CN101863917A - Methocarbamol salt - Google Patents
Methocarbamol salt Download PDFInfo
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- CN101863917A CN101863917A CN 201010201124 CN201010201124A CN101863917A CN 101863917 A CN101863917 A CN 101863917A CN 201010201124 CN201010201124 CN 201010201124 CN 201010201124 A CN201010201124 A CN 201010201124A CN 101863917 A CN101863917 A CN 101863917A
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Abstract
The invention relates to methocarbamol salt, belonging to the technical field of chemicals, wherein methocarbamol is a central muscle relaxant and a medicine for treating common diseases and frequently-occurring diseases; and the methocarbamol has exact curative effects and high safety, but the shortcoming of water insolubility thereof is a key obstacle for development and improvement. The methocarbamol salt solves the problem and changes the water solubility of methocarbamol from 1:210 into that of the methocarbamol salt of 1:1; the methocarbamol salt is easily dissolved in water and the bioavailability in vivo is improved; and on the basis of comprehensive and deep experimental study, the invention explores a novel process route for synthesizing the water-soluble methocarbamol salt.
Description
Technical field
The invention belongs to the technical field of pharmaceutical chemicals, particularly relate to the Methocarbamol salt that improves bioavailability.
Background technology
Medicine is a kind of specialty goods that concerns the life safety, and new drug development has and has high input; Construction cycle is long, generally needs about 10 years; The development new drug must be preceding topic with multidisciplinary basic theory, uses various modern science and technology means with combining research, could find to some extent and innovation to some extent.Market competitiveness is strong, and the research of developed country is much crossed the threshold from modifying lead compound, and this is a kind of shortcut method in the many research strategies of developed country.For example, the derivative of erythromycin is many, and some is to utilize the effect of intermolecular sour alkali or Van der Waals force to be combined into double salt, has plenty of to modify the lead compound structure and make new compound.Now the erythromycin of Shou Jiing is that routine chemical combination is as follows:
More than be in the world former drug compound structure to be modified, derive an example of new compound, all have developer's patent right, these new compound medicines improve to some extent than former medicine or improve.This development scheme risk is less, success ratio is high, and competitive power is strong.
Methocarbamol is the active drug of treatment muscle epitonos, spasm, disease such as tetanic.Several large hospital clinical applications show in the Beijing-Tianjin two places beginning of the seventies for domestic twentieth century, this medicine is not only to several slight illness such as the muscle sprain of external clinical treatment, dampen, lumbar muscle strain, sciatica, Lumbar intervertebral disc prolapse, scapulohumeral periarthritis, the cervical vertebra palm fibre is closed disease, the obvious effective rate of diseases such as intramuscular pain is very high, and the doctor of hospital of medical courses in general institute of the State Physical Culture and Sports Commission, also further opened up and do not carried out clinical chronic disease (ankylosing spondylitis) abroad, they are main with the methocarbamol injection and tablet cooperates, and treatment has been got well vertebra skeleton and merged, the patient who can't take care of oneself.Just because of the determined curative effect of methocarbamol, toxic side effect are slight, safe.So after nineteen fifty-seven was taken the lead in going on the market by the U.S., a lot of countries in each continent and area all produced and use in the Europe, Asia and Africa, five more than ten years are still flourishing long time so far.Recent two decades comes, and the research of many scientific workers around developing methocarbamol derivative is abroad arranged.We have consulted domestic and international pertinent literature, and simple synthetic the description only arranged, and all do not carry out structural identification, and the physicochemical data that yet there is no need did not more carry out toxicity and pharmacological research.So, all do not have to form the medicine of curing the disease so far.
On the basis of existing product research, we have carried out multianalysis to methocarbamol, and the shortcoming of finding out methocarbamol itself is to be insoluble in water.Just because of this is insoluble in the weakness of water, making can only be that solvent is manufactured injection with polyoxyethylene glycol and water then, thereby some patient swollen untoward reaction of rising occurs at intramuscular injection site in clinical; Also, make that the bioavailability of methocarbamol is lower just because of this is insoluble in the weakness of water, so its oral dosage is bigger, each 0.75-1.0 gram, every day 3-4 time.Though methocarbamol is flourishing long time for many years, its injection solvent is still the binary solvent of polyoxyethylene glycol and water, domestic prescription still be usefulness be poly(oxyethylene glycol) 400 and water, the U.S. still uses Liquid Macrogol and water.
Summary of the invention
The present invention has used for reference that other medicines carry out the group transformation and successful experience is carried out structural modification to methocarbamol, improves its water solubility, to reach the purpose that improves its bioavailability.
In order to reach purpose of the present invention, we provide: Methocarbamol salt is characterized in that the structural formula of Methocarbamol salt:
X is: Li, Na, K.
Described Methocarbamol salt is characterized in that raw materials used is methocarbamol, phosphorus oxychloride, tribromo oxygen phosphorus, triethylamine, yellow soda ash, salt of wormwood, sodium-acetate, pyridine, metallic lithium, sodium Metal 99.5, potassium metal, lithium hydroxide, sodium hydroxide, potassium hydroxide.
Described Methocarbamol salt is characterized in that its preparation method is:
(1), preparation intermediate: biphosphate methocarbamol
(1) in cooling pool, clean reaction flask and electric stirring, thermometer, addition funnel are installed.Drop into the major ingredient methocarbamol of metering, add any one solvent in the claim 4, under-20 ℃～0 ℃, drip halogenating agent, drip and finish, add claim 4 kind of any one neutralizing agent, be incubated 30～180 fens.
(2) two of hydrolysis and elutriation kinds of technologies, can select a kind of method: 1. add the water of 3～4 times of molar weights, hydrolysis, remove organic solvent under reduced pressure after, add the above water of 4 times of molar weights, separate out intermediate, cooling, filter, washing, drying.2. add the above water of 5 times of molar weights, extract midbody product, cooling, filtration, washing, drying; Fusing point 120-124 ℃.
(3) carry out recrystallization, its methyl alcohol, consumption of ethanol are 2～20 times of major ingredient, and purification operations is the method for general routine; If the fusing point and the color and luster of crude product are good, can not need recrystallization.
(2), salt-forming reaction prepares Methocarbamol salt:
(1) intermediate biphosphate methocarbamol and salt-forming reagent reaction.In the reaction flask of cleaning, electric stirring, thermometer, addition funnel are installed; Drop into intermediate biphosphate methocarbamol, under 5～30 ℃, drip salt-forming reagent liquid; Finish, be incubated 10～90 minutes.Cooling, filtration, drying.
(2) carry out recrystallization, refining solvent is methyl alcohol, ethanol, pure water; Its consumption is 3～20 times of major ingredient, and purification operations is the method for general routine.
Described Methocarbamol salt is characterized in that described solvent is: acetone, chloroform, tetracol phenixin, methylene dichloride, ethylene dichloride, benzene, toluene, methyl alcohol, ethanol, acetonitrile; Its consumption is 2～15 times of methocarbamols; Described halogenating agent is: phosphorus oxychloride, tribromo oxygen phosphorus; Described neutralizing agent is: pyridine, triethylamine, yellow soda ash, salt of wormwood, sodium-acetate etc.; Described salt-forming reagent is: lithium hydroxide, sodium hydroxide, potassium hydroxide, metallic lithium, sodium Metal 99.5, potassium metal.
Effect of the present invention: methocarbamol is the maincenter muscle relaxant, is the medicine of treatment common disease frequently-occurring disease; Its determined curative effect, safe; The key that yet its weakness that is insoluble in water is development to be improved hinders; The invention solves this problem, by introducing the useful phosphorus of HUMAN HEALTH, lithium, sodium, potassium etc. are formed new compound, thereby improved the water-soluble of former medicine to organic drug; Synthesized Methocarbamol salt, these new variety do not smell for having, tasteless white powdered drug.The structure of product has repeatedly been done comprehensively conclusive evidence such as ultimate analysis, ultra-violet analysis, infrared spectra, mass spectrum, nuclear magnetic resonance spectrum, X-powdery diffractometry, thermogravimetric analysis, now enclosed the partial analysis spectrogram and (see Fig. 1～Fig. 5).To the quality of this new drug, carried out comprehensive careful experimental study by the Chinese Pharmacopoeia requirement again.In water-soluble key link, by the condition of Chinese Pharmacopoeia requirement, repeatedly compare test simultaneously, test-results: Methocarbamol salt is water-soluble to be 1: 1; Former methocarbamol is water-soluble to be 1: 210, thereby has improved the water-soluble of former medicine.Correlation data shows that existing original new drug is soluble in water.Just because of this weakness that is insoluble in water is resolved, make the solvent of injection can change into water, the human muscle easily absorbs water.Because this product is soluble in water, bioavailability in vivo is improved, and also just can reduce the dosage of oral preparations, and dosage reduces just can make sustained release preparation.
The present invention explores a cover novel artistic route and has obtained the water-soluble Methocarbamol salt very big raising, process stabilizing that has through deep experimental study comprehensively.Operational path of the present invention can make single salt and two salt: More's ratio of biphosphate methocarbamol and salt-forming reagent is to make single salt at 1: 1; More's ratio of biphosphate methocarbamol and salt-forming reagent is to make two salt at 1: 2.Single salt water-soluble not as better than two salt.The operational path of these new variety: do not produce harmful three refuses, free from environmental pollution during raw materials used and auxiliary material is easy to get, produces; Working condition is general, and is safe; Process stabilizing, yield height, quality reach existing Chinese Pharmacopoeia requirement.
Description of drawings
Fig. 1 is the mass spectrum of biphosphate methocarbamol.
Fig. 2 is the mass spectrum of methocarbamol potassiumphosphate.
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of methocarbamol potassiumphosphate.
Fig. 4 is the nuclear magnetic resonance of carbon spectrogram of methocarbamol potassiumphosphate.
Fig. 5 is the phosphorus nuclear magnetic resonance spectrum figure of methocarbamol potassiumphosphate.
Embodiment
1, the biphosphate methocarbamol is synthetic:
In cooling pool, reaction flask and electric stirring, thermometer, addition funnel are installed, drop into 120.62 gram methocarbamols, trichloromethane 1500mL, stir, cool to-15 ℃, drip 153 gram phosphorus oxychloride and 153mL chloroform solutions, keep under the low temperature, drip pyridine 90mL, temperature is not higher than 20 ℃.Finish, reacted 120 minutes.Add entry 100mL, decompression steams organic solvent.Add entry 2400mL, separate out crystallization, cooling, filtration, washing filtering layer, drying.Biphosphate 132 gram, mP120～124 ℃.
2, the Di-Sodium Phosphate methocarbamol is synthetic:
In water bed, reaction flask and electric stirring, thermometer, addition funnel are installed, drop into biphosphate methocarbamol 160.5 grams, add methyl alcohol 1600mL, stir down, drip 1mol sodium alkoxide liquid, make temperature of reaction maintain about 20 ℃.Finish, reacted 60 minutes.Cool to below 5 ℃, filter drying.Get Di-Sodium Phosphate methocarbamol 168 grams.Ethanol with 5 times of crude product amounts is made with extra care.The water-soluble of this product is 1: 3.
Embodiment 2 preparation Rhodiaphos DKP methocarbamols:
1, the biphosphate methocarbamol is synthetic:
In cooling pool, reaction flask and electric stirring, thermometer, addition funnel are installed, drop into 120.62 gram methocarbamols, trichloromethane 1200mL, stir, cool to-15 ℃, drip 153 gram phosphorus oxychloride and 153mL trichloromethane liquid, keep dripping triethylamine 160mL under the low temperature, temperature is not higher than 20 ℃.Finish, reacted 120 fens.Add water 1000mL, reaction solution is poured into separating funnel, left standstill, tells chloroform layer, collect the water extract, add water 800mL, extract, add water 800mL again, extract, merge water extract, cooling, filtration, washing filtering layer, drying.Biphosphate 137 gram, mP120～123 ℃.
2, the Rhodiaphos DKP methocarbamol is synthetic:
In water bed, reaction flask and electric stirring, thermometer, addition funnel are installed, drop into biphosphate methocarbamol 160.5 grams, add ethanol 1000mL, stir down, drip 1mol potassium alcoholate liquid, make temperature of reaction maintain about 20 ℃, finish, reacted 60 minutes.Cool to below 5 ℃, filter drying.Get Rhodiaphos DKP methocarbamol 190 grams.Ethanol with 5 times of crude product amounts is made with extra care.The water-soluble of this product is 1: 1.
Claims (4)
1. Methocarbamol salt is characterized in that the structural formula of Methocarbamol salt:
X is: Li, Na, K.
2. Methocarbamol salt according to claim 1 is characterized in that raw materials used is methocarbamol, phosphorus oxychloride, tribromo oxygen phosphorus, triethylamine, yellow soda ash, salt of wormwood, sodium-acetate, pyridine, metallic lithium, sodium Metal 99.5, potassium metal, lithium hydroxide, sodium hydroxide, potassium hydroxide.
3. Methocarbamol salt according to claim 1 is characterized in that its preparation method is:
(1), preparation intermediate: biphosphate methocarbamol
(1) in cooling pool, clean reaction flask and electric stirring, thermometer, addition funnel are installed, drop into the major ingredient methocarbamol of metering, add any one solvent in the claim 4, under-20 ℃～0 ℃, drip halogenating agent, drip and finish, add claim 4 kind of any one neutralizing agent, be incubated 30～180 fens;
(2) two of hydrolysis and elutriation kinds of technologies, can select a kind of method: 1. add the water of 3～4 times of molar weights, hydrolysis, remove organic solvent under reduced pressure after, add the above water of 4 times of molar weights, separate out intermediate, cooling, filter, washing, drying; 2. add the above water of 5 times of molar weights, extract midbody product, cooling, filtration, washing, drying; Fusing point 120-124 ℃;
(3) carry out recrystallization, its methyl alcohol, consumption of ethanol are 2～20 times of major ingredient, and purification operations is the method for general routine; If the fusing point and the color and luster of crude product are good, can not need recrystallization;
(2), salt-forming reaction prepares Methocarbamol salt:
(1) intermediate biphosphate methocarbamol and salt-forming reagent reaction; In the reaction flask of cleaning, electric stirring, thermometer, addition funnel are installed; Drop into intermediate biphosphate methocarbamol, under 5～30 ℃, drip salt-forming reagent liquid; Finish, be incubated 10～90 minutes; Cooling, filtration, drying;
(2) carry out recrystallization, refining solvent is methyl alcohol, ethanol, pure water; Its consumption is 3～20 times of major ingredient, and purification operations is the method for general routine.
4. Methocarbamol salt according to claim 3 is characterized in that described solvent is: acetone, chloroform, tetracol phenixin, methylene dichloride, ethylene dichloride, benzene, toluene, methyl alcohol, ethanol, acetonitrile; Its consumption is 2～15 times of methocarbamols; Described halogenating agent is: phosphorus oxychloride, tribromo oxygen phosphorus; Described neutralizing agent is: pyridine, triethylamine, yellow soda ash, salt of wormwood, sodium-acetate etc.; Described salt-forming reagent is: lithium hydroxide, sodium hydroxide, potassium hydroxide, metallic lithium, sodium Metal 99.5, potassium metal.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130684A (en) * | 2013-03-22 | 2013-06-05 | 南开大学 | Polymorphism of methocarbamol dipotassium phosphate and preparation method thereof |
| CN103130828A (en) * | 2013-03-22 | 2013-06-05 | 南开大学 | Methocarbamol diammonium phosphate, and polymorphism and preparation method thereof |
| CN103130683A (en) * | 2013-03-22 | 2013-06-05 | 南开大学 | Polymorphism of methocarbamol dihydric phosphate and preparation method thereof |
| CN103193677A (en) * | 2013-03-22 | 2013-07-10 | 南开大学 | Polymorphic form of methocarbamol disodium phosphate and preparation method thereof |
| CN107260717A (en) * | 2017-07-19 | 2017-10-20 | 天津市美索药物研发有限公司 | Methocarbamol salt is preparing the application of novel muscle relaxant external medical approach |
| CN114163469A (en) * | 2021-03-18 | 2022-03-11 | 天津市美索药物研发有限公司 | Formulation of methocarbamol sodium phosphate new medicine family medicine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8707179A1 (en) * | 1986-06-24 | 1987-07-16 | Lasa Lab | Metho-carbamol di:hydrogen phosphate prepn. |
| CN1823741A (en) * | 2005-12-28 | 2006-08-30 | 严洁 | Methocarbamol dry mixing suspension |
| CN1843343A (en) * | 2006-02-16 | 2006-10-11 | 严洁 | Methocarbamol dispersion tablet |
-
2010
- 2010-06-17 CN CN 201010201124 patent/CN101863917B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8707179A1 (en) * | 1986-06-24 | 1987-07-16 | Lasa Lab | Metho-carbamol di:hydrogen phosphate prepn. |
| CN1823741A (en) * | 2005-12-28 | 2006-08-30 | 严洁 | Methocarbamol dry mixing suspension |
| CN1843343A (en) * | 2006-02-16 | 2006-10-11 | 严洁 | Methocarbamol dispersion tablet |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130684A (en) * | 2013-03-22 | 2013-06-05 | 南开大学 | Polymorphism of methocarbamol dipotassium phosphate and preparation method thereof |
| CN103130828A (en) * | 2013-03-22 | 2013-06-05 | 南开大学 | Methocarbamol diammonium phosphate, and polymorphism and preparation method thereof |
| CN103130683A (en) * | 2013-03-22 | 2013-06-05 | 南开大学 | Polymorphism of methocarbamol dihydric phosphate and preparation method thereof |
| CN103193677A (en) * | 2013-03-22 | 2013-07-10 | 南开大学 | Polymorphic form of methocarbamol disodium phosphate and preparation method thereof |
| CN107260717A (en) * | 2017-07-19 | 2017-10-20 | 天津市美索药物研发有限公司 | Methocarbamol salt is preparing the application of novel muscle relaxant external medical approach |
| CN114163469A (en) * | 2021-03-18 | 2022-03-11 | 天津市美索药物研发有限公司 | Formulation of methocarbamol sodium phosphate new medicine family medicine |
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| CN101863917B (en) | 2013-06-12 |
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