CN105753875A - Acetylated Delta-7 methylnaltrexone formate and preparation method thereof - Google Patents
Acetylated Delta-7 methylnaltrexone formate and preparation method thereof Download PDFInfo
- Publication number
- CN105753875A CN105753875A CN201410778182.5A CN201410778182A CN105753875A CN 105753875 A CN105753875 A CN 105753875A CN 201410778182 A CN201410778182 A CN 201410778182A CN 105753875 A CN105753875 A CN 105753875A
- Authority
- CN
- China
- Prior art keywords
- delta
- acetylation
- reaction
- methylnaltrexone bromide
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- JKFIYCWEPIQNJN-UHFFFAOYSA-N CC(Oc(ccc(CC1[N+](C)(CC2CC2)CC2)c3C22C1(CC1)O)c3OC2C1=O)=O Chemical compound CC(Oc(ccc(CC1[N+](C)(CC2CC2)CC2)c3C22C1(CC1)O)c3OC2C1=O)=O JKFIYCWEPIQNJN-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses an acetylated Delta-7 methylnaltrexone formate and a preparation method thereof. HPLC is used to prepare Delta-7 methylnaltrexone, and column chromatography is carried out to purify the acetylated Delta-7 methylnaltrexone and prepare the acetylated Delta-7 methylnaltrexone formate.
Description
Technical field
The present invention relates to the synthesis preparation method of a kind of Delta-7 methylnaltrexone bromide and the preparation method of acetylation methylnaltrexone bromide, acetylation Delta-7 methylnaltrexone bromide, acetylation Delta-7 methyl naltrexone formates, Delta-7 methyl naltrexone formates.Belong to pharmaceutical chemistry synthesis technical field.
Background technology
Methylnaltrexone bromide (methylnaltrexone bromide, methylnaltrexonebromide) is by the mu opioid receptor antagonists of Wyeth Pharmaceuticals of the U.S. and the joint study exploitation of Progenics company.U.S. FDA approval methylnaltrexone bromide injection (methylnaltrexonebromide in 2008, Relistor) listing, commodity are called Rdistor, for treating the constipation (opioid-inducedconstipation, OIC) that opioid drug causes and the situation using laxative invalid.
Methylnaltrexone bromide structure is as follows:
Delta-7 methylnaltrexone bromide be in methylnaltrexone bromide crude drug exist the compound with potential genetoxic matter, be in methylnaltrexone bromide crude drug exist have related substance (i.e. impurity).Need to set up the analyzing detecting method for Delta-7 methylnaltrexone bromide, setting up the premise for the analyzing detecting method of Delta-7 methylnaltrexone bromide is set up Delta-7 methylnaltrexone bromide synthetic method, and the Delta-7 methylnaltrexone bromide of synthesis of high purity is as reference substance.
Delta-7 methylnaltrexone bromide occurs in Related Drug pharmacological research describes, it is indicated that be likely to be of potential genetoxic matter.But report preparation method there are no technical literature, so this compound has valuable pharmacological meaning, synthesize this compound and to the pharmacokinetic properties of research methylnaltrexone bromide and instruct clinical application significant.
The English language Chemical name of Delta-7 methylnaltrexone bromide is: 3-(cyclopropylmethyl)-4a, 9-dihydroxy-3-methyl-7-oxo-2,3,4,4a, 7,7a-hexahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinolin-3-ium.Structural formula is:
The structure of Delta-7 methylnaltrexone bromide is disclosed in Chinese patent 200780050175.1, this patent name for " be used for synthesizing season 4; 5-epoxy-morphinan analogs and isolate their method of N-stereoisomer ", the preparation method not disclosing Delta-7 methylnaltrexone bromide in this patent documentation.
Summary of the invention
The final purpose of the present invention is in that the preparation method providing a kind of Delta-7 methylnaltrexone bromide; reference substance with the impurity analysis that synthesis of high purity Delta-7 methylnaltrexone bromide is used as in the preparation of methylnaltrexone bromide crude drug; simultaneously; a kind of intermediate acetyl Delta-7 methyl naltrexone formates synthesizing Delta-7 methylnaltrexone bromide and the preparation method of the purification of a kind of acetylation Delta-7 methylnaltrexone bromide and acetylation Delta-7 methyl naltrexone formates are provided.
Technical scheme is as follows:
Acetylation Delta-7 methyl naltrexone formates provided by the present invention is shown below:
The preparation method of above-mentioned acetylation Delta-7 methyl naltrexone formates is: use HPLC to prepare column chromatography and acetylation Delta-7 methylnaltrexone bromide is purified, prepare acetylation Delta-7 methyl naltrexone formates simultaneously.
Wherein, chromatographic column: C18 liquid-phase chromatographic column；Mobile phase is: A phase: the aqueous formic acid of 0.1%, B phase: acetonitrile.Reaction equation is as follows:
Further, the chromatographic condition of HPLC is:
Chromatographic column: Gemini5uC18150 × 21.2mm；
Mobile phase: A phase: the aqueous formic acid of 0.1%, B phase: acetonitrile；
Flow velocity: 20mL/min；
Detection wavelength: 214nm；
According to following table linear elution, collect the first component liquid:
Described first component liquid is the 1st～3 minute component liquid flowed out, it is preferred to the component liquid flowed out for the 1.5th～3 minute.
Described acetylation Delta-7 methylnaltrexone bromide can be prepared via a method which to obtain:
Step 1: with methylnaltrexone bromide for raw material, through acetylation, obtains acetylation methylnaltrexone bromide；Reaction equation is as follows:
Step 2: acetylation methylnaltrexone bromide, through dehydrogenation reaction, obtains acetylation Delta-7 methylnaltrexone bromide；Reaction equation is as follows:
Preferably, the acetylizad reaction condition in above-mentioned steps 1 is: acetylation reagent is chloroacetic chloride；Reaction alkali is triethylamine；Reaction dissolvent is dichloromethane.Concrete operations can be as follows: adds dichloromethane in reactor; methylnaltrexone bromide, adds triethylamine under stirring, is cooled to-5～-15 DEG C; it is preferably-10 DEG C; dropping chloride solution, stirring, it is warming up to room temperature; continue stirring to reacting completely; add dichloromethane, separate organic facies, organic facies is washed, obtains acetylation methylnaltrexone bromide after dry, concentration.Wherein, ingredient proportion may is that methylnaltrexone bromide 125～175mg, dichloromethane first time 5～15mL, triethylamine 50～150mg, chloride solution 30～100mg, dichloromethane second time 10～40mL.
Preferably, the dehydrogenation reaction of above-mentioned steps 2 is oxidative dehydrogenation, and reaction temperature is room temperature；Dehydrating agent is IBX/NMO system；Reaction dissolvent is acetonitrile；Described IBX is 2-iodosobenzoic acid；Described NMO is N-methyl morpholine oxide.Further, described oxidative dehydrogenation adds catalyst dimethyl sulfoxide.
The concrete operations of above-mentioned steps 2 can be as follows: adds acetonitrile, 2-iodosobenzoic acid, N-methyl morpholine oxide in reactor, is stirred at room temperature 1～2 hour, it is preferable that 1.5 hours；Add acetylation methylnaltrexone bromide, continue stirring 15～35 hours, it is preferred to 20～28 hours, stopped reaction；Decompression boils off solvent, obtains acetylation Delta-7 methylnaltrexone bromide.Further, gained acetylation Delta-7 methylnaltrexone bromide is through column chromatography purification, and column chromatography purification condition is: silica gel column chromatography, and mobile phase is CH2Cl2/CH3OH=6/1 (volume ratio), obtains acetylation Delta-7 methylnaltrexone bromide highly finished product.Wherein, reaction rate of charge is: acetylation methylnaltrexone bromide 1～3g, acetonitrile 40～80mL, 2-iodosobenzoic acid 3～4g, N-methyl morpholine oxide 1～2g, dimethyl sulfoxide 0～1mL.
Further, acetylation Delta-7 methyl naltrexone formates, through hydrolysis, removes acetyl protection base, can obtain Delta-7 methyl naltrexone formates.Reaction equation is as follows:
And Delta-7 methyl naltrexone formates and bromide ion carry out anion exchange, obtain Delta-7 methylnaltrexone bromide.Reaction equation is as follows:
Preferably, the reaction solution of said hydrolyzed reaction is ammonia or 1～3mol/L hydrogen bromide solution.Concrete operations are: add acetonitrile, Delta-7 acetylation methyl naltrexone formates, ammonia or 1-3mol/L hydrogen bromide solution in reactor, be stirred at room temperature to reacting completely, stopped reaction, boil off solvent, obtain Delta-7 methyl naltrexone formates.Further, the Delta-7 methyl naltrexone formates methanol/ethyl acetate recrystallization that will obtain, obtain Delta-7 methyl naltrexone formates.Wherein, in step 4, rate of charge is: acetonitrile 3～7mL, acetylation Delta-7 methyl naltrexone formates 60～80mg, ammonia 0.5-2mL；Or: acetonitrile 3～7mL, acetylation Delta-7 methyl naltrexone formates 60～80mg, 2mol/L hydrogen bromide solution 0.5～2mL.
Preferably, in above-mentioned anion exchange, bromide ion is provided by hydrogen bromide.It is dissolved in methanol by hydrogen bromide to be formed the methanol solution of hydrogen bromide.Realized the anion exchange reaction of Delta-7 methyl naltrexone formates and bromide ion by crystallization operation, the recrystallisation solvent of described crystallization operation is methanol solution and the ethyl acetate of hydrogen bromide.Concrete operations may is that the methanol solution of the hydrogen bromide that Delta-7 methyl naltrexone formates is dissolved in pH1～2, the consumption of the methanol solution adjusting this hydrogen bromide is 2～4 (being preferably pH3) to reactant liquor pH, dropping ethyl acetate, stand cooling crystallization, cross filter solid, after drying under reduced pressure, obtain Delta-7 methylnaltrexone bromide.Wherein, reaction ingredient proportion is: Delta-7 methyl naltrexone formates 20～30mg, the methanol solution 0.3～3mL of hydrogen bromide, ethyl acetate 2～6mL.
The preparation method of the methanol solution of described hydrogen bromide is: pass in methanol by hydrogen bromide gas, obtains when testing pH value and being 1～2.
The present invention is described as follows:
Part I: the selection of Delta-7 methylnaltrexone bromide synthetic route
Inventor's structural property according to Delta-7 methylnaltrexone bromide compound, with methylnaltrexone bromide for raw material, designs and has screened 3 synthetic route schemes and prepare Delta-7 methylnaltrexone bromide.
Scheme I: be obtained by reacting target product by halogenating reaction, elimination.Reaction scheme is as follows:
Reaction condition: i.Br2,CH3COOH；ii.Li2CO3,DMF,LiBr,130℃。
Experimental result: screen through multifactorial experiment condition, identifies and obtains the mono-substituted product of bromine, its structure is compound D.
Experiment conclusion: compound D is the byproduct of reaction undesirably obtained, illustrates this synthetic route reaction site poor selectivity, fail higher yields obtain expection product.Therefore, abandon one's plan I synthetic route.
Scheme II: design nucleopilic reagent attack carbonyl α position replace, with after through eliminate be obtained by reacting product.Reaction scheme is as follows:
Reaction condition: i.AcCl, Et3N；ii.PhSeCl,HCl(cat),EtOAc；iii.NaIO4,THF-H2O；iv.NH4OH。
Experimental result: scheme II is in the process of synthesis compound H, and LC/MS detection generates having structure by-product:
Fail to obtain target product by scheme II.
Experiment conclusion: methylnaltrexone bromide 9-position hydroxyl is relatively big on reaction impact, causes that this reaction condition cannot be applied to the preparation of object.Therefore, abandon one's plan II synthetic route.
The result of association scheme I and scheme II, reaction condition is proposed the requirement of harshness by the 9-position hydroxyl existed in methylnaltrexone bromide structure, and the existence of 9-position hydroxyl makes compound unstable under violent reaction condition, side reaction easily occurs, improves the difficulty of synthesis.
The present inventor have passed through substantial amounts of research, the preparation method having invented Delta-7 methylnaltrexone bromide: utilizes dehydrating agent to carry out dehydrogenation reaction, prepares Delta-7 methylnaltrexone bromide.The phenolic hydroxyl group considered in methylnaltrexone bromide structure is easier to dehydrogenation reaction relative to 9-position hydroxyl, so needing first phenolic hydroxyl group to be protected, then carries out dehydrogenation reaction.
The synthetic route that the present invention adopts is scheme III: first protects phenolic hydroxyl group, then carries out dehydrogenation reaction then deprotection base, obtain target product.
In above-mentioned reaction equation:
Compound A is: methylnaltrexone bromide；
Compound G is: acetylation methylnaltrexone bromide；
Compound M is: acetylation Delta-7 methylnaltrexone bromide；
Compound E is: acetylation Delta-7 methyl naltrexone formates；
Compound J is: Delta-7 methyl naltrexone formates；
Compound Q is: Delta-7 methylnaltrexone bromide；
Reaction condition a is: acetylation；
Reaction condition b is: dehydrogenation reaction；
Reaction condition c is: purification and formic acid salt；
Reaction condition d is: hydrolysis elimination acetyl protection base；
Reaction condition e is: carry out anion exchange purification with bromide ion.
The advantage of the present invention (scheme III):
1, reaction condition is gentle.Reaction system can be achieved with dehydrogenation reaction at ambient temperature, it is to avoid causes the unstability of reactant under high temperature, strong acid, highly basic.
2, reaction site selectivity is high.Reaction system is not by the impact of exposed reactive group, in scheme I and scheme II, all it is not avoided that the impact on reaction of the 9-position active hydroxyl groups, cause the generation of a large amount of by-product, the reaction system of operational version III of the present invention can under the situation that 9-position hydroxyl exists, gentle, generate α, alpha, beta-unsaturated ketone product efficiently.
3, reaction yield is high.Target product (yield > 20%) is obtained with higher yield by the reaction system screened.
Conclusion: selection scheme III is as Delta-7 methylnaltrexone bromide synthetic route.
Part II: illustrating of each step of the present invention
One, the preparation method of acetylation methylnaltrexone bromide:
With methylnaltrexone bromide for raw material, through acetylation, obtain acetylation methylnaltrexone bromide:
Reaction equation:
There are two hydroxyls in methylnaltrexone bromide structure, chemical property is active, and phenolic hydroxyl group therein is easier to dehydrogenation reaction relative to 9-position hydroxyl, so needing first phenolic hydroxyl group to be protected, then carries out dehydrogenation reaction.
Meanwhile, reaction condition is proposed the requirement of harshness by the 9-position hydroxyl existed in methylnaltrexone bromide structure, and the existence of 9-position hydroxyl makes compound unstable under violent reaction condition, side reaction easily occurs, improves the difficulty of synthesis.
Inventors performed following experiment screening:
The protection base of experiment screening has acetyl group and silicon protection reagent, and the related reagent of Select to use has: chloroacetic chloride, acetic anhydride, TMSCl (trim,ethylchlorosilane), TBDMSCl (tert-butyl chloro-silicane).
Experiment screening reaction alkali includes: triethylamine, DIPEA, sodium hydride, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, Lithium hydrate.
Experiment screening solvent includes: dichloromethane, ethyl acetate, methanol, ethanol, dioxane, DMF, dimethyl sulfoxide, acetonitrile, oxolane.
Screening operation example: weigh methyl naltrexone (150mg, 0.39mmol) in there-necked flask, adds dichloromethane (10mL), triethylamine (160mg, 1.58mmol).Under nitrogen protection, system is cooled to-10 DEG C.Weigh chloroacetic chloride (68mg, 0.87mmol), be added dropwise in above-mentioned system, react 1 hour under low temperature, reaction 2 hour, stopped reaction are stirred at room temperature subsequently.Column chromatography purification (eluant: methylene chloride/methanol=50/1, volume ratio) obtains product 120mg, yield 72.3%.
All conditions to be screened carry out screening operation according to above-mentioned example.
Find through experiment: chloroacetic chloride is swift in response as acetylation reagent, and yield is higher.Chloroacetic chloride low price simultaneously, the source of goods is easy to get, and protects the phenolic hydroxyl group of the protection methylnaltrexone bromide of the base property of can select that, namely chloroacetic chloride is excessive in the hydroxyl reaction with 9-position, will not generate diacetyl protection product.Diacetyl protection product structure is as follows:
X: diacetyl protection product
Two, the preparation method of acetylation Delta-7 methylnaltrexone bromide:
Acetylation methylnaltrexone bromide, through dehydrogenation reaction, obtains acetylation Delta-7 methylnaltrexone bromide:
Reaction equation:
Methylnaltrexone bromide raw material is not particularly stable, there are two hydroxyls in structure, and chemical property is active, uses the reaction condition of gentleness, is conducive to stablizing of product.
Phenolic hydroxyl group in methylnaltrexone bromide structure is easier to dehydrogenation reaction relative to 9-position hydroxyl, so needing first phenolic hydroxyl group to be protected, then carries out dehydrogenation reaction.If reaction condition is relatively more violent, all can there is oxidative dehydrogenation in phenolic hydroxyl group and 9-position hydroxyl, so needing to select gentle oxidative dehydrogenation condition to carry out dehydrogenation reaction.
Nineteen ninety-five, ArthurG.Schultz report (ArthurG.Schultz, RobertD.Lucci, et.al.J.Org.Chem.1985,50,2646-2650) is under DDQ (DDQ) acts on, it is possible to oxidative dehydrogenation.
Inventor uses report condition, by methylnaltrexone bromide raw material mixing DDQ, heats to 130 DEG C of reactions in dioxane solvent, and LC/MS (liquid chromatography-mass spectrography is used in conjunction instrument) fails dehydrogenation target product to be detected.
2002, K.C.Nicolaou reported (K.C.Nicolaou, T.Montagnon; P.S.Baran, Y.L.Zhong.J.Am.Chem.Soc, 2002; 124,2245-2258) 2-iodosobenzoic acid (IBX) can the hydrogen of oxidation removal benzyl position.
Inventor uses report condition, screens solvent dimethyl sulfoxide, DMF, dichloromethane, toluene, acetonitrile, and reaction temperature 25 DEG C～80 DEG C, all fails to obtain desirable oxidative dehydrogenation product.
2002, K.C.Nicolaou reports (K.C.Nicolaou, TamsynMontagnon, PhilS.Baran.AngewandteChemieInternationalEdition.2002,41,993 996.) ligand complex that IBX is formed can at room temperature realize the alpha-position dehydrogenation reaction of aldehyde, ketone.
Inventor uses report condition, has screened IBX-Ac system；IBX-THF system；IBX-DMSO system；IBX-N-Oxide system, finally found that IBX-N-Oxide system can at room temperature realize dehydrogenation reaction.
The Chinese of Ac is: acetic acid；The Chinese of THF is: oxolane；The Chinese of DMSO is: dimethyl sulfoxide；The Chinese of N-Oxide is: nitrogen-oxide；The Chinese of IBX is: 2-iodosobenzoic acid；The Chinese of NMO is: N-methyl morpholine oxide.
Inventor has screened reaction dissolvent: dichloromethane, ethyl acetate, DMF, dimethyl sulfoxide, acetonitrile, dioxane, oxolane.
Inventor has screened oxidation system: IBX；IBX (heating, 40～60 DEG C)；IBX/THF；IBX/DMSO；IBX/NMO.
Inventor has screened the response time: 6 hours；12 hours；18 hours；24 hours；30 hours.
Screening operation example: weigh IBX (1.23g, 4.40mmol), NMO (514mg, 4.40mmol), adds acetonitrile solution 30mL, and stirred under nitrogen atmosphere reacts 1.5 hours.Weigh acetylizad methylnaltrexone bromide (700mg, 1.46mmol), DMSO (210 μ L), add in above-mentioned system, stirred overnight at room temperature.Being evaporated by system solvent, residue, through column chromatography preliminary purification (eluant: methylene chloride/methanol=80/1, volume ratio), obtains acetylation Delta-7 methylnaltrexone bromide crude product.
All conditions to be screened carry out screening operation according to above-mentioned example
Find through experiment: room temperature, reaction dissolvent acetonitrile, use IBX/NMO system, react 24 hours, it is possible to the methylnaltrexone bromide that acetylation is protected, by oxidative dehydrogenation, obtain acetylation Delta-7 methylnaltrexone bromide.
IBX-N-Oxide reaction system advantage: reaction condition is gentle, can be achieved with dehydrogenation reaction, it is to avoid cause the unstability of substrate under high temperature, strong acid, highly basic under the reaction system room temperature condition of the present invention.
Three, the preparation of the purification of acetylation Delta-7 methylnaltrexone bromide and acetylation Delta-7 methyl naltrexone formates
Inventor is by acetylation Delta-7 methylnaltrexone bromide crude product, and after column chromatography purification, LC/MS detection still has a small amount of acetylation methylnaltrexone bromide to there is (non-dehydrogenation product), and preparation HPLC need to be used to separate purification.
If not purified, reacting through final step, after sloughing protection base, it will a small amount of methylnaltrexone bromide of remaining, methylnaltrexone bromide and final goal thing Delta-7 methylnaltrexone bromide polarity are close, it is virtually impossible to separate.
Inventor uses HPLC (high performance liquid chromatography) to prepare column chromatography and acetylation Delta-7 methylnaltrexone bromide is purified.Owing to mobile phase employing aqueous formic acid, so, being prepared by of the purification of acetylation Delta-7 methylnaltrexone bromide and acetylation Delta-7 methyl naltrexone formates carries out simultaneously.
Reaction equation:
HPLC prepares purification process:
Chromatographic column: Gemini5uC18150 × 21.2mm
Mobile phase: A phase: the aqueous formic acid of 0.1%；B phase: acetonitrile.
Flow velocity: 20mL/min
Detection wavelength: 214nm
According to table 1 linear elution, collect the first component liquid:
Table 1
Described first component liquid is the 1st～3 minute component liquid flowed out, it is preferred to the component liquid flowed out for the 1.5～-3rd minute.
The explanation of his-and-hers watches 1: inventor's method therefor is that HPLC prepares column chromatography, the eluting purpose at 0～9 minute is to isolate required acetylation Delta-7 methyl naltrexone formates, so, between 0～9 minute, eluate concentration graded is slower.Eluting purpose between 9～12 minutes is by under all Impurity elution not.Eluting purpose at 12～14 minutes is to recover the mobile phase polarity in chromatographic column, prepares for sample introduction eluting next time.
Fig. 1 is shown in by HPLC collection of illustrative plates.
Four, the preparation method of Delta-7 methyl naltrexone formates
Acetylation Delta-7 methyl naltrexone formates, through hydrolysis, removes acetyl protection base, obtains Delta-7 methyl naltrexone formates:
Reaction equation is:
Inventor's screening to reaction condition:
Inventor have found that use acid condition or alkali condition deprotection base, all can obtain Delta-7 methyl naltrexone formates.
The hydrolysis condition of screening: dilute hydrochloric acid, dilute sulfuric acid, rare hydrogen bromide solution, sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, ammonia.
Screening operation example: weigh acetylizad Delta-7 methyl naltrexone formates; add the mixed solution (mixed volume ratio: 1/6) of ammonia/acetonitrile; reaction 3 hour is stirred at room temperature, boils off solvent, obtain Delta-7 methyl naltrexone formates crude product.
All conditions to be screened carry out screening operation according to above-mentioned example
Experiment finds: the comparatively acidic condition of hydrolysis rate is fast in the basic conditions, and it is high that weak base generates target product purity than the reaction of highly basic.Thus, it is found that use weakly alkaline ammonia spirit can remove acetyl protection base at 3 hours.
Five, the preparation of Delta-7 methylnaltrexone bromide and purification:
Delta-7 methyl naltrexone formates and bromide ion carry out anion exchange, obtain Delta-7 methylnaltrexone bromide.Reaction carries out the purification of Delta-7 methylnaltrexone bromide simultaneously.
Reaction equation is:
In order to Delta-7 methyl naltrexone formates is converted into Delta-7 methylnaltrexone bromide, inventor attempts making spent ion exchange resin carry out anion exchange, strong basic type anion-exchange resin and weak base type anion exchange resin are selected in experiment respectively, find in the process of ion exchange, target product generation side reaction, purity is substantially reduced.
For avoiding target product instability to degrade, the present inventor has invented " one-step method " and has carried out the preparation and purification of Delta-7 methylnaltrexone bromide.
Described " one-step method " is: carry out the anion exchange of Delta-7 methyl naltrexone formates and bromide ion with method for crystallising, product Delta-7 methylnaltrexone bromide is purified simultaneously.
Described bromide ion is provided by hydrogen bromide.
Described hydrogen bromide is dissolved in methanol, forms the methanol solution of hydrogen bromide.
" one-step method ", particularly as follows: Delta-7 methyl naltrexone formates crude product is dissolved in the methanol solution of hydrogen bromide, drips ethyl acetate solution, stands cooling crystallization, crosses filter solid, drying under reduced pressure.
The preparation of the methanol solution of described hydrogen bromide: passed into by hydrogen bromide gas in methanol and prepare, obtains when testing pH1～2.
Crystallization experiment conditional filtering: by the dissolubility of SCREENED COMPOUND, with mixed solvent recrystallization.
Acetylation Delta-7 methyl naltrexone formates and Delta-7 methylnaltrexone bromide solubility experiment are in Table 2:
In table, dissolubility standard is: good (dissolubility >=20mg/mL)；In (20mg/mL >=dissolubility >=5mg/mL)；Difference (dissolubility≤5mg/mL).
Through experiment, inventor finds that methanol/ethyl acetate system recrystallization can obtain the higher target product of purity (HPLC purity > 95%).Experimental design uses hydrogen bromide methanol solution, and regulating pH value is acid (pH=2～4), it is possible to a step realizes the bromide ion displacement to formate anion and the purification of Delta-7 methylnaltrexone bromide.
Accompanying drawing explanation
Fig. 1: HPLC collection of illustrative plates acetylation Delta-7 methyl naltrexone formates purified by HPLC method.
Detailed description of the invention
The invention will be further described by the following examples, but this is not limitation of the present invention, those skilled in the art's basic thought according to the present invention, it is possible to make various amendment or improvement, but without departing from the basic thought of the present invention, all within the scope of the present invention.
Embodiment 1: the preparation of acetylation methylnaltrexone bromide
Adding dichloromethane 10mL, methylnaltrexone bromide 150mg (0.39mmol, 1eq) in 50mL round-bottomed flask, stirring is lower adds triethylamine 100mg (0.99mmol, 3eq).System is cooled to-10 DEG C, is slowly added dropwise after chloride solution 61mg (0.78mmol, 2eq) is added dropwise to complete and stirs 1 hour, be to slowly warm up to room temperature, continues stirring 1 hour.TLC (thin layer chromatography) monitoring reacts completely.Stopped reaction, adds dichloromethane 20mL, washes from the beginning twice (20mL × 2), and saturated sodium-chloride water solution washes twice (20mL × 2), and anhydrous sodium sulfate dries.Obtain product 160mg, yield 86% after organic layer concentration, be directly used in next step reaction.
1H-NMR(400MHz,D2O): δ 7.09 (d, 1H, J=8.0Hz), 7.01 (s, 1H, J=8.0Hz), 5.15 (s, 1H), 4.23 (d, 1H, J=4.4Hz), 4.06 (m, 1H), 3.78 (m, 3H), 3.44 (d, 1H, J=12.0Hz), 3.31 (d, 1H, J=12.0Hz), 3.10 (m, 2H), 2.93 (m, 2H), 2.40 (s, 3H, CH3), 2.36 (d, 1H, J=12.0Hz), 2.25 (s, 1H), 2.19 (d, 1H, J=12.0Hz), 1.87 (m, 2H), 1.26 (s, 1H), 0.95 (m, 1H), 0.83 (m, 1H), 0.66 (m, 1H), 0.47 (m, 1H).
Embodiment 2: the preparation of acetylation Delta-7 methylnaltrexone bromide
150mL round-bottomed flask adds acetonitrile 60mL, 2-iodosobenzoic acid 3.6g (12.85mmol, 3.07eq), N-methyl morpholine oxide 1.6g (13.67mmol, 3.2eq), nitrogen protection, reaction 1.5 hour is stirred at room temperature.System adds acetylation methylnaltrexone bromide 2g (4.19mmol, 1eq), dimethyl sulfoxide 0.6mL (8.46mmol, 2eq), continues stirring 24 hours.Stopped reaction, decompression boils off solvent, and solid is through column chromatography purification (eluant: CH2Cl2/CH3OH=6/1, volume ratio), obtain crude product 400mg, yield 20.1%, use HPLC to prepare purification further.
Embodiment 3: the purification of acetylation Delta-7 methylnaltrexone bromide and the preparation of acetylation Delta-7 methyl naltrexone formates
Chromatographic column: Gemini5uC18150 × 21.2mm
Mobile phase: A phase: the aqueous formic acid of 0.1%, B phase: acetonitrile.
Flow velocity: 20mL/min
Detection wavelength: 214nm
According to table 1 linear elution, collect the first component liquid:
Table 1
Described first component liquid is the 1st～3 minute component liquid flowed out, it is preferred to the component liquid flowed out for the 1.5th～3 minute.
Fig. 1 is shown in by HPLC collection of illustrative plates.
Delta-7 acetylation methyl naltrexone formates nuclear magnetic resonance data after purification:
1H-NMR(400MHz,D2O): δ 7.17 (d, 1H, J=8.0Hz), 7.01 (d, 1H, J=8.0Hz), 6.93 (d, 1H, J=8.0Hz), 6.16 (d, 1H, J=8.0Hz), 5.11 (s, 1H), 4.30 (s, 1H), 4.01 (d, 1H, J=12.0Hz), 3.83 (d, 2H, J=12.0Hz), 3.72 (s, 3H), 3.47 (d, 1H, J=12.0Hz), 3.15 (d, 2H, J=12.0Hz), 2.99 (m, 1H), 2.89 (m, 1H), 2.32 (s, 3H, CH3), 2.03 (d, 1H, J=12.0Hz), 1.23 (s, 1H), 0.93 (s, 1H), 0.82 (s, 1H), 0.62 (s, 1H), 0.43 (s, 1H).
13C-NMR(100MHz,D2O):δ195.70,171.92,147.87,146.66,132.70,131.60,129.80,128.14,124.34,121.53,86.72,72.74,69.88,57.63,53.19,46.73,28.08,23.39,20.20,6.26,3.68,2.79.
The preparation of embodiment 4:Delta-7 methyl naltrexone formates
Method one: 25mL round-bottomed flask adds acetonitrile 5mL, Delta-7 acetylation methyl naltrexone formates 70mg (0.15mmol, 1eq), ammonia 1mL (26mmol, 174eq).Reaction 3 hour is stirred at room temperature, and TCL monitoring reacts completely, stopped reaction.Boiling off solvent, methanol/ethyl acetate recrystallization obtains product 30mg.Yield 47.1%.
The preparation of embodiment 5:Delta-7 methyl naltrexone formates
Method two: 25mL round-bottomed flask adds acetonitrile 5mL, Delta-7 acetylation methyl naltrexone formates 70mg (0.15mmol, 1eq), hydrogen bromide solution 1mL (2mol/L, 2mmol, 14eq).Reaction 6 hour is stirred at room temperature, and TCL monitoring reacts completely, stopped reaction.Boiling off solvent, methanol/ethyl acetate recrystallization obtains product 23mg.Yield 36.5%.
The preparation of embodiment 6:Delta-7 methylnaltrexone bromide and purification
The preparation of the methanol solution of hydrogen bromide: passed into by hydrogen bromide gas in methanol and prepare, when testing pH1-2 and get final product.
Above-mentioned crude product is dissolved in the methanol solution (pH1-2 of hydrogen bromide,), the consumption of the methanol solution adjusting hydrogen bromide is 3 to pH, and now the methanol solution of hydrogen bromide used is 0.5mL, dropping ethyl acetate solution (2.5-3.0mL), stands cooling crystallization.Cross filter solid, after drying under reduced pressure, obtain Delta-7 methylnaltrexone bromide.
1H-NMR(400MHz,D2nullO):δ7.17(d,1H,J=8.0Hz),6.84(d,1H,J=8.0Hz),6.79(d,1H,J=8.0Hz),6.16(d,1H,J=8.0Hz),5.08(s,1H),4.26(s,1H),4.01(d,1H,J=12.0Hz),3.83(d,2H,J=12.0Hz),3.72(s,3H),3.45(d,1H,J=12.0Hz),3.19(m,1H),3.09(m,1H),2.99(m,1H),2.88(m,1H),2.06(d,1H,J=12.0Hz),1.24(s,1H),0.95(s,1H),0.84(s,1H),0.62(s,1H),0.43(s,1H).
Claims (10)
1. the acetylation Delta-7 methyl naltrexone formates shown in following formula:
2. a preparation method for acetylation Delta-7 methyl naltrexone formates, uses HPLC to prepare column chromatography and acetylation Delta-7 methylnaltrexone bromide is purified, prepare acetylation Delta-7 methyl naltrexone formates simultaneously；Wherein, chromatographic column: C18 liquid-phase chromatographic column；Mobile phase is: A phase: the aqueous formic acid of 0.1%, B phase: acetonitrile；Reaction equation is as follows:
3. preparation method according to claim 2, it is characterised in that the chromatographic condition of HPLC is:
Chromatographic column: Gemini5uC18150 × 21.2mm；
Mobile phase: A phase: the aqueous formic acid of 0.1%, B phase: acetonitrile；
Flow velocity: 20mL/min；
Detection wavelength: 214nm；
According to following table linear elution, collect the first component liquid:
Described first component liquid is the 1st～3 minute component liquid flowed out, it is preferred to the component liquid flowed out for the 1.5th～3 minute.
4. preparation method according to claim 2, it is characterised in that described acetylation Delta-7 methylnaltrexone bromide is prepared via a method which to obtain:
Step 1: with methylnaltrexone bromide for raw material, through acetylation, obtains acetylation methylnaltrexone bromide；Reaction equation is as follows:
Step 2: acetylation methylnaltrexone bromide, through dehydrogenation reaction, obtains acetylation Delta-7 methylnaltrexone bromide；Reaction equation is as follows:
5. preparation method according to claim 4, it is characterised in that the acetylizad reaction condition in described step 1 is: acetylation reagent is chloroacetic chloride；Reaction alkali is triethylamine；Reaction dissolvent is dichloromethane.
6. preparation method according to claim 5, it is characterised in that step 1 concrete operations are: add dichloromethane in reactor; methylnaltrexone bromide, adds triethylamine under stirring, is cooled to-5～-15 DEG C; it is preferably-10 DEG C; dropping chloride solution, stirring, it is warming up to room temperature; continue stirring to reacting completely; add dichloromethane, separate organic facies, organic facies is washed, obtains acetylation methylnaltrexone bromide after dry, concentration.
7. preparation method according to claim 4, it is characterised in that the dehydrogenation reaction of step 2 is oxidative dehydrogenation, reaction temperature is room temperature；Dehydrating agent is IBX/NMO system；Reaction dissolvent is acetonitrile；Described IBX is 2-iodosobenzoic acid；Described NMO is N-methyl morpholine oxide.
8. preparation method according to claim 7, it is characterised in that described oxidative dehydrogenation condition also includes adding catalyst dimethyl sulfoxide.
9. preparation method according to claim 8, it is characterised in that step 2 concrete operations are: add acetonitrile, 2-iodosobenzoic acid, N-methyl morpholine oxide in reactor, be stirred at room temperature 1～2 hour, it is preferable that 1.5 hours；Add acetylation methylnaltrexone bromide, continue stirring 15～35 hours, it is preferred to 20～28 hours, stopped reaction；Decompression boils off solvent, obtains acetylation Delta-7 methylnaltrexone bromide.
10. preparation method according to claim 9, it is characterised in that acetylation Delta-7 methylnaltrexone bromide claim 9 obtained is through column chromatography purification, and column chromatography purification condition is: silica gel column chromatography, and mobile phase is CH2Cl2/CH3OH=6/1, obtains acetylation Delta-7 methylnaltrexone bromide highly finished product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410778182.5A CN105753875A (en) | 2014-12-15 | 2014-12-15 | Acetylated Delta-7 methylnaltrexone formate and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410778182.5A CN105753875A (en) | 2014-12-15 | 2014-12-15 | Acetylated Delta-7 methylnaltrexone formate and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105753875A true CN105753875A (en) | 2016-07-13 |
Family
ID=56336857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410778182.5A Pending CN105753875A (en) | 2014-12-15 | 2014-12-15 | Acetylated Delta-7 methylnaltrexone formate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105753875A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189229A (en) * | 2005-03-17 | 2008-05-28 | 哈佛大学校长及研究员协会 | Synthesis of avrainvillamide, stephacidin B, and analogues thereof |
| CN101636400A (en) * | 2006-11-22 | 2010-01-27 | 普罗基因制药公司 | Be used for synthetic season 4,5-epoxy-morphinane analogue and the method for isolating their N-steric isomer |
| CN101781303A (en) * | 2007-03-06 | 2010-07-21 | 马林克罗特公司 | Process for the preparation of quaternary n-alkyl morphinan alkaloid salts |
| CN101115757B (en) * | 2005-02-11 | 2010-12-22 | 希莱格有限公司 | Method for purifying noroxymorphone compounds |
-
2014
- 2014-12-15 CN CN201410778182.5A patent/CN105753875A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101115757B (en) * | 2005-02-11 | 2010-12-22 | 希莱格有限公司 | Method for purifying noroxymorphone compounds |
| CN101189229A (en) * | 2005-03-17 | 2008-05-28 | 哈佛大学校长及研究员协会 | Synthesis of avrainvillamide, stephacidin B, and analogues thereof |
| CN101636400A (en) * | 2006-11-22 | 2010-01-27 | 普罗基因制药公司 | Be used for synthetic season 4,5-epoxy-morphinane analogue and the method for isolating their N-steric isomer |
| CN101781303A (en) * | 2007-03-06 | 2010-07-21 | 马林克罗特公司 | Process for the preparation of quaternary n-alkyl morphinan alkaloid salts |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105175401A (en) | Preparation method of brexpiprazole | |
| CN101863948B (en) | High-purity (2 beta, 3 alpha, 5 alpha, 16 beta, 17 beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol or composition thereof and preparation method thereof | |
| US9840456B2 (en) | Process for preparation of dimethyl fumarate | |
| CN111704573B (en) | Preparation method of rabeprazole chloride and intermediate thereof | |
| CN102993205B (en) | High-yield purification method for preparation of high-purity sildenafil freebases | |
| CN105263945A (en) | Method for synthesizing saponin | |
| CN106543220A (en) | Phosphoramidate compounds and preparation method thereof and crystal | |
| CN110305142B (en) | Stereoselective synthesis method of 6 beta-hydroxymorphine derivative | |
| Wu et al. | Facile synthesis of chromeno [4, 3-b] quinolin-6-ones from unexpected reactions of aryl isocyanides with 4-chloro-2-oxo-2 H-chromene-3-carbaldehyde | |
| CN105712919A (en) | Application of amide condensing agent in vildagliptin synthetic method | |
| CN111943854A (en) | Synthetic method of 3, 4-dichloro-2-nitrobenzoic acid | |
| WO2017205622A1 (en) | Method of making benznidazole | |
| CN105777766B (en) | The preparation method of the methylnaltrexone bromides of Delta 7 | |
| CN105753875A (en) | Acetylated Delta-7 methylnaltrexone formate and preparation method thereof | |
| CN105777767A (en) | Acetylated Delta-7 methylnaltrexone bromide and preparation method therefor | |
| CN105753874A (en) | Delta-7 methylnaltrexone formate and preparation method thereof | |
| CN105753876A (en) | Preparation method of Delta-7 methyhaaltrexone bromide | |
| CN105777765A (en) | Acetylated methylnaltrexone bromide and preparation method therefor | |
| CN114989061A (en) | Preparation method of brivaracetam | |
| CN108530468A (en) | A kind of Cefpodoxime Proxetil impurity and its preparation method and application | |
| EP4063349A1 (en) | Method for producing pyrrolidine compound | |
| CN104447776A (en) | Novel heterocyclic organic compound and preparation method thereof | |
| CN106588786A (en) | Preparation method of high purity favipiravir impurity | |
| CN104450851B (en) | A kind of preparation method for removing acetyl cefathiamidine | |
| CN111662356A (en) | Impurity control method of fulvestrant |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160713 |
|
| WD01 | Invention patent application deemed withdrawn after publication |