CN1164598C - Heptahydrated fosphenytoin and its preparing process - Google Patents
Heptahydrated fosphenytoin and its preparing process Download PDFInfo
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- CN1164598C CN1164598C CNB021038880A CN02103888A CN1164598C CN 1164598 C CN1164598 C CN 1164598C CN B021038880 A CNB021038880 A CN B021038880A CN 02103888 A CN02103888 A CN 02103888A CN 1164598 C CN1164598 C CN 1164598C
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Abstract
The present invention discloses phosphorus phenytoin heptahydrate and a preparation method thereof. The preparation method comprises the following steps: (1), dibenzyl phosphoric acid is used for preparing dibenzyl silver phosphate; (2), 3-chloromethyl-5, 5-diphenyl phenytoin reacts with dibenzyl silver phosphate in toluene for preparing 3-hydroxymethyl-5, 5-diphenyl phenytoin dibenzyl phosphate ester; (3), the products of step (2) in propanone/ethanol is pressurized and hydrogenated under the existence of Pd/C for preparing 3-hydroxymethyl-5, 5-diphenyl phenytoin phosphate ester; (4), obtained products in step (3) is salified by sodium hydroxide for obtaining phenytoin phosphate crude products; (5), the phenytoin phosphate crude products are refined by water/ethanol for obtaining the phosphorus phenytoin heptahydrate. The obtained phosphorus phenytoin heptahydrate of the present invention has high stability to light, temperature and humidity and has the advantages of convenient production and storage, simple, convenient and feasible production technology, high product yield and high purity.
Description
Technical field
The present invention relates to a kind of medicine, relate to a kind of anti-epileptic, anticonvulsant drug and preparation method thereof in particular.
Background technology
Antiepileptic drug is paroxysmal or the imbalance of temporary brain function that prevention and treatment are caused by the epileptics outbreak, but the antiepileptic drug that uses clinically is invalid to about 25～30% patient at present, and in the treatment disease, occur general toxic action, cause epilepsy effect, teratogenesis risk and the untoward reaction that is proportionate with dosage etc.Is a Phenytoin Sodium Salt precursor medicine that goes through to go on the market that beats the world by Warner-Lambert AG Safnern in the prophenytoin of application listing in 1996.It can control idiopathic epilepsy patient's spasm symptom by the mode of quiet swimming instillation or administered intramuscular, the convulsions that occurs in prevention and the treatment neurosurgery.It has following characteristics: better tolerance, no phlebitis and local tissue necrosis, no burning sensation and local pain; Maximum drip velocity can reach 3 times of phenytoin Sodium, the control of the patient symptom that helps showing effect; Can replace diphenylhydantoin oral suspension to use (can not pill taker) in a short time; To each age patient particularly pediatric patient obvious superiority etc. is arranged.Prophenytoin has overcome the deficiency of Phenytoin Sodium Salt, has kept its advantage, has expanded its clinical indication, is the regeneration product of Phenytoin Sodium Salt.
But the synthetic method of present prophenytoin (Journal of Pharmaceutical Sciences.1984. (8): the solvent toxicity of 1068) using in preparation process is big, complicated operation, and the quality of intermediate is wayward, has therefore influenced the quality of finished product.What adopt particularly that this method finally obtains is the prophenytoin or the dihydrate of prophenytoin, and these two is to light, temperature sensitive, and especially to humidity sensitive, poor stability brings certain difficulty to industrial production.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, provide a kind of technological operation easy, power consumption is few, and cost is low, to light, temperature, moisture stable, is easy to Heptahydrated fosphenytoin of producing, storing and preparation method thereof.
Technical scheme of the present invention is summarized as follows:
Heptahydrated fosphenytoin, its molecular formula are C
16H
13N
2Na
2O
6P7H
2O has following structure:
The preparation method of Heptahydrated fosphenytoin of the present invention may further comprise the steps:
(1) preparation of dibenzyl Trisilver phosphate:
Dibenzyl phosphoric acid fully is dissolved in the aqueous solution that contains sodium hydroxide, makes reaction solution keep pH4～7, drip silver nitrate aqueous solution at 10～40 ℃ with nitric acid, after dropwising, insulation is fully reacted it, after reaction finishes, filter, obtain the solid of white dibenzyl Trisilver phosphate, keep in Dark Place;
(2) 3-methylol-5, the appropriate English Preparation of dibenzyl phosphate of 5-phenylbenzene:
With 3-chloromethyl-5, the appropriate English of 5-phenylbenzene is dissolved in the toluene of heat, and gradation adds the white dibenzyl Trisilver phosphate solid that step (1) makes, 40～80 ℃ of insulation reaction 3～10 hours, reaction finishes, and filtered while hot, filtrate decompression reclaim toluene to most, add ethanol, white crystals is separated out in placement, filters, and washes with ethanol, obtain white 3-methylol-5, the solid of the appropriate English dibenzyl phosphate of 5-phenylbenzene;
(3) 3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
The 3-methylol-5 that step (2) is obtained, the solid of the appropriate English dibenzyl phosphate of 5-phenylbenzene adds acetone: ethanol made its dissolving in 1: 9～9: 1, and in the presence of Pd/C, feed hydrogen, 10～70 ℃ of temperature, pressure 0.29～0.68mPa, reaction is filtered till the resorb hydrogen not, and filtrate decompression is recycled to the greatest extent, get 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene;
(4) preparation of prophenytoin:
With the solid 3-methylol-5 that step (3) obtains, the appropriate English phosphoric acid ester of 5-phenylbenzene adds dehydrated alcohol, is cooled to 0～20 ℃, and the aqueous sodium hydroxide solution with 10～50% is regulated pH to 10～12, and the adularescent solid produces, and filters, and gets the prophenytoin solid;
(5) preparation of Heptahydrated fosphenytoin:
Prophenytoin solid water with step (4) gained: ethanol is 2: 8～8: 2 heating for dissolving, add gac, filtered while hot, place, separate out white solid, filter, vacuum-drying under 10～30 ℃ of conditions, vacuum tightness is 0.08～0.09mPa, promptly gets Heptahydrated fosphenytoin to constant weight in 24 hours.
In the preparation of dibenzyl Trisilver phosphate, reacting liquid pH value is preferably 5～6, and temperature is 15～20 ℃.
At 3-methylol-5, in the appropriate English Preparation of dibenzyl phosphate of 5-phenylbenzene, temperature of reaction is preferably selected 78 ℃, and the reaction times is 4～5 hours.
At 3-methylol-5, in the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene, select acetone: ethanol is preferably 1: 1, and temperature of reaction is 25 ℃, and pressure is 0.34～0.44mPa.
In the preparation of prophenytoin, temperature of reaction is 15～20 ℃, and pH is 10～11.
In the preparation of Heptahydrated fosphenytoin, water: ethanol selects 3: 7, and vacuum-drying is best under 25 ℃ of conditions.
More than Fan Ying chemical equation is as follows:
Adopt the molecular structure of the prepared Heptahydrated fosphenytoin of the present invention to pass through H
1-NMR spectrogram, x-ray spectrogram and thermogravimetric spectrogram are confirmed that its product content is indicated by high pressure liquid chromatography figure.
Adopt the prepared Heptahydrated fosphenytoin technological operation of the present invention easy, cost is low, is easy to labour protection, and finished product is easy to suitability for industrialized production and is easy to store to light, temperature, moisture stable.
Adopt the prepared Heptahydrated fosphenytoin of the present invention to be used to make the pharmaceutical injection agent, use, be used for the generation that anti-epileptic and prevention of brain surgical operation are fainted from fear for vein, intramuscular injection.
Description of drawings
Fig. 1 is the H of Heptahydrated fosphenytoin
1-NMR spectrogram.
Fig. 2 is the C of Heptahydrated fosphenytoin
13-NMR spectrogram.
Fig. 3 is the x-ray spectrogram of Heptahydrated fosphenytoin.
Fig. 4 is the high pressure liquid chromatography figure of Heptahydrated fosphenytoin.
Fig. 5 is the thermogravimetric spectrogram of Heptahydrated fosphenytoin.
Embodiment
Below in conjunction with embodiment Heptahydrated fosphenytoin of the present invention and preparation method thereof is described further.
1, the preparation of dibenzyl Trisilver phosphate:
Mechanical stirring is being housed, in 5 liters of reaction flasks of thermometer, add 45g sodium hydroxide, 3.6 after rising distilled water, start stirring sodium hydroxide is all dissolved, gradation adds 150g dibenzyl phosphoric acid, continue to stir and make its dissolving, occur suspended substance in the reaction solution, filter, filtrate is refunded in 5 liters of reaction flasks, the cooling bath cooling, temperature is remained in 15～20 ℃ the aqueous solution, make reaction solution keep pH4～5, drip 10% silver nitrate aqueous solution 900ml with nitric acid, after dropwising, insulation makes its reaction 30 minutes, filters washing, get the solid of dibenzyl Trisilver phosphate, 60 ℃ of dryings (lucifuge) in baking oven.
2, the preparation of dibenzyl Trisilver phosphate:
Mechanical stirring is being housed, in 5 liters of reaction flasks of thermometer, add 45g sodium hydroxide, 3.6 after rising distilled water, start stirring sodium hydroxide is all dissolved, gradation adds 150g dibenzyl phosphoric acid, continue to stir and make its dissolving, occur suspended substance in the reaction solution, filter, filtrate is refunded in 5 liters of reaction flasks, cooling bath is but cool, temperature is remained in 15～20 ℃ the aqueous solution, make reaction solution keep pH5～6, drip 10% silver nitrate aqueous solution 900ml with nitric acid, after dropwising, insulation makes its reaction 30 minutes, filters washing, get the solid of dibenzyl Trisilver phosphate, 60 ℃ of dryings (lucifuge) in baking oven.
3, the preparation of dibenzyl Trisilver phosphate:
Mechanical stirring is being housed, in 5 liters of reaction flasks of thermometer, add 45g sodium hydroxide, 3.6 after rising distilled water, start stirring sodium hydroxide is all dissolved, gradation adds 150g dibenzyl phosphoric acid, continue to stir and make its dissolving, occur suspended substance in the reaction solution, filter, filtrate is refunded in 5 liters of reaction flasks, cooling bath is but cool, temperature is remained in 15～20 ℃ the aqueous solution, make reaction solution keep pH6～7, drip 10% silver nitrate aqueous solution 900ml with nitric acid, after dropwising, insulation makes its reaction 30 minutes, filters washing, get the solid of dibenzyl Trisilver phosphate, 60 ℃ of dryings (lucifuge) in baking oven.
4, the preparation of dibenzyl Trisilver phosphate:
Mechanical stirring is being housed, in 5 liters of reaction flasks of thermometer, add 45g sodium hydroxide, 3.6 after rising distilled water, start stirring sodium hydroxide is all dissolved, gradation adds 150g dibenzyl phosphoric acid, continue to stir and make its dissolving, occur suspended substance in the reaction solution, filter, filtrate is refunded in 5 liters of reaction flasks, cooling bath is but cool, temperature is remained in 10 ℃ the aqueous solution, make reaction solution keep pH5～6, drip 10% silver nitrate aqueous solution 900ml with nitric acid, after dropwising, insulation makes its reaction 30 minutes, filters washing, get the solid of dibenzyl Trisilver phosphate, 60 ℃ of dryings (lucifuge) in baking oven.
5, the preparation of dibenzyl Trisilver phosphate:
Mechanical stirring is being housed, in 5 liters of reaction flasks of thermometer, add 45g sodium hydroxide, 3.6 after rising distilled water, start stirring sodium hydroxide is all dissolved, gradation adds 150g dibenzyl phosphoric acid, continue to stir and make its dissolving, occur suspended substance in the reaction solution, filter, filtrate is refunded in 5 liters of reaction flasks, cooling bath is but cool, temperature is remained in 40 ℃ the aqueous solution, make reaction solution keep pH5～6, drip 10% silver nitrate aqueous solution 900ml with nitric acid, after dropwising, insulation makes its reaction 30 minutes, filters washing, get the solid of dibenzyl Trisilver phosphate, 60 ℃ of dryings (lucifuge) in baking oven.
6,3-methylol-5, the appropriate English Preparation of dibenzyl phosphate of 5-phenylbenzene:
Stirring is being housed, temperature is taken into account and is added 106g3-chloromethyl-5 in 3 liters of reaction flasks of condenser, and appropriate English of 5-phenylbenzene and 1700ml toluene heat up and is stirred to 57 ℃, molten entirely, add 70g dibenzyl Trisilver phosphate and continue to be warming up to 78 ℃, refluxing adds 70g dibenzyl Trisilver phosphate again after 1 hour, reflux to amount to 4 hours, after reaction finishes, filtered while hot, filter cake is given a baby a bath on the third day after its birth inferior with toluene, merging filtrate, toluene is to the greatest extent steamed in decompression, add 200ml ethanol, shake up, place, separate out white solid, filter, the filter cake drying at room temperature gets 120g3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, m.p.105～106 ℃ (thermometer is not proofreaied and correct), purity are 98.5% (HPLC normalization method).
7,3-methylol-5, the appropriate English Preparation of dibenzyl phosphate of 5-phenylbenzene:
Stirring is being housed, temperature is taken into account and is added 106g3-chloromethyl-5 in 3 liters of reaction flasks of condenser, and appropriate English of 5-phenylbenzene and 1700ml toluene heat up and is stirred to 57 ℃, molten entirely, add 70g dibenzyl Trisilver phosphate and continue to be warming up to 78 ℃, refluxing adds 70g dibenzyl Trisilver phosphate again after 1 hour, reflux to amount to 3 hours, after reaction finishes, filtered while hot, filter cake is given a baby a bath on the third day after its birth inferior with toluene, merging filtrate, toluene is to the greatest extent steamed in decompression, add 200ml ethanol, shake up, place, separate out white solid, filter, the filter cake drying at room temperature gets 120g3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, m.p.105～106 ℃ (thermometer is not proofreaied and correct), purity are 98.5% (HPLC normalization method).
8,3-methylol-5, the appropriate English Preparation of dibenzyl phosphate of 5-phenylbenzene:
Stirring is being housed, temperature is taken into account and is added 106g3-chloromethyl-5 in 3 liters of reaction flasks of condenser, and appropriate English of 5-phenylbenzene and 1700ml toluene heat up and is stirred to 57 ℃, molten entirely, add 70g dibenzyl Trisilver phosphate and continue to be warming up to 78 ℃ of backflows, refluxing adds 70g dibenzyl Trisilver phosphate again after 1 hour, reflux to amount to 10 hours, after reaction finishes, filtered while hot, filter cake is given a baby a bath on the third day after its birth inferior with toluene, merging filtrate, toluene is to the greatest extent steamed in decompression, add 200ml ethanol, shake up, place, separate out white solid, filter, the filter cake drying at room temperature gets 120g3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, m.p.105～106 ℃ (thermometer is not proofreaied and correct), purity are 98.5% (HPLC normalization method).
9,3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
With 119g 3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, 5g (5%) Pd/C and acetone: ethanol (1: 1) 1440ml drops in 2 liters of autoclaves, feeds hydrogen and makes pressure remain on 0.34～0.44mPa, 25 ℃ of following stirring reactions, to not inhaling till the hydrogen, need 1 hour approximately, filtration is finished in reaction, and filtrate is poured into to reduce pressure in 2 liters of reaction flasks and steamed solvent to the greatest extent, get 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene.
10,3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
With 119g 3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, 5g (5%) Pd/C and acetone: ethanol (1: 9) 1440ml drops in 2 liters of autoclaves, feeds hydrogen and makes pressure remain on 0.34～0.44mPa, 25 ℃ of following stirring reactions, to not inhaling till the hydrogen, need 1 hour approximately, filtration is finished in reaction, and filtrate is poured into to reduce pressure in 2 liters of reaction flasks and steamed solvent to the greatest extent, get 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene.
11,3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
With 119g 3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, 5g (5%) Pd/C and acetone: ethanol (9: 1) 1440ml drops in 2 liters of autoclaves, feeds hydrogen and makes pressure remain on 0.34～0.44mPa, 25 ℃ of following stirring reactions, to not inhaling till the hydrogen, need 1 hour approximately, filtration is finished in reaction, and filtrate is poured into to reduce pressure in 2 liters of reaction flasks and steamed solvent to the greatest extent, get 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene.
12,3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
With 119g 3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, 5g (5%) Pd/C and acetone: ethanol (1: 1) 1440ml drops in 2 liters of autoclaves, feeds hydrogen and makes pressure remain on 0.34～0.44mPa, 10 ℃ of stirring reactions, to not inhaling till the hydrogen, need 1 hour approximately, filtration is finished in reaction, and filtrate is poured into to reduce pressure in 2 liters of reaction flasks and steamed solvent to the greatest extent, get 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene.
13,3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
With 119g 3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, 5g (5%) Pd/C and acetone: ethanol (1: 1) 1440ml drops in 2 liters of autoclaves, feeds hydrogen and makes pressure remain on 0.34～0.44mPa, 70 ℃ of following stirring reactions, to not inhaling till the hydrogen, need 1 hour approximately, filtration is finished in reaction, and filtrate is poured into to reduce pressure in 2 liters of reaction flasks and steamed solvent to the greatest extent, get 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene.
14,3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
With 119g 3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, 5g (5%) Pd/C and acetone: ethanol (1: 1) 1440ml drops in 2 liters of autoclaves, feeds hydrogen and makes pressure remain on 0.29mPa, 25 ℃ of following stirring reactions, to not inhaling till the hydrogen, need 1 hour approximately, filtration is finished in reaction, and filtrate is poured into to reduce pressure in 2 liters of reaction flasks and steamed solvent to the greatest extent, get 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene.
15,3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
With 119g 3-methylol-5, the appropriate English dibenzyl phosphate of 5-phenylbenzene, 5g (5%) Pd/C and acetone: ethanol (1: 1) 1440ml drops in 2 liters of autoclaves, feeds hydrogen and makes pressure remain on 0.68mPa, 25 ℃ of following stirring reactions, to not inhaling till the hydrogen, need 1 hour approximately, filtration is finished in reaction, and filtrate is poured into to reduce pressure in 2 liters of reaction flasks and steamed solvent to the greatest extent, get 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene.
16, the preparation of prophenytoin:
With 3-methylol-5, the appropriate English phosphoric acid ester of 5-phenylbenzene drops in the reaction flask, add the 1000ml dehydrated alcohol, be cooled to 10～15 ℃, stir down and regulate pH to 10～11, have solid to separate out with 30% aqueous sodium hydroxide solution, continue to stir 1 hour, filter, filter cake is washed with dehydrated alcohol, gets prophenytoin.
17, the preparation of prophenytoin:
With 3-methylol-5, the appropriate English phosphoric acid ester of 5-phenylbenzene drops in the reaction flask, adds the 1000ml dehydrated alcohol, is cooled to 10～15 ℃, stir down and regulate pH to 12, have solid to separate out, continue to stir 1 hour with 30% aqueous sodium hydroxide solution, filter, filter cake is washed with dehydrated alcohol, gets prophenytoin.
18, the preparation of prophenytoin:
With 3-methylol-5, the appropriate English phosphoric acid ester of 5-phenylbenzene drops in the reaction flask, adds the 1000ml dehydrated alcohol, is cooled to 0 ℃, stir down and regulate pH to 10～11, have solid to separate out, continue to stir 1 hour with 30% aqueous sodium hydroxide solution, filter, filter cake is washed with dehydrated alcohol, gets prophenytoin.
19, the preparation of prophenytoin:
With 3-methylol-5, the appropriate English phosphoric acid ester of 5-phenylbenzene drops in the reaction flask, adds the 1000ml dehydrated alcohol, is cooled to 20 ℃, stir down and regulate pH to 10～11, have solid to separate out, continue to stir 1 hour with 30% aqueous sodium hydroxide solution, filter, filter cake is washed with dehydrated alcohol, gets prophenytoin.
20, the preparation of Heptahydrated fosphenytoin:
Get the water that prophenytoin 90g adds 10 times: ethanol (3: 7) is heated to backflow, on the bottle wall a small amount of insolubles is arranged, and adds the 4g activated carbon decolorizing about 10 minutes, the heat filter, place, separate out white solid, filter, wash with the 20ml dehydrated alcohol, drain, filter cake is put into vacuum drying oven, 25 ℃ of decompressions (vacuum tightness 0.08～0.09mPa) dry 24 hours to constant weight, obtain the white solid of Heptahydrated fosphenytoin, purity is 99.9 (HPLC normalization methods).
21, the preparation of Heptahydrated fosphenytoin:
Get the water that prophenytoin 90g adds 10 times: ethanol (2: 8) is heated to backflow, on the bottle wall a small amount of insolubles is arranged, and adds the 4g activated carbon decolorizing about 10 minutes, the heat filter, place, separate out white solid, filter, wash with the 20ml dehydrated alcohol, drain, filter cake is put into vacuum drying oven, 25 ℃ of decompressions (vacuum tightness 0.08～0.09mPa) dry 24 hours to constant weight, obtain the white solid of Heptahydrated fosphenytoin, purity is 99.9 (HPLC normalization methods).
22, the preparation of Heptahydrated fosphenytoin:
Get the water that prophenytoin 90g adds 10 times: ethanol (8: 2) is heated to backflow, on the bottle wall a small amount of insolubles is arranged, and adds the 4g activated carbon decolorizing about 10 minutes, the heat filter, place, separate out white solid, filter, wash with the 20ml dehydrated alcohol, drain, filter cake is put into vacuum drying oven, 25 ℃ of decompressions (vacuum tightness 0.08～0.09mPa) dry 24 hours to constant weight, obtain the white solid of Heptahydrated fosphenytoin, purity is 99.9 (HPLC normalization methods).
23, the preparation of Heptahydrated fosphenytoin:
Get the water that prophenytoin 90g adds 10 times: ethanol (3: 7) is heated to backflow, on the bottle wall a small amount of insolubles is arranged, and adds the 4g activated carbon decolorizing about 10 minutes, the heat filter, place, separate out white solid, filter, wash with the 20ml dehydrated alcohol, drain, filter cake is put into vacuum drying oven, 10 ℃ of decompressions (vacuum tightness 0.08～0.09mPa) dry 24 hours to constant weight, obtain the white solid of Heptahydrated fosphenytoin, purity is 99.9 (HPLC normalization methods).
24, the preparation of Heptahydrated fosphenytoin:
Get the water that prophenytoin 90g adds 10 times: ethanol (3: 7) is heated to backflow, on the bottle wall a small amount of insolubles is arranged, and adds the 4g activated carbon decolorizing about 10 minutes, the heat filter, place, separate out white solid, filter, wash with the 20ml dehydrated alcohol, drain, filter cake is put into vacuum drying oven, 30 ℃ of decompressions (vacuum tightness 0.08～0.09mPa) dry 24 hours to constant weight, obtain the white solid of Heptahydrated fosphenytoin, purity is 99.9 (HPLC normalization methods).
Claims (7)
1, a kind of Heptahydrated fosphenytoin, the molecular formula that it is characterized in that it is C
16H
13N
2Na
2O
6P7H
2O has following structure:
2, a kind of preparation method of Heptahydrated fosphenytoin, it comprises the steps:
(1) preparation of dibenzyl Trisilver phosphate:
Dibenzyl phosphoric acid fully is dissolved in the aqueous solution that contains sodium hydroxide, makes reaction solution keep pH4～7, drip silver nitrate aqueous solution at 10～40 ℃ with nitric acid, after dropwising, insulation is fully reacted it, after reaction finishes, filter, obtain the solid of white dibenzyl Trisilver phosphate, keep in Dark Place;
(2) 3-methylol-5, the appropriate English Preparation of dibenzyl phosphate of 5-phenylbenzene:
With 3-chloromethyl-5, the appropriate English of 5-phenylbenzene is dissolved in the toluene of heat, the solid of the white dibenzyl Trisilver phosphate that gradation adding step (1) makes, 40～80 ℃ of insulation reaction 3～10 hours, reaction finishes, and filtered while hot, filtrate decompression reclaim toluene to most, add ethanol, white crystals is separated out in placement, filters, and washes with ethanol, obtain white 3-methylol-5, the solid of the appropriate English dibenzyl phosphate of 5-phenylbenzene;
(3) 3-methylol-5, the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene:
The 3-methylol-5 that step (2) is obtained, the solid of the appropriate English dibenzyl phosphate of 5-phenylbenzene, add acetone: ethanol made its dissolving in 1: 9～9: 1, and in the presence of Pd/C, feed hydrogen, 10～70 ℃ of temperature, pressure 0.29～0.68mPa, reaction is till the resorb hydrogen not, filter, filtrate decompression is recycled to the greatest extent, gets 3-methylol-5, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene;
(4) preparation of prophenytoin:
With the 3-methylol-5 that step (3) obtains, the solid of the appropriate English phosphoric acid ester of 5-phenylbenzene adds dehydrated alcohol, is cooled to 0～20 ℃, and the aqueous sodium hydroxide solution with 10～50% is regulated pH to 10～12, and the adularescent solid produces, and filters, and gets the solid of prophenytoin;
(5) preparation of Heptahydrated fosphenytoin:
Solid water with step (4) gained prophenytoin: ethanol is 2: 8～8: 2 heating for dissolving, add gac, filtered while hot, place, separate out white solid, filter, vacuum-drying under 10～30 ℃ of conditions, vacuum tightness is 0.08～0.09mPa, promptly gets Heptahydrated fosphenytoin to constant weight in 24 hours.
3, method according to claim 2 is characterized in that the pH of reaction solution in the preparation of described dibenzyl Trisilver phosphate is 5～6, and temperature is 15～20 ℃.
4, method according to claim 2 is characterized in that described 3-methylol-5, and in the appropriate English Preparation of dibenzyl phosphate of 5-phenylbenzene, temperature of reaction is 78 ℃, and the reaction times is 4～5 hours.
5, method according to claim 2 is characterized in that described 3-methylol-5, and in the preparation of the appropriate English phosphoric acid ester of 5-phenylbenzene, acetone: ethanol is 1: 1, and temperature of reaction is 25 ℃, and pressure is 0.34～0.44mPa.
6, method according to claim 2 is characterized in that in the preparation of described prophenytoin that temperature of reaction is 15～20 ℃, and pH is 10～11.
7, method according to claim 2 is characterized in that in the preparation of described Heptahydrated fosphenytoin water: ethanol is 3: 7, vacuum-drying under 25 ℃ of conditions.
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| CH696765A5 (en) * | 2004-06-02 | 2007-11-30 | Cilag Ltd | Process for the preparation of fosphenytoin sodium. |
| CN101768190B (en) * | 2010-02-03 | 2013-01-23 | 天津红日药业股份有限公司 | Improvement method for refining and extracting technique in production process of fosphenytoin sodium intermediate |
| CN103288877B (en) * | 2013-05-10 | 2016-03-09 | 安徽省先锋制药有限公司 | Organic amine salt that prophenytoin is stable and its production and use |
| CN106279279B (en) * | 2016-08-15 | 2018-06-01 | 广安凯特制药有限公司 | A kind of preparation process of fosphenytoin sodium |
| CN114685561B (en) * | 2020-12-28 | 2023-10-31 | 四川科瑞德制药股份有限公司 | Preparation method of fosphenytoin sodium intermediate |
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2002
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