CN102351869A - Preparation method of high-purity methylnaltrexone bromide - Google Patents
Preparation method of high-purity methylnaltrexone bromide Download PDFInfo
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Abstract
The invention relates to a preparation method of high-purity methylnaltrexone bromide. The technique is simple, and the prepared product has high yield and high purity. The method comprises the following steps: carrying out quaternary amination on naltrexone hydrochloride to obtain a quaternary ammonium salt mixture, carrying out demethylation treatment on the byproducts in the mixture to completely generate simple N-methylnaltrexone, and carrying out ion exchange and purification to obtain the pure finished product. The preparation method provided by the invention has the advantages of fewer reaction steps, high yield and simple technique; the purity of the prepared product is up to higher than 99.8%, and the content of the single impurity is lower than 0.1%; and the product has high stability, and is suitable for industrial production. Besides, the method provided by the invention overcomes the defects of long period, high solvent consumption, low yield and the like when column chromatography is used for purifying the product, and can easily implement large-scale production.
Description
Technical field
The present invention relates to the preparation method of the high methylnaltrexone bromide of the simple yield high purity of a kind of technology, belong to medical production technical field.
Background technology
Methylnaltrexone bromide (CAS:73232-52-7, Methylnaltrexone bromide), chemistry bromination-17-(cyclopropyl methyl)-4 by name, 5 α-epoxy-3,14-dihydroxyl-17-methyl-6-oxo morphinan, structural formula is:
Methylnaltrexone bromide is being learned synthetic first by Univ Chicago USA the seventies in last century, have good peripheral opioid receptor blocking effect.Thereafter, U.S. Hui Shi Wyeth pharmacy Subsidiary Company and Progenics Pharmaceuticals company unite and have carried out follow-up study and follow-up popularization.In April, 2008, Her Majesty the Queen in right of Canada as represented by the minister of Healt and U.S. FDA were ratified methylnaltrexone bromide injection (Methylnaltrexone bromide respectively; Trade(brand)name Relistor) listing; Be used for subcutaneous injection; (opioid-induced constipation OIC) uses the invalid situation of laxative in the constipation that the treatment opioid drug causes.
Opioid drug is clinical common analgesics thing, has a wide range of applications clinically, and it is through with the interior brain of cns (CNS) and spinal cord mu opioid receptor specific effect and alleviating pain.Late period the patient with severe symptoms, like cancer, often need in long period of time, to use continuously opioid drug by chronic obstructive pulmonary disease (COPD), heart failure, alzheimer's disease and AIDS patients with terminal due to the pulmonary emphysema development.But untoward reactions such as opioid drug can cause nausea with the μ sheet receptor acting of (in gi tract) beyond the cns, constipation.Relistor is the verivate of TREXUPONT, is opiate receptor antagonist, the mu opioid receptor on the antagonism enteron aisle optionally, thus alleviate the caused constipation symptom of opium kind analgesics.Methylnaltrexone bromide does not influence their analgesic activity through reducing constipation untoward reaction such as opioid drugs such as morphine and morphine monomethyl ethers and playing a role.Because Relistor has the unique chemical structure; So it can not pass the hemato encephalic barrier of human body; Can only with the opiate receptor effect of periphery; Can not influence the analgesic effect of opioid drug, thereby can greatly palliate the agonizing sufferings for the terminal illness patient who takes the caused constipation of opioid drug (OIC) to cns.
The disclosed synthetic patent of relevant methylnaltrexone bromide has US4176186, WO2004/43964, WO2006/127899 (CN101208344A), WO2008/034973 (CN101516892A), CN101607963, CN101845047, CN10037941.Synthetic route such as Fig. 1.
Disclosed the earliest patent US4176186 in 1979 is to be that raw material is with the direct N-alkylation of methyl iodide, obtain the N-SC-37359 through ion conversion (is not under the situation of bromide anion like the quaternary ammoniated product negatively charged ion that obtains) again with Naltrexone Hydrochloride (or free alkali).Shortcomings such as this method does not add base catalysis in quaternary ammonium reaction, exist raw material reaction incomplete, and side reaction produces a large amount of phenolic hydroxyl group alkylates and fails effectively to utilize, and the complicated yield of aftertreatment is low.
It is raw material that patent WO2004/43964 discloses with the TREXUPONT, with monobromethane in dipolar nature solvents such as NMP normal pressure or slightly with the condition of pressure under the method for prepared in reaction methylnaltrexone bromide.This method raw material reaction is not thorough, is prone to produce the phenol alkylate by-product, and refining yield is on the low side, and the difficult amplification preparation of monobromethane complicated operation is produced.
In order to overcome the shortcoming that produces the phenol alkylate by-product; Patent WO2006/127899 (CN101208344A) has adopted isobutyryl earlier the phenolic hydroxyl group of TREXUPONT to be protected, and obtains the title product methylnaltrexone bromide with methyl iodide N-alkylation, hydrolysis, IX then.Though this method has overcome the shortcoming of easy generation alkylate by-product, reactions step is long, and the midbody aftertreatment needed column purification, quaternary ammoniatedly directly in methyl iodide, carries out, and need in pressurized vessel, carry out and react not exclusively, still has the not high shortcoming of yield.
WO2008/034973 (CN101516892A) is that starting raw material prepares TREXUPONT with the noroxymorphone; Adopt benzyl that the phenolic hydroxyl group of TREXUPONT is protected; And then carry out quaternary ammoniated with dimethyl sulfate; Repeated hydrogenation is sloughed benzyl, in the presence of alkali, obtains quaternary amine alkali, handles obtaining methylnaltrexone bromide at last with Hydrogen bromide.Though this method has improved yield; But the technology that is unfavorable for industrial amplification production that has adopted bromobenzyl with strong lacrimation and hydrogenation to take off benzyl; Alkaline purification simultaneously prepares in the process of quaternary amine alkali, and quaternary ammonium salt is the unstable generation Hofmann degradation generation impurity that is prone under alkaline condition.
It is raw material with the Naltrexone Hydrochloride that CN101607963A discloses a kind of, and first spent glycol is protected ketal, and the recycle silicon alkyl is protected phenolic hydroxyl group, and quaternary ammoniated then, hydrolysis, IX obtain product.This route is long, and cost is higher and complicated, and quaternary ammonium reagent trifluoromethanesulfonic acid methyl esters, methyl mesylate costliness are difficult to obtain.
Summary of the invention
The objective of the invention is to overcome the weak point that exists in the prior art, the preparation method of the methylnaltrexone bromide that a kind of technology is simple, reactions step is few, yield is high, purity is high is provided.
The present invention about one of purpose of the preparation method of methylnaltrexone bromide for preparation a kind of formula I or formula II or comprise the formula I simultaneously and the midbody or the mixture of the morphinan quaternary amine of formula II:
Wherein, X
-Be acid radical anion.
Another purpose of the present invention is carried out abundant N-alkylation under situation about phenolic hydroxyl group not being protected, directly using alkylating reagent; There is portion of product that side reaction also takes place simultaneously and generates the alkylating by product of phenolic hydroxyl group (formula I); Effectively utilize the alkylating by product of phenolic hydroxyl group (formula I) again; It is taken off the O-methyl through reaction all be converted into title product N-SC-37359 (formula II), improve overall yield.
A kind of preparation method of highly purified methylnaltrexone bromide, its technology is simple, and reactions step is few, and synthetic route is as shown in Figure 2, and prepared product yield is high, purity＞99.8%, list mixes＜0.1%, it is characterized in that, comprises following steps:
(1) it is quaternary ammoniated to use alkylating reagent in the presence of alkali, in anhydrous non-proton dipole solvent, directly Naltrexone Hydrochloride to be carried out, and makes its complete N-alkylation obtain the quaternary ammonium mixture of N-SC-37359 and 3-O-methyl TREXUPONT;
(2) to resulting quaternary ammonium mixture with the directed demethylation of mineral acid; Make by product 3-O-methyl TREXUPONT take off the O-methyl; Aftertreatment separates with a kind of non-protonic solvent hybrid extraction with a kind of protic solvent; Utilize by product to change into title product fully again, improve yield, obtain the quaternary ammonium salt of the higher N-SC-37359 of purity;
The quaternary ammonium salt of the N-SC-37359 that (3) obtains obtains the bullion of methylnaltrexone bromide again through IX, bullion is made with extra care with mixed solvent and obtained pure methylnaltrexone bromide, and its total recovery is high, and purity is greater than 99.8%, and is single assorted less than 0.1%.
In the aforesaid method, described alkylating reagent is selected from a kind of in methyl iodide, dimethyl sulfate, methylcarbonate, monobromethane, methyl tosylate and the trifluoromethanesulfonic acid methyl esters.
In the aforesaid method, described alkali is one or more mixtures in salt of wormwood, yellow soda ash, cesium carbonate, sodium hydroxide, sodium hydride, the triethylamine.
In the aforesaid method, described anhydrous non-proton dipole solvent is selected from one or more the mixture in DMF, NMP, acetone, the acetonitrile.
In the aforesaid method, described mineral acid reacts under 10 ~ 120 ℃ of temperature, makes the alkylating quaternary ammonium salt by product of phenolic hydroxyl group take off the O-methyl, the sulfuric acid that used acid is, hydrochloric acid, hydrobromic a kind of.Preferred Hydrogen bromide, mass concentration is 10 ~ 48%; Temperature of reaction is 10 ~ 120 ℃.
In the aforesaid method, the protic solvent that the aftertreatment of the described O-of taking off methyl is used is a kind of of methylene dichloride, trichloromethane or combination, and the aprotic extraction solvent is a kind of or combination of sherwood oil, ether, isopropyl ether; The volume ratio of said protic solvent and non-protonic solvent is 1:1～3:1; The crystallization solvent is a kind of in methyl alcohol, ethanol, the acetonitrile.Preferred scheme is that protic solvent is a methylene dichloride, and the aprotic extraction solvent is an ether, and the mixed solvent ratio is 1:1, and the crystallization solvent is a methyl alcohol.
In the aforesaid method, mixed solvent is selected from described in the step (3): a kind of combination in ethanol-acetone, DMF-acetone, the DMF-ETHYLE ACETATE.
The end product optical purity that the present invention obtains is greater than 99.8%, single impurity < 0.1%.The HPLC condition is Phenomenex Inertsil ODS-3,150*4.6mm, 3 μ m; Column temperature: 50.0 ℃; Flow velocity: 1.5ml/> minute; Sampling volume: 20 μ l; Detect wavelength: 280nm; Mobile phase A=water: MeOH:TFA (95:5:0.1%; V/v/v), B=water: MeOH:TFA (25:75:0.1%; V/v/v); Analysis time: 60 minutes.
The gradient characteristic:
| Time (minute) | %A | %B | Curve |
| 0：00 | 100 | 0 | Initially |
| 45 | 50 | 50 | Linear |
| 48 | 100 | 0 | Linear |
| 55 | 100 | 0 | Keep |
MeOH=methyl alcohol, the TFA=trifluoroacetic acid.
Method of the present invention has following technique effect:
1) the methylnaltrexone bromide bulk drug that adopts method of the present invention to prepare; Product purity is more than 99.8%; Single impurity is less than 0.1%; Quality product can satisfy the requirement of injection raw material, has reached the correlation technique requirement of the quality approach technical director of European Union principle ICH equally, for preparation research provides up-to-standard starting material;
2) preparing method's technological process of the present invention is easy, and cost is low, and technology is easy to suitability for industrialized production; The preparation impurity that adopts this raw material to process is few, good effect, and untoward reaction is low, for the patient brings maximum benefit.
Description of drawings
Fig. 1 is existing synthetic route chart.
Fig. 2 is a synthetic route chart of the present invention.
Embodiment
Further specify the present invention through embodiment below.Should correct understanding be: the method in the embodiments of the invention is only used for the present invention is described and provides, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the present invention and requires the scope protected.
Reference examples 1 (referenceUS4176186 prepares methylnaltrexone bromide)
8.0g (21.1mmol) Naltrexone Hydrochloride is changed into the TREXUPONT free alkali, and free alkali adds pressurized vessel after being dissolved in 50ml acetone, and solution adds 8ml (0.128mmol) methyl iodide again and mixes; Sealed pressure vessel; Reaction mixture is heated to 4 days postcooling of 70 ℃ of reactions, pours out the stillness of night, and residuum is used the methanol recrystallization; Obtain 5.8g methyl iodide, yield 57%.
Gained 5.8g N-SC-37359 iodide are converted to 4.8g (yield 94.7%) Methobromide through ion exchange resin.Product gets methylnaltrexone bromide 4.4g (yield 91.7%), purity 96.4% with the methanol recrystallization again.
Reference examples 2 (referencesWO2006/127899 prepares methylnaltrexone bromide)
In the 500ml there-necked flask, add 370ml anhydrous tetrahydro furan, 5.0g (14.65mmol) TREXUPONT, stirring and dissolving postcooling to 0 ℃ drips the 4.3ml triethylamine, drips isobutyryl chloride 3.3ml down at 0 ℃ again, behind the insulation reaction 1h again stirring at room to reacting completely.Add the cancellation of 200ml sodium hydrogen carbonate solution; Twice extraction of 800ml methylene dichloride phenol merges the organic layer of telling and uses the 300ml brine wash more once, is concentrated into dried behind the anhydrous sodium sulfate drying; Concentrate through quick silicagel column column purification again and obtain 4.71g white midbody 1, yield 78.2%.
4.71g (11.45mmol) midbody 1 joins in the glass pressure container, adds methyl iodide 6.3 g (44.37mmol), the sealing glass pressurized vessel, and oil bath is heated to 88～90 ℃ of reaction 17h, and vacuum extracts unnecessary methyl iodide and obtains the off-white color solid.Solid is dissolved in methylene chloride (4:1) and is applied to the silicagel column purifying, collects to obtain the concentrated midbody 2 that obtains 5.83g white of title product, yield 91.5%.
Midbody 2 (5.83g 10.53mmol) is dissolved in the 90ml methyl alcohol, adds 48% Hydrogen bromide of 78ml water and 10ml, stirring reaction 6.5h under the following 65 ℃ of oil baths of nitrogen protection, and reaction solution is evaporated to the dried brown solid 4.0g (midbody 3) that obtains for 25 ℃.
4.0g midbody 3 usefulness 50ml water dissolution are after strong basicity bromide anion exchange resin exchanges, elutriant concentrates for 35 ℃ and obtains 3.5 yellow solids.Obtain the 3.1g methylnaltrexone bromide with recrystallizing methanol, total recovery 48.5%, purity 98.2%.
Embodiment 1 contains the preparation of the mixture of morphinan quaternary amine
With acetonitrile 20ml, Naltrexone Hydrochloride (5g, 13.2mmol), salt of wormwood (5g, 36.18mmol) and methyl iodide (15g 105.68mmol) joins in the 100ml single port bottle, loads onto spherical condensation tube, N
260 ℃ of reflux of the airtight back oil bath of ball; Magnetic agitation reaction 72h; TLC detects that (developping agent: methylene dichloride: methyl alcohol=10:1) shows no raw material; Produce 2 products (product at Rf ≈ 0.2 place is a SC-37359, and the product at Rf ≈ 0.4 place is the methylated quaternary ammonium salt of phenolic hydroxyl group), stopped reaction at Rf ≈ 0.2 and 0.4 place.Reaction solution is cooled to room temperature, filters, and filter cake is drained with an amount of acetonitrile washing, filtrates that it is dried to be evaporated in 38 ℃ of water-baths, obtains the 6.5g faint yellow solid.
Embodiment 2 contains the preparation of the mixture of morphinan quaternary amine
With acetone 20ml, Naltrexone Hydrochloride (4g, 10.55mmol), yellow soda ash (4.2g, 39.62mmol) and dimethyl sulfate (10g 79.28mmol) joins in the 100ml single port bottle, loads onto spherical condensation tube, N
260 ℃ of heating of ball airtight back oil bath; Magnetic agitation reaction 36h; TLC detects that (developping agent: methylene dichloride: methyl alcohol=10:1) shows no raw material; (product at Rf ≈ 0.2 place is a SC-37359, and the product at Rf ≈ 0.4 place is the methylated quaternary ammonium salt of phenolic hydroxyl group to produce 2 products at Rf ≈ 0.2 and 0.4 place.), stopped reaction.Reaction solution is cooled to room temperature, filters, and filter cake is drained with an amount of acetonitrile washing, filtrates that it is dried to be evaporated in 38 ℃ of water-baths, obtains yellow oil 6.2g.
Embodiment 3 contains the preparation of the mixture of morphinan quaternary amine
With DMF 20ml, Naltrexone Hydrochloride (5g, 13.2mmol), triethylamine (2.8g, 27.70mmol) and dimethyl carbonate (7.5g 83.26mmol) joins in the 100ml single port bottle, loads onto spherical condensation tube, N
280 ℃ of reflux of the airtight back oil bath of ball; Magnetic agitation reaction 72h; TLC detects that (developping agent: methylene dichloride: methyl alcohol=10:1) shows no raw material; (product at Rf ≈ 0.2 place is a SC-37359, and the product at Rf ≈ 0.4 place is the methylated quaternary ammonium salt of phenolic hydroxyl group to produce 2 products at Rf ≈ 0.2 and 0.4 place.), stopped reaction.Reaction solution is cooled to room temperature, filters, and filter cake is drained with an amount of acetonitrile washing, filtrates that it is dried to be evaporated in 80 ℃, obtains faint yellow solid 5.8g.
Embodiment 4 contains the preparation of the mixture of morphinan quaternary amine
With NMP 20ml, (5g, 13.2mmol), (0.7g, 29.17nmol) (15g 158mmol) joins in the 100ml single port bottle sodium hydride Naltrexone Hydrochloride, loads onto spherical condensation tube, N with the refrigerated of cryosel bath in advance monobromethane
240 ℃ of reflux of the airtight back oil bath of ball; Magnetic agitation reaction 5 days; TLC detects (developping agent: methylene dichloride: methyl alcohol=10:1) show not have raw material basically; Produce 2 products (product at Rf ≈ 0.2 place is a SC-37359, and it is the methylated quaternary ammonium salt of phenolic hydroxyl group that Rf ≈ 0.4 place gets product), stopped reaction at Rf=0.2 and 0.4 place.Reaction solution is cooled to room temperature, filters, and filter cake is drained with an amount of acetonitrile washing, filtrates that it is dried to be evaporated in 80 ℃, obtains the 5.8g yellow solid.
Embodiment 5 contains the preparation of the mixture of morphinan quaternary amine
With acetonitrile 20ml, Naltrexone Hydrochloride (6g, 15.8mmmol), sodium hydroxide (0.53g, 13.25mmol) and methyl tosylate (10g 53.70mmol) joins in the 100ml single port bottle, loads onto spherical condensation tube, N
240 ℃ of reflux of the airtight back oil bath of ball; Magnetic agitation reaction 5 days; TLC detects (developping agent: methylene dichloride: methyl alcohol=10:1) show not have raw material basically; (product at Rf ≈ 0.2 place is a SC-37359, and it is the methylated quaternary ammonium salt of phenolic hydroxyl group that Rf ≈ 0.4 place gets product to produce 2 products at Rf ≈ 0.2 and 0.4 place.), stopped reaction.Reaction solution is cooled to room temperature, filters, and filter cake is drained with an amount of acetonitrile washing, filtrates that it is dried to be evaporated in 38 ℃ of water-baths, obtains 7.1g palm fibre xanchromatic oily matter.
Embodiment 6 contains the preparation of the mixture of morphinan quaternary amine
With acetonitrile 20ml, (7.5g, 19.8mmol), (5g, 36.18mmol), (2g, 6.14mmol) (6.6g 40.22mmol) joins in the 100ml single port bottle cesium carbonate salt of wormwood Naltrexone Hydrochloride, loads onto spherical condensation tube, N with the trifluoromethanesulfonic acid methyl esters
260 ℃ of reflux of the airtight back oil bath of ball; Magnetic agitation reaction 72h; TLC detects that (developping agent: methylene dichloride: methyl alcohol=10:1) shows no raw material; Produce 2 products (product at Rf ≈ 0.2 place is a SC-37359, and the product at Rf ≈ 0.4 place is the methylated quaternary ammonium salt of phenolic hydroxyl group), stopped reaction at Rf ≈ 0.2 and 0.4 place.Reaction solution is cooled to room temperature, filters, and filter cake is drained with an amount of acetonitrile washing, filtrates that it is dried to be evaporated in 38 ℃ of water-baths, obtains the 7.2g yellow solid.
The preparation of embodiment 7 N-SC-37359 quaternary ammonium salts
In the 6.5g solid for preparing with reference to embodiment 1, add the 40ml dissolve with methanol, add >=40% Hydrogen bromide 40ml again, obtain the Hydrogen bromide reaction solution of 20% concentration, be heated to 60～80 ℃ of back flow reaction 5～6h under stirring.The product of TLC monitoring Rf ≈ 0.4 all is converted into the product of Rf ≈ 0.2, is cooled to room temperature, with methylene dichloride/ether (volume ratio 1/1) extraction 2 times; Tell lower aqueous layer, 50 ℃ are evaporated to no cut and steam the methyl alcohol of 3 times of weight of adding; Be cooled to 0～5 ℃ and separate out needle-like solid, filter, cold methanol wash is drained; 40 ℃ of forced air dryings get white or off-white color solid 5.4g, purity 99.06%, yield 93.6% (feeding intake by the 5g Naltrexone Hydrochloride).
The preparation of embodiment 8 N-SC-37359 quaternary ammonium salts
In the 6.5g solid for preparing with reference to embodiment 1, add the 10ml dissolve with methanol, add >=40% Hydrogen bromide 30ml again, obtain the Hydrogen bromide reaction solution of 30% concentration, be heated to 60～80 ℃ of back flow reaction 5～6h under stirring.The product of TLC monitoring Rf ≈ 0.4 all is converted into the product of Rf ≈ 0.2, is cooled to room temperature, with isopyknic trichloromethane/isopropyl ether (volume ratio 1/1) extraction 2 times; Tell lower aqueous layer, 50 ℃ are evaporated to no cut and steam the methyl alcohol of 3 times of weight of adding; Be cooled to 0～5 ℃ and separate out needle-like solid, filter, cold methanol wash is drained; 40 ℃ of forced air dryings get white or off-white color solid 5.3g, purity 98.90%, yield 91.9% (feeding intake by the 5g Naltrexone Hydrochloride).
The preparation of embodiment 9 N-SC-37359 quaternary ammonium salts
In the 6.5g solid for preparing with reference to embodiment 1, add the 30ml dissolve with methanol, add >=40% Hydrogen bromide 10ml again, obtain the Hydrogen bromide reaction solution of 10% concentration, be heated to 120 ℃ of back flow reaction 12～15h under stirring.The product of TLC monitoring R ≈ 0.4 all is converted into the product of Rf ≈ 0.2, is cooled to room temperature, with methylene dichloride/ether (volume ratio 3/1) extraction 2 times; Tell lower aqueous layer, 50 ℃ are evaporated to no cut and steam the methyl alcohol of 3 times of weight of adding; Be cooled to 0～5 ℃ and separate out needle-like solid, filter, cold methanol wash is drained; 40 ℃ of forced air dryings get white or off-white color solid 5.3g, purity 98.65%, yield 91.9% (feeding intake by the 5g Naltrexone Hydrochloride).
The preparation of embodiment 10 N-SC-37359 quaternary ammonium salts
The Hydrogen bromide 30ml of adding 48% stirs following 10～20 ℃ of reactions and spends the night in the 5.8g solid for preparing with reference to embodiment 3.The product of TLC monitoring Rf ≈ 0.4 all is converted into the product of Rf ≈ 0.2, is cooled to room temperature, with methylene dichloride/ether (volume ratio 2/1) extraction 2 times; Tell lower aqueous layer, 50 ℃ are evaporated to no cut and steam the ethanol of 3 times of weight of adding; Be cooled to 0～5 ℃ and separate out needle-like solid, filter, cold washing with alcohol is drained; 40 ℃ of forced air dryings get white or off-white color solid 5.2g, purity 98.20%, yield 90.2% (feeding intake by the 5g Naltrexone Hydrochloride).
The preparation of embodiment 11 N-SC-37359 quaternary ammonium salts
In the 6.2g oily matter for preparing with reference to embodiment 2, add entry 40ml, 98% sulfuric acid 10ml stirs 80～100 ℃ of reaction 24h down.The product of TLC monitoring Rf ≈ 0.4 all is converted into the product of Rf ≈ 0.2, is cooled to room temperature, with isopyknic methylene dichloride/sherwood oil (volume ratio 2/1) extraction 2 times; Tell lower aqueous layer, regulate pH3～4 with saturated sodium carbonate solution, water obtains solid in 50 ℃ of following concentrating under reduced pressure; Add the acetonitrile making beating of 10 times of weight, separate out solid, filter; The acetonitrile washing is drained; 40 ℃ of forced air dryings get white or off-white color solid 4.5g, purity 98.50%, yield 74.9% (feeding intake by the 5g Naltrexone Hydrochloride).
The preparation of embodiment 12 N-SC-37359 quaternary ammonium salts
In the 5.8g solid for preparing with reference to embodiment 4, add methyl alcohol 20ml, concentrated hydrochloric acid 20ml stirs 80～100 ℃ of reaction 24h down.The product of TLC monitoring Rf ≈ 0.4 all is converted into the product of Rf ≈ 0.2, is cooled to room temperature, with isopyknic trichloromethane/ether (volume ratio 1/1) extraction 2 times; Tell lower aqueous layer, regulate pH3～4 with saturated sodium carbonate solution, water obtains solid in 50 ℃ of following concentrating under reduced pressure; Add the acetone making beating of 5 times of weight, filter, washing with acetone is drained; 40 ℃ of forced air dryings get white or off-white color solid 4.2g, purity 98.52%, yield 81.1% (feeding intake by the 5g Naltrexone Hydrochloride).
The preparation of embodiment 13 methylnaltrexone bromides
60g strong base bromide anion exchanger water is mixed the ion exchange column of packing into (among the φ 20mm * 300mm); The 5.4g solid that again embodiment 7 is prepared is dissolved in and obtains upper prop liquid in the 60ml water; Slowly add in the chromatography column, with 500ml water flushing post bed, collect elutriant again.Elutriant is evaporated to the dried 5.3g of obtaining bullion, white or off-white color solid, purity 99.8%, yield 98.1% in 50 ℃.
Making with extra care of embodiment 14 methylnaltrexone bromides
5.3g bullion joins in the 60ml ethanol; Being heated with stirring to the full back adding 0.5g activated carbon decolorizing that dissolves that refluxes filters; The acetone that adds 60ml heat in the filtrating; Slowly stirring is cooled to 0～10 ℃ and separates out crystal, filters, and filter cake is drained back 40 ℃ of forced air dryings with washing with acetone and obtained white solid 5.0g (yield 94.3%).HPLC content 99.95%, maximum simple substance 0.04%, fusing point (DSC): 261.6 ℃, molecular weight (M
+): 356.Refining yield 94.3%, total recovery 86.7%.
1HNMR：δ9.52（1H），δ6.68（2H），δ6.41（1H），δ4.93（1H），δ4.04-4.05（1H），δ3.90-3.93（1H），δ3.67（3H），δ3.51-3.55（1H），δ3.33-3.36（1H），δ2.89-3.09（3H），δ2.75-2.77（2H），δ2.05-2.11（2H），δ1.54-1.62（2H），δ1.22-1.24（1H），δ0.75-0.79（1H），δ0.67-0.74（1H），δ0.60-0.66（1H），δ0.37-0.40（1H）
13CNMR：δ207.9（1C），δ144.2（1C），δ141.0（1C），δ128.3（1C），δ120.8（1C），δ120.3（1C），δ118.7（1C），δ89.0（1C），δ72.3（1C），δ71.5（1C），δ57.2（1C），53.3（1C），48.9（1C），δ40.0（1C），δ35.4（1C），δ32.6（1C），δ27.8（1C），δ25.0（1C），δ6.2（1C），δ4.4（1C），δ3.3（1C）
Making with extra care of embodiment 15 methylnaltrexone bromides
The 5g bullion joins among the 15mlDMF; Be heated with stirring to 60 ℃ of full backs of dissolving and add the small amount of activated decolorization filtering; The ETHYLE ACETATE that adds 150ml heat in the filtrating; Slowly stirring is cooled to 0～10 ℃ and separates out crystal, filters, and filter cake is drained back 40 ℃ of forced air dryings with washing with acetone and obtained white solid 4.4g (88%).HPLC content 99.85%, maximum simple substance 0.05%.Refining yield 88.7%, total recovery 81.5%.
Making with extra care of embodiment 16 methylnaltrexone bromides
26.5g bullion joins among the 60mlDMF; Be heated with stirring to 60 ℃ of full backs of dissolving and add the small amount of activated decolorization filtering; The acetone that adds 1000ml heat in the filtrating; Slowly stirring is cooled to 0～10 ℃ and separates out crystal, filters, and filter cake is drained back 40 ℃ of forced air dryings with washing with acetone and obtained white solid 22.5g (84.9%).HPLC content 99.85%, maximum simple substance 0.04%.Refining yield 84.9%, total recovery 78.0%.
Claims (9)
1. the preparation method of a highly purified methylnaltrexone bromide is characterized in that comprising following steps:
(1) it is quaternary ammoniated to use alkylating reagent in the presence of alkali, in anhydrous non-proton dipole solvent, directly Naltrexone Hydrochloride to be carried out, and makes its complete N-alkylation obtain the quaternary ammonium mixture of N-SC-37359 and 3-O-methyl TREXUPONT;
(2) to resulting quaternary ammonium mixture with the directed demethylation of mineral acid; Make by product 3-O-methyl TREXUPONT take off the O-methyl; Aftertreatment separates with a kind of non-protonic solvent hybrid extraction with a kind of protic solvent; Concentrate, crystallization obtains the quaternary ammonium salt of the higher N-SC-37359 of purity;
The quaternary ammonium salt of the N-SC-37359 that (3) obtains obtains the bullion of methylnaltrexone bromide again through IX, bullion is made with extra care with mixed solvent and obtained pure methylnaltrexone bromide, and its total recovery is high, and purity is greater than 99.8%, and is single assorted less than 0.1%.
2. preparation method according to claim 1 is characterized in that, described alkylating reagent is selected from methyl iodide, dimethyl sulfate, methylcarbonate, monobromethane, methyl tosylate and trifluoromethanesulfonic acid methyl esters.
3. preparation method according to claim 1 is characterized in that, described alkali is one or more mixtures in salt of wormwood, yellow soda ash, cesium carbonate, sodium hydroxide, sodium hydride, the triethylamine.
4. preparation method according to claim 1 is characterized in that, described anhydrous non-proton dipole solvent is selected from one or more the mixture in DMF, NMP, acetone, the acetonitrile.
5. preparation method according to claim 1 is characterized in that, described mineral acid makes the alkylating quaternary ammonium salt by product of phenolic hydroxyl group take off the O-methyl 10 ~ 120 ℃ of down reactions, and said mineral acid is a kind of in sulfuric acid, hydrochloric acid, the Hydrogen bromide.
6. preparation method according to claim 5 is characterized in that said mineral acid is a Hydrogen bromide, and mass concentration is 10 ~ 48%; Temperature of reaction is 10 ~ 120 ℃.
7. preparation method according to claim 1; It is characterized in that; The protic solvent that the aftertreatment of the described O-of taking off methyl is used is a kind of of methylene dichloride, trichloromethane or their combination, and the aprotic extraction solvent is one or more combination of sherwood oil, ether, isopropyl ether; The volume ratio of said protic solvent and non-protonic solvent is 1:1～3:1; The crystallization solvent is a kind of in methyl alcohol, ethanol, the acetonitrile.
8. preparation method according to claim 7 is characterized in that protic solvent is a methylene dichloride, and the aprotic extraction solvent is an ether, and volume ratio is 1:1, and the crystallization solvent is a methyl alcohol.
9. according to the said preparation method of claim 1, it is characterized in that mixed solvent is selected from described in the step (3): a kind of combination in ethanol-acetone, DMF-acetone, the DMF-ETHYLE ACETATE.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626782A (en) * | 2013-12-13 | 2014-03-12 | 山东新华制药股份有限公司 | Preparation method of methylnaltrexone bromide |
| CN108976240A (en) * | 2017-06-02 | 2018-12-11 | 扬子江药业集团有限公司 | A kind of refining methd of methylnaltrexone bromide |
| CN111777617A (en) * | 2020-07-10 | 2020-10-16 | 华润三九医药股份有限公司 | Refining method of methylnaltrexone bromide |
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| US4176186A (en) * | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
| CN101115757A (en) * | 2005-02-11 | 2008-01-30 | 希莱格有限公司 | Method for purifying noroxymorphone compounds |
| CN101646675A (en) * | 2007-03-06 | 2010-02-10 | 马林克罗特公司 | Process for the preparation of quaternary N-alkyl morphinan alkaloid salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4176186A (en) * | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
| CN101115757A (en) * | 2005-02-11 | 2008-01-30 | 希莱格有限公司 | Method for purifying noroxymorphone compounds |
| CN101646675A (en) * | 2007-03-06 | 2010-02-10 | 马林克罗特公司 | Process for the preparation of quaternary N-alkyl morphinan alkaloid salts |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103626782A (en) * | 2013-12-13 | 2014-03-12 | 山东新华制药股份有限公司 | Preparation method of methylnaltrexone bromide |
| CN103626782B (en) * | 2013-12-13 | 2016-07-13 | 山东新华制药股份有限公司 | The preparation method of methylnaltrexone bromide |
| CN108976240A (en) * | 2017-06-02 | 2018-12-11 | 扬子江药业集团有限公司 | A kind of refining methd of methylnaltrexone bromide |
| CN108976240B (en) * | 2017-06-02 | 2021-03-02 | 扬子江药业集团有限公司 | Refining method of methylnaltrexone bromide |
| CN111777617A (en) * | 2020-07-10 | 2020-10-16 | 华润三九医药股份有限公司 | Refining method of methylnaltrexone bromide |
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