CN1379032A - Heptahydrated fosphenytoin and its preparing process - Google Patents
Heptahydrated fosphenytoin and its preparing process Download PDFInfo
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- CN1379032A CN1379032A CN 02103888 CN02103888A CN1379032A CN 1379032 A CN1379032 A CN 1379032A CN 02103888 CN02103888 CN 02103888 CN 02103888 A CN02103888 A CN 02103888A CN 1379032 A CN1379032 A CN 1379032A
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- phenylbenzene
- reaction
- methylol
- dibenzyl
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- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 title claims description 32
- 229960000693 fosphenytoin Drugs 0.000 title claims description 32
- 238000000034 method Methods 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 71
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 24
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 claims abstract description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 52
- 238000002360 preparation method Methods 0.000 claims description 51
- 239000007787 solid Substances 0.000 claims description 49
- -1 dibenzyl Trisilver phosphate Chemical compound 0.000 claims description 32
- 229960004756 ethanol Drugs 0.000 claims description 27
- 150000003014 phosphoric acid esters Chemical class 0.000 claims description 26
- 239000000706 filtrate Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 14
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 14
- 230000006837 decompression Effects 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 238000009413 insulation Methods 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract 1
- 239000010452 phosphate Substances 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 28
- 239000012065 filter cake Substances 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 238000010606 normalization Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 206010013786 Dry skin Diseases 0.000 description 5
- 239000001961 anticonvulsive agent Substances 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 238000010907 mechanical stirring Methods 0.000 description 5
- 230000000630 rising effect Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical class [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 229960002790 phenytoin sodium Drugs 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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Abstract
A heptahydrated phospho-phenyltoin is prepared through preparing dibenzyl phosphate from dibenzyl phosphoric acid, reaction on 3-chloromethyl-5,5-phenyltoin in toluene to obtain 3-hydroxymethyl-5,5-diphenyltoin dibenzylphosphate, pressure hydrogenating in acetone/alcohol under the existance of Pd/C to obtain 3-hydroxymethyl-5,5-diphenyltoin phosphate, using sodium hydroxide for forming salt to obtain coarse product, and refining by water/alcohol. It has high optical temp. and moisture stability, and high output rate and 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.
Technical background
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 Co. 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, C
13-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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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7235666B2 (en) * | 2004-06-02 | 2007-06-26 | Cilag Ltd. | Process for the preparation of sodium fosphenytoin |
| 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 |
| WO2014180264A1 (en) * | 2013-05-10 | 2014-11-13 | 安徽省先锋制药有限公司 | Stable organic amine salt of fosphenytoin and preparation method and use thereof |
| CN106279279A (en) * | 2016-08-15 | 2017-01-04 | 广安凯特医药化工有限公司 | A kind of preparation technology of fosphenytoin sodium |
| CN114685561A (en) * | 2020-12-28 | 2022-07-01 | 四川科瑞德制药股份有限公司 | Preparation method of fosphenytoin sodium intermediate |
-
2002
- 2002-04-10 CN CNB021038880A patent/CN1164598C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7235666B2 (en) * | 2004-06-02 | 2007-06-26 | Cilag Ltd. | Process for the preparation of sodium fosphenytoin |
| 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 |
| WO2014180264A1 (en) * | 2013-05-10 | 2014-11-13 | 安徽省先锋制药有限公司 | Stable organic amine salt of fosphenytoin and preparation method and use thereof |
| CN106279279A (en) * | 2016-08-15 | 2017-01-04 | 广安凯特医药化工有限公司 | A kind of preparation technology of fosphenytoin sodium |
| 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 |
| CN114685561A (en) * | 2020-12-28 | 2022-07-01 | 四川科瑞德制药股份有限公司 | Preparation method of fosphenytoin sodium intermediate |
| 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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