CN106349112A - Preparation method of methocarbamol beta isomer - Google Patents
Preparation method of methocarbamol beta isomer Download PDFInfo
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- CN106349112A CN106349112A CN201610728594.7A CN201610728594A CN106349112A CN 106349112 A CN106349112 A CN 106349112A CN 201610728594 A CN201610728594 A CN 201610728594A CN 106349112 A CN106349112 A CN 106349112A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
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Abstract
The invention provides a preparation method of a methocarbamol beta isomer. According to the preparation method, a 2-((Methoxyphenoxy)methyl)ethylene oxide compound 1 is taken as a starting raw material and is sequentially subjected to chlorination, esterification, amidation, acetylation and acid digestion degreasing reaction so as to obtain a target product compound 6; and the synthetic route is as follows: formula (shown in the description).
Description
Technical field
The invention belongs to medicinal chemistry art, it is specifically related to a kind of methocarbamol impurity, the system of methocarbamol beta isomer
Preparation Method.
Background technology
Methocarbamol is a kind of muscle relaxant, sprains for articular muscles, the disease such as lumbar muscle strain, sciatica,
It is a kind of central muscle relaxant, and Central nervous system has selection, particularly bright to neuron operation in spinal cord
Aobvious, suppress the nerve synapse reflection relevant with skeleton muscular spasm, have the eclamptogenic effect of anti-strychnine and electricity irritation institute, and have solution
Bitterly, analgesia, antiinflammatory action, the structural formula of methocarbamol is as described below:
Methocarbamol beta isomer is one of methocarbamol crude drug critical impurities, and its chemical name is: (±) -3-
[o- methoxy phenoxy] -1,3-PD -1- carbamate, its structural formula is:
Methocarbamol beta isomer is very great for the correlational study meaning of methocarbamol impurity, therefore it provides a kind of letter
Just the method efficiently preparing highly purified methocarbamol beta isomer, the correlational study for methocarbamol impurity is significant.It
Can be used for the impurity quantification during methocarbamol produces and quantitative analysis, such that it is able to improve the quality standard of methocarbamol,
There is provided important directive significance for people's masses'safety medication.
Content of the invention
In order to improve the quality of methocarbamol, reduce the risk of clinical application, it is an object of the invention to provide a kind of U.S. rope
The preparation method of bar not beta isomer.The present invention program can quickly, simply, efficiently obtain the comparison of methocarbamol beta isomer
Product, are contributed to strictly being controlled the aspects such as the quality of methocarbamol using impurity Standard reference.
For realizing goal of the invention, the present invention takes following technological means:
The preparation method of methocarbamol beta isomer, is initial with 2- ((methoxy phenoxy) methyl) oxirane compound 1
Raw material, comprises the steps:
1) in presence of organic solvent, there is chlorination in compound 1 and hydrogen chloride gas, obtains compound 2；
2) in the presence of organic solvent and alkali, there is esterification with triphosgene in compound 2, obtain compound 3；
3) in presence of organic solvent, compound 3 and ammonia occur amidation process to obtain compound 4；
4) in the presence of acetic acid, tetrabutyl ammonium bromide and dimethyl pyrrolidone, there is acetyl with potassium acetate in compound 4
Change reaction and obtain compound 5；
5) in presence of organic solvent, compound 5 and p-methyl benzenesulfonic acid occur acidolysis de-ester reaction to obtain target product；
Synthetic route is:
Preferably, described step 1) in organic solvent be selected from dioxane, oxolane, methanol or ethanol, reaction
60 ± 5 DEG C of temperature.
Preferably, described step 2) in organic solvent be selected from dichloromethane, chloroform, carbon tetrachloride or dichloroethanes,
Described alkali is selected from pyridine or triethylamine.
Preferably, described step 3) in organic solvent be selected from isopropanol, methanol or ethanol.
Preferably, described step 5) in organic solvent be methanol or ethanol
More specifically, the preparation method of methocarbamol beta isomer, with 2- ((methoxy phenoxy) methyl) oxirane chemical combination
Thing 1 is initiation material, comprises the steps:
1) in the presence of dioxane, at a temperature of 60 ± 5 DEG C, there is chloro with hydrogen chloride gas in compound 1
Reaction, reaction is concentrated in vacuo after terminating to obtain compound 2；
2) in the presence of dichloromethane and pyridine, there is esterification with triphosgene in compound 2, and reaction temperature is 25-
Between 30 DEG C, after reaction terminates, extracted with dichloromethane, organic layer is concentrated to give compound 3；
3) in the presence of isopropanol, there is amidation process with ammonia in compound 3, obtain compound 4 and compound 2,
Compound 4 is obtained to product alcohol crystal；
4) in the presence of acetic acid, tetrabutyl ammonium bromide and dimethyl pyrrolidone, reaction temperature be 90 DEG C of compounds 4 with
There is acetylization reaction in potassium acetate, reaction terminates to add water in rear reactant liquor, then is extracted with ethyl acetate, and then uses bicarbonate respectively
Sodium and hydrochloric acid are washed, and ethyl acetate layer is concentrated to give compound 5；
5) in the presence of methanol, under room temperature there is acidolysis de-ester reaction in compound 5 and p-methyl benzenesulfonic acid, after reaction terminates
Reactant liquor is concentrated, adds water and toluene, this system is heated to 75-80 DEG C, stratification, use acetic acid in the water layer obtaining
Ethyl ester extracts, and ethyl acetate layer is concentrated to dryness, and adds water and toluene, is cooled at 0～-5 DEG C after stirring and dissolving at 75-80 DEG C
Crystallization, obtains target product.
The invention provides one kind passes through five step reaction preparations with 2- ((methoxy phenoxy) methyl) oxirane for raw material
Obtain methocarbamol beta isomer, the program has synthetic route briefly, easy and simple to handle, the higher (hplc of gained impurity product purity
Purity 99.6%～99.7%), the features such as can be applicable to research of the chemical standard product.
Specific embodiment
With reference to specific preferred embodiment, technical scheme is described further.
Embodiment 1 prepare compound 2
90g compound 1 is put in 1000ml reaction bulb, adds 450ml dioxane, then dissolving is stirred at room temperature, plus
Thermal response liquid to 60 ± 5 DEG C, starts to say that hydrogen chloride gas are passed through in reactant liquor, notes tail gas absorption.Keep ventilatory response 3 hours
± 1 hour.After reaction is complete, reactant liquor is directly concentrated under vacuum.At 90 DEG C of outer temperature, till dripless flows out.
Obtain compound 2 product 100g, molar yield about 92.2%.
Dioxane in reaction can be replaced with oxolane, methanol or alcohol solvent, and concrete operation step is as above.
Embodiment 2 prepare compound 3
In the reaction bulb that 100g compound 2 is put into 1000ml together with 54.7g pyridine and 300ml dichloromethane, stir
Mix after being uniformly dissolved, reactant liquor is cooled to 10 DEG C about.106.2g triphosgene is dissolved in the dichloromethane of 150ml, molten
Solution is heat absorption.After all dissolving completely, start Deca triphosgene solution.Note ventilation simultaneously, take care, prevent outside phosgene
Let out and cause personal security dangerous.Side Deca keeps reacting liquid temperature between 10-20 DEG C, after completion of dropping, is naturally warmed up to room
(25-30 DEG C) reaction 6-8 hour of temperature, when after completion of the reaction, starting terminating reaction, reactant liquor being cooled to first 0 DEG C, starts pole
Slow speed Deca water, releases gas (may comprise phosgene, most carbon dioxide it should be noted that safety).Attention response liquid
Temperature does not exceed 20 DEG C.When the gas released significantly reduces, accelerate the speed of Deca water.After completion of dropping, continue stirring
10 minutes.Static layering, is layered dichloromethane layer, adds 150ml to extract water layer once in water layer.Water layer is abandoned, and merges dichloro
Methane layer.It is dried, concentrate.Obtain 122g compound 3, yield 114%.
Here the dichloromethane in reaction can use chloroform, carbon tetrachloride or dichloroethanes to replace, and pyridine can use triethylamine
Replace, concrete operation step is as above.
The preparation of embodiment 3 compound 4
122g compound 3 is dissolved in 450ml isopropanol, logical ammonia reaction 4-8 hour at keeping 20-25 DEG C.Logical ammonia
Solid/liquid/gas reactions, except generating compound 4, generate compound 2 simultaneously.Both poor conversion not 4.5:5.5=compound 2: chemical combination
Thing 4.Compound 4 is solid, it is possible to use both 3 times of w ethanol Crystallization Separation, obtains the pure compound of 110g 4.
Organic solvent isopropanol in reaction can be replaced with alcohols solvents such as methanol or ethanol, and concrete operation step is as above.
The preparation of embodiment 4 compound 5
By 110g compound 4,110g acetic acid, 58g potassium acetate, 41g tetrabutyl ammonium bromide and 500ml dimethyl pyrrolidone
(nmp) it is added in 1000ml reaction bulb, starts to stir, be warming up to reaction 4-8 hour at 90 DEG C, after reaction is complete, locate afterwards
Reason, cooling reactant liquor, to room temperature, is subsequently adding 3 times of water, adds the ethyl acetate of 1 times of reactant liquor volume, stirring, static point
Layer, is layered ethyl acetate layer, and water layer continues to be extracted respectively once with 1 times of ethyl acetate * 2.Merge 3 extracting solution, add 1 times instead
Answer the saturated sodium bicarbonate that liquid amasss, in reaction a moment, prevent gas slug.Till there is no gas, (sodium bicarbonate is not
Enough, can be again plus a part of), separate water layer, ethyl acetate layer be washed once with 1 times of hydrochloric acid water of ph2 again, ethyl acetate layer is done
Dry, it is concentrated to dryness, obtain 83.9g compound 5 syrup thing.
The preparation of embodiment 6 compound 6 (methocarbamol beta isomer)
83.9g compound 5 and 250ml methanol and 10g p-methyl benzenesulfonic acid are added in reaction bulb, reaction is stirred at room temperature
6-10 hour.After reaction completely, directly concentrate methanol, be subsequently adding water 400ml, toluene 200ml, this system is heated to 75-
80 DEG C, after stirring fully, static layering, continuously add toluene 200ml in water layer, be again heated to 75-80 DEG C, stirring is fully
Afterwards, static layering.Layering water layer, water layer is cooled to room temperature, is subsequently adding ethyl acetate 150ml once, extracts water layer respectively
Three times.Abandon water layer, ethyl acetate layer is directly thickened to do, obtain syrup thing 50g, be subsequently adding pure water 200ml, toluene 50ml,
After stirring and dissolving is complete at 75-80 DEG C, add a small amount of activated carbon, stir 20 minutes, filter activity charcoal.Filtrate is tied at -5 DEG C
Brilliant.Filter to obtain 20g compound 6 (dry product meter).
Recrystallization: 20g crude product is added 100ml water, is heated to 75-80 DEG C, stirring and dissolving 20 minutes, after dissolving completely,
Naturally cool to crystallization 1-2 hour at 0～-5 DEG C, filter to obtain 14.14g compound 6 (dry product meter), hplc purity 99.6%.
Claims (6)
1. the preparation method of methocarbamol beta isomer is it is characterised in that with 2- ((methoxy phenoxy) methyl) oxirane chemical combination
Thing 1 is initiation material, comprises the steps:
1) in presence of organic solvent, there is chlorination in compound 1 and hydrogen chloride gas, obtains compound 2；
2) in the presence of organic solvent and alkali, there is esterification with triphosgene in compound 2, obtain compound 3；
3) in presence of organic solvent, compound 3 and ammonia occur amidation process to obtain compound 4；
4) in the presence of acetic acid, tetrabutyl ammonium bromide and dimethyl pyrrolidone, compound 4 and potassium acetate occur acetylation anti-
Compound 5 should be obtained；
5) in presence of organic solvent, compound 5 and p-methyl benzenesulfonic acid occur acidolysis de-ester reaction to obtain target product；
Synthetic route is:
2. the preparation method of methocarbamol beta isomer according to claim 1 is it is characterised in that described step 1) in have
Machine solvent is selected from dioxane, oxolane, methanol or ethanol, 60 ± 5 DEG C of reaction temperature.
3. the preparation method of methocarbamol beta isomer according to claim 1 is it is characterised in that described step 2) in have
Machine solvent is selected from dichloromethane, chloroform, carbon tetrachloride or dichloroethanes, and described alkali is selected from pyridine or triethylamine.
4. the preparation method of methocarbamol beta isomer according to claim 1 is it is characterised in that described step 3) in have
Machine solvent is selected from isopropanol, methanol or ethanol.
5. the preparation method of methocarbamol beta isomer according to claim 1 is it is characterised in that described step 5) in have
Machine solvent is methanol or ethanol.
6. the preparation method of methocarbamol beta isomer according to claim 1 is it is characterised in that with 2- ((methoxycarbonyl phenoxy
Base) methyl) oxirane compound 1 be initiation material, comprise the steps:
1) in the presence of dioxane, at a temperature of 60 ± 5 DEG C, compound 1 and hydrogen chloride gas there is chlorination,
Reaction is concentrated in vacuo after terminating to obtain compound 2；
2) in the presence of dichloromethane and pyridine, there is esterification with triphosgene in compound 2, and reaction temperature is 25-30 DEG C
Between, after reaction terminates, extracted with dichloromethane, organic layer is concentrated to give compound 3；
3) in the presence of isopropanol, there is amidation process with ammonia in compound 3, obtain compound 4 and compound 2, to product
Thing alcohol crystal obtains compound 4；
4) in the presence of acetic acid, tetrabutyl ammonium bromide and dimethyl pyrrolidone, reaction temperature is 90 DEG C of compounds 4 and acetic acid
There is acetylization reaction in potassium, reaction terminates to add water in rear reactant liquor, then is extracted with ethyl acetate, then use respectively sodium bicarbonate and
Hydrochloric acid is washed, and ethyl acetate layer is concentrated to give compound 5；
5) in the presence of methanol, under room temperature there is acidolysis de-ester reaction in compound 5 and p-methyl benzenesulfonic acid, reacts after terminating to anti-
Answer liquid to be concentrated, add water and toluene, this system is heated to 75-80 DEG C, stratification, use ethyl acetate in the water layer obtaining
Extraction, ethyl acetate layer is concentrated to dryness, and adds water and toluene, is cooled to knot at 0～-5 DEG C after stirring and dissolving at 75-80 DEG C
Crystalline substance, obtains target product.
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| CN201610728594.7A CN106349112A (en) | 2016-08-24 | 2016-08-24 | Preparation method of methocarbamol beta isomer |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3807522C1 (en) * | 1988-03-08 | 1989-03-30 | Boehringer Ingelheim Kg, 6507 Ingelheim, De | |
| CN102558097A (en) * | 2011-12-27 | 2012-07-11 | 辅仁药业集团有限公司 | Improved method for synthesizing ranolazine |
| CN103130684A (en) * | 2013-03-22 | 2013-06-05 | 南开大学 | Polymorphism of methocarbamol dipotassium phosphate and preparation method thereof |
-
2016
- 2016-08-24 CN CN201610728594.7A patent/CN106349112A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3807522C1 (en) * | 1988-03-08 | 1989-03-30 | Boehringer Ingelheim Kg, 6507 Ingelheim, De | |
| FR2628420B1 (en) * | 1988-03-08 | 1993-08-20 | Boehringer Ingelheim Kg | PROCESS FOR THE PREPARATION OF METHOCARBAMOL |
| CN102558097A (en) * | 2011-12-27 | 2012-07-11 | 辅仁药业集团有限公司 | Improved method for synthesizing ranolazine |
| CN103130684A (en) * | 2013-03-22 | 2013-06-05 | 南开大学 | Polymorphism of methocarbamol dipotassium phosphate and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| LOKESWARA RAO MADIVADA等: "An Efficient Synthesis of 1 ‑ (2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β‑Adrenoblockers", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| SCHMID, O.; VOAK, D.: "Acyl migration and acyl elimination in the two isomeric monocarbamic acid esters of 3-guaiacylglycerol ether and their O-acetyl derivatives", 《MONATSHEFTE FUER CHEMIE》 * |
| SHINDIKAR, A. V.; VISWANATHAN, C. L.: "Efficient synthesis of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol", 《SYNTHETIC COMMUNICATIONS 》 * |
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