make the opiate receptor antagonist of methylnaltrexone bromide as a kind of peripheral action, act on as in stomach intestinal tissue, therefore, methylnaltrexone bromide has reduced the constipation effect of opioid drug, and do not affect opioid drug to central nervous system analgesic activity.
Methylnaltrexone bromide has following characteristics: 1) acting on the μ acceptor of periphery, do not activate the opiate receptor of central nervous system, may be competitive antagonism; 2) safety, series of experiments does not all find that it has serious toxic side effect, common adverse reactions is stomachache, diarrhoea, flatulence and dizzy; 3) effect is fast, within several minutes, gets final product onset; 4) treatment constipation is than the logical purgatives of stool and tenderizer good effect; 5) action pathway is not unique, and directly the opiate receptor on gi tract is combined onset, can be combined with opiate receptor through the blood whole body that distributes yet.Therefore, methylnaltrexone bromide not only can be treated the gastrointestinal side-effect of opioid drug, also can treat parenteral untoward reaction; 6) not by hemato encephalic barrier, do not weaken the Central Analgesic 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 as follows:
Methylnaltrexone bromide belongs to the derivative of morphine ketone, by the preparation were established of methylnaltrexone bromide is carried out to literature search and investigation, discovery is prepared methylnaltrexone bromide all taking Naltrexone Hydrochloride as raw material, and alkalization obtains free alkali, then methylates and obtain the finished product methylnaltrexone bromide.Induction-arrangement goes out its synthetic route and is broadly divided into three:
Synthetic route one (referring to Chinese patent application prospectus CN101516892A):
This route is first protected the phenolic hydroxyl group of TREXUPONT, then methyl, hydrogenation Deprotection, ion-exchange, bromination reaction synthesize target product methylnaltrexone bromide on methyl-sulfate.
Synthetic route two (referring to US Patent No. 4176186):
This route is first protected the phenolic hydroxyl group of TREXUPONT, then methyl, hydrolysis Deprotection, ion-exchange, bromination reaction synthesize target product methylnaltrexone bromide on methyl iodide.
Synthetic route three (referring to US Patent No. 4176186):
The free alkali that this technique syntheti c route is Naltrexone Hydrochloride directly carries out bromomethylation with monobromethane and reacts, and a step obtains product methylnaltrexone bromide.
From three circuits that methylnaltrexone bromide is synthetic above, the reaction reagent toxicity that synthetic route one adopts is larger, and synthesis condition is comparatively harsh, carries out and gets up to have certain difficulty; Synthetic route two is similar to synthetic route one principle, not too harsh but synthetic route two requires, and relatively easily carries out; Synthetic route three steps are the shortest, and intermediate 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 refined.
In US4176186 embodiment 5, specifically disclose the method that is prepared as follows of methylnaltrexone bromide: in reactor, add 50ml anhydrous propanone, 0.5ml dimethyl formamide, mix, add 2.5g (7.35mmol) TREXUPONT alkali, add 4.25g (44.8mmol) monobromethane, room temperature confined reaction 21 days, after having reacted, concentrating under reduced pressure reaction solution, add methanol crystallization, methanol/ether recrystallization, obtains reaction product methylnaltrexone bromide.What in the method, FF adopted 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 the method obtains can not fulfilling medicinal.
Summary of the invention
The object 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, is applicable to industrialized production, and utilizes the methylnaltrexone bromide product that the inventive method obtains to meet the medicinal needed purity of high-quality methylnaltrexone bromide highly finished product.
Technical scheme of the present invention is as follows:
A process for purification for methylnaltrexone bromide, adopts reversed-phase silica gel column chromatography separation and purification methylnaltrexone bromide.
Further, the aqueous solution of methylnaltrexone bromide crude product is crossed reverse phase silica gel post by above-mentioned methylnaltrexone bromide process for purification, first with 1% methanol aqueous solution (volumn concentration, lower same) wash-out, with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography again, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product.The developping agent of wherein said thin-layer chromatography is ethyl acetate-sherwood oil-methanol mixed solvent, and three's volume ratio is ethyl 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 to carry out recrystallization purifying to methylnaltrexone bromide crude product.Common way is: methylnaltrexone bromide crude product is added in the mixed solvent of first alcohol and water, stirring heating makes it to dissolve, and then adds gac to reflux, be cooled to again room temperature, under stirring, separate out solid, filter, filter cake is drained by methanol wash, and vacuum-drying obtains white products.Wherein, described gac is preferably medicinal carbon, more preferably needle-use activated carbon, the methylnaltrexone bromide of pharmaceutically acceptable to prepare (particularly injection is used).In the mixed solvent of first alcohol and water, the volume ratio of first alcohol and water is preferably 3～5: 1, and more preferably 4: 1.The consumption of gac adds 5g gac with every 100mL solution and is advisable.Return time is preferably 30min.Vacuum drying temperature is preferably 80 DEG C, 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 to carry out recrystallization purifying to methylnaltrexone bromide.Be generally that the methylnaltrexone bromide obtaining through reversed-phase silica gel column chromatography is added in the mixed solvent of first alcohol and water, stirring heating makes it to dissolve, and refluxes, then be cooled to room temperature, under stirring, separate out solid, filter, filter cake is drained by methanol wash, and vacuum-drying obtains purified product.Wherein, in the mixed solvent of first alcohol and water, the volume ratio of first alcohol and water is preferably 3～5: 1, and more preferably 4: 1; Return time is preferably 30min; Vacuum drying temperature is preferably 80 DEG C, 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) methylnaltrexone bromide crude product is added in the mixed solvent that methyl alcohol and water volume ratio are 4: 1, stirring heating makes it to dissolve, after slightly cold, adding consumption is the needle-use activated carbon of 5% (g/mL), backflow 30min, then be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (methylnaltrexone bromide highly finished product 1).
2) by step 1) suitable quantity of water is crossed reverse phase silica gel post after dissolving for the product that obtains, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product (methylnaltrexone bromide highly finished product 2).
3) by step 2) obtain methylnaltrexone bromide product add in the mixed solvent that methyl alcohol and water volume ratio are 4: 1, stirring heating dissolve, backflow 30min, then be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain purified product.
Methylnaltrexone bromide crude product involved in the present invention can use any synthetic method of the prior art to obtain; include but not limited to following method: under nitrogen protection; in there-necked flask, add 11.6g (34.0mmol) TREXUPONT alkali; 175mL anhydrous propanone, 23.2mLDMF, 11.4mL (208mmol) monobromethane; close nitrogen; 25 DEG C of confined reactions 21 days, TLC monitoring experiment process, developping agent is ethyl acetate-sherwood oil-methyl alcohol (volume ratio 1: 1: 1).Reacted rear concentrating under reduced pressure reaction solution to dry, add 150mL washing with acetone after suction filtration obtain methylnaltrexone bromide crude product.80 DEG C of vacuum-drying 6h, obtain 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 High Temperature High Pressure, mild condition.
(2) yield is high.Experimental results show that (referring to the table 1-6 in embodiment), the process for purification of methylnaltrexone bromide of the present invention is under the prerequisite of purity that ensures finished product, and yield is higher.
(3) be applicable 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, simple to operate, is applicable to industrialized production.
(4) highly finished product purity is high.Referring to the table 7 in embodiment, the methylnaltrexone bromide finished product purity that process for purification of the present invention obtains is very high, exceed the purity that in prior art, methylnaltrexone bromide process for purification can reach, 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.
Brief description of the 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 nitrogen protection; in there-necked flask, add 11.6g (34.0mmol) TREXUPONT alkali, 175mL anhydrous propanone, 23.2mL DMF; 11.4mL (208mmol) monobromethane; close nitrogen, 25 DEG C of confined reactions 21 days, have reacted rear concentrating under reduced pressure reaction solution to dry; add suction filtration after 150mL washing with acetone; get 80 DEG C of vacuum-drying 6h of filter cake, obtain 13.4g methylnaltrexone bromide crude product, yield 90.17%.
Embodiment 1: methylnaltrexone bromide refining
In 250mL four-hole boiling flask, add 13.4g methylnaltrexone bromide crude product, 75mL methyl alcohol, 19mL pure water, stirring heating is dissolved, after slightly cold, add 0.7g needle-use activated carbon, backflow 30min, is cooled to stirring at room temperature 4h, filters, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 1 ") 10.4g, yield 77.61%.
Above-mentioned 10.4g methylnaltrexone bromide highly finished product 1 use suitable quantity of water is crossed reverse phase silica gel post after dissolving, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product (being denoted as " methylnaltrexone bromide highly finished product 2 ") 7.15g, yield 68.75%.
In 100mL four-hole boiling flask, add 7.15g methylnaltrexone bromide highly finished product 2,42.0mL methyl alcohol, 10.5mL pure water, stirring heating is dissolved, backflow 30min, be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 3 ") 5.86g, yield 81.96%.
1h-NMR (500MHz d
6-DMSO δ ppm) 9.48 (s, 1H can D
2o exchange), 6.67 (s, 2H), 6.39 (s, 1H can D
2o 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
In 250mL four-hole boiling flask, add 13.4g methylnaltrexone bromide crude product, 75mL methyl alcohol, 19mL pure water, stirring heating is dissolved, and adds 0.7g needle-use activated carbon after slightly cold, and backflow 30min, is cooled to stirring at room temperature 4h.Filter, filter cake is drained by methanol wash, and 80 DEG C of vacuum-drying 6h obtain white products (being denoted as " methylnaltrexone bromide highly finished product 1 ") 10.2g.
Above-mentioned 10.2g methylnaltrexone bromide highly finished product 1 use suitable quantity of water is crossed reverse phase silica gel post after dissolving, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product (being denoted as " methylnaltrexone bromide highly finished product 2 ") 7.05g.
Embodiment 3: methylnaltrexone bromide refining
13.4g methylnaltrexone bromide crude product is crossed reverse phase silica gel post after dissolving by suitable quantity of water, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product 7.25g.
Embodiment 4: methylnaltrexone bromide refining
13.4g methylnaltrexone bromide crude product is crossed reverse phase silica gel post after dissolving by suitable quantity of water, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product 7.30g.
In 100mL four-hole boiling flask, add above-mentioned 7.30g methylnaltrexone bromide product, 42.0mL methyl alcohol, 10.5mL pure water, stirring heating is dissolved, backflow 30min, be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products 5.76g.
Embodiment 5: methylnaltrexone bromide refining
In reactor, add 90.7g methylnaltrexone bromide crude product, 508mL methyl alcohol, 127mL pure water, stirring heating is dissolved, after slightly cold, add gac 5g, backflow 30min, is cooled to stirring at room temperature 4h, filters, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 1 ") 71.9g, yield 79.3%.
71.9g methylnaltrexone bromide highly finished product 1 use suitable quantity of water is crossed reverse phase silica gel post after dissolving, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product (being denoted as " methylnaltrexone bromide highly finished product 2 ") 48.84g, yield 67.95%.
In reactor, add 48.84g methylnaltrexone bromide highly finished product 2,273.6mL methyl alcohol, 68.4mL pure water, stirring heating is dissolved, backflow 30min, be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 3 ") 40.15g, yield 82.21%.
Embodiment 6: methylnaltrexone bromide refining
In reactor, add 74.4g methylnaltrexone bromide crude product, 416mL methyl alcohol, 104mL pure water, stirring heating is dissolved, after slightly cold, add gac 5g, backflow 30min, is cooled to stirring at room temperature 4h, filters, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 1 ") 56.5g, yield 76.0%.
56.5g methylnaltrexone bromide highly finished product 1 use suitable quantity of water is crossed reverse phase silica gel post after dissolving, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product (being denoted as " methylnaltrexone bromide highly finished product 2 ") 38.84g, yield 68.70%.
In reactor, add 38.84g methylnaltrexone bromide highly finished product 2,217.6mL methyl alcohol, 54.4mL pure water, stirring heating is dissolved, backflow 30min, be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 3 ") 31.64g, yield 81.47%.
Embodiment 7: methylnaltrexone bromide refining
In reactor, add 481.04g methylnaltrexone bromide crude product, 2696mL methyl alcohol, 674mL pure water, stirring heating is dissolved, after slightly cold, add needle-use activated carbon 5g, backflow 30min, is cooled to stirring at room temperature 4h, filters, filter cake methanol wash is drained, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 1 ") 365.72g, yield 76.03%.
365.72g methylnaltrexone bromide highly finished product 1 use suitable quantity of water is crossed reverse phase silica gel post after dissolving, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product (being denoted as " methylnaltrexone bromide highly finished product 2 ") 251.76g, yield 68.84%.
In reactor, add 251.76g methylnaltrexone bromide highly finished product 2,1408mL methyl alcohol, 352mL pure water, stirring heating is dissolved, backflow 30min, be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 3 ") 204.74g, yield 81.32%.
Embodiment 8: methylnaltrexone bromide refining
In reactor, add 488.81g methylnaltrexone bromide crude product, 2736mL methyl alcohol, 684mL pure water, stirring heating is dissolved, after slightly cold, add needle-use activated carbon 5g, backflow 30min, is cooled to stirring at room temperature 4h, filters, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 1 ") 371.52g, yield 76.00%.
371.52g methylnaltrexone bromide highly finished product 1 use suitable quantity of water is crossed reverse phase silica gel post after dissolving, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product (being denoted as " methylnaltrexone bromide highly finished product 2 ") 256.54g, yield 69.05%.
In reactor, add 256.54g methylnaltrexone bromide highly finished product 2,1440mL methyl alcohol, 360mL pure water, stirring heating is dissolved, backflow 30min, be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 3 ") 207.21g, yield 80.77%.
Embodiment 9: methylnaltrexone bromide refining
In reactor, add 493.97g methylnaltrexone bromide crude product, 2768mL methyl alcohol, 692mL pure water, stirring heating is dissolved, after slightly cold, add needle-use activated carbon 5g, backflow 30min, is cooled to stirring at room temperature 4h, filters, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 1 ") 370.42g, yield 74.98%.
Product is crossed reverse phase silica gel post after dissolving by suitable quantity of water, first with 1% methanol aqueous solution wash-out, again with 5% methanol aqueous solution wash-out, thin-layer chromatography (TLC) monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product (being denoted as " methylnaltrexone bromide highly finished product 2 ") 256.09g, yield 69.14%.
In reactor, add 256.09g methylnaltrexone bromide crude product, 1432mL methyl alcohol, 358mL pure water, stirring heating is dissolved, backflow 30min, be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain white products (being denoted as " methylnaltrexone bromide highly finished product 3 ") 206.63g, yield 80.68%.
Data to above-described embodiment and result are summarized and are analyzed below, feasibility and the stability of checking process for refining of the present invention.
Three batches of product lab scale datas:
Table 1: refining 1 (raw material: methylnaltrexone bromide crude product) of finished product
Table 2: refining 2 (raw materials: methylnaltrexone bromide highly finished product 1) of finished product
Table 3: refining 3 (raw materials: methylnaltrexone bromide highly finished product 2) of finished product
Three batches of product amplification quantity datas:
Table 4: refining 1 (raw material: methylnaltrexone bromide crude product) of finished product
Table 5: refining 2 (raw materials: methylnaltrexone bromide highly finished product 1) of finished product
Table 6: 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 powder
HPLC detects: high performance liquid phase 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 DEG C
Theoretical plate number: press methylnaltrexone bromide and calculate, should be not less than 3000.
HPLC method detected result is in table 7.
Table 7: the quality control of the purifying end product of methylnaltrexone bromide and with the comparison of US4176186 recrystallization method:
Note: US4176186 recrystallization method is: methylnaltrexone bromide crude product is first used methanol crystallization, then use methanol/ether recrystallization, obtain product methylnaltrexone bromide.
Can see by 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 US4176186 recrystallization method obtains is lower, related substance (impurity) is more, is not suitable as the raw material of medicinal methylnaltrexone bromide preparation.
The technique 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 technique circulation ratio is good, products obtained therefrom steady quality.Figure of description 1,2 is shown in by the purity detecting HPLC collection of illustrative plates of embodiment 1 and embodiment 5 end products.
Claims (2)
1. a process for purification for methylnaltrexone bromide, comprises the following steps:
1) methylnaltrexone bromide crude product is added in the mixed solvent that methyl alcohol and water volume ratio are 4: 1, stirring heating makes it to dissolve, and then adds needle-use activated carbon, backflow 30min, then be cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, and 80 DEG C of vacuum-drying 6h, obtain white products;
2) product step 1) being obtained is with crossing reverse phase silica gel post after water dissolution, first with 1% methanol aqueous solution wash-out, then with 5% methanol aqueous solution wash-out, thin-layer chromatography monitoring, in the time there is principal constituent spot in thin-layer chromatography, collect corresponding elutriant, the elutriant concentrating under reduced pressure of collection is obtained to product;
3) by step 2) obtain product add in the mixed solvent that methyl alcohol and water volume ratio are 4: 1, stirring heating dissolve, backflow 30min, is then cooled to stirring at room temperature 4h, filter, filter cake is drained by methanol wash, 80 DEG C of vacuum-drying 6h, obtain purified product.
2. process for purification as claimed in claim 1, is characterized in that step 2) described in the developping agent of thin-layer chromatography be that volume ratio is ethyl acetate-sherwood oil-methanol mixed solvent of 1: 1: 1.
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