97240-79-4 Usage
Uses
Used in Neurology:
Topiramate is used as an anticonvulsant for the treatment and control of partial seizures and severe tonic-clonic (grand mal) seizures. It is also used for the prevention of migraine headaches and in children for the treatment of Lennox-Gastaut syndrome.
Used in Pharmaceutical Industry:
Topiramate may be used as a pharmaceutical reference standard for the quantification of the analyte in pharmaceutical formulations using high-performance liquid chromatography technique and spectrophotometric technique.
Used in Weight Loss Treatment:
Topiramate is also used in combination with phentermine under the brand name Qsymia for the treatment of obesity in adults with a body mass index (BMI) of 30 or higher, or a BMI of 27 or higher in the presence of at least one weight-related medical condition such as hypertension, type 2 diabetes, or high cholesterol.
Broad-spectrum anti-epileptic drugs
Topiramate (the TPM) is a naturally existing monosaccharide D-fructose sulfide, and together with felbamate, lamotrigine and vigabatrin are current several broad-spectrum anti-epileptic drugs with relatively wide clinical application and can be used to control different types of epilepsy with excellent efficacy and pharmacokinetics. But in cases of being applied to children or fast increase of the amount can cause cognitive impairment and neurotoxicity, and easy to trigger kidney stones. In 1980, scientists had first successfully synthesized tipiramate in the laboratory. It had been applied to patients with epilepsy for the first time in 1986. In 1995, it was approved for entering into the market of UK for the first time. Its basic structure is fructopyranose sulfamate. Unlike other kinds of anti-epileptic drug, TPM has various kinds of anti-epileptic mechanisms including blocking the voltage-dependent sodium channels, enhancing the activity of GABA in the location of the γ-aminobutyric acid A (GABAA) receptor as well as blocking the activity of the AMPA glutamate receptor. In addition, there is still mild effect of carbonic anhydrase inhibitors. Europe and the United States had conducted double-blind, placebo-controlled studies and demonstrated that the adjunctive therapy with topiramate has excellent efficacy, safety and is well tolerated in the treatment of various types of refractory epilepsy. Now it has begun with topiramate monotherapy and has also achieved good results with 62% of patients with epileptic seizures disappearing completely. This product is generally used for the adjuvant treatment of antiepileptic drugs and is effective in treating simple and complex seizures as well as systemic tonic-clonic seizures and can also be used for the treatment of infantile spasms. Features of this product include excellent long-term efficacy, no significant resistance as well as being able to be used alone for antiepileptic purpose.
Indications
Epilepsy: monotherapy and adjunctive therapy of focal and generalized seizures.
Recommendations summarized from NICE (2012)
Seizure types: first line (myoclonic seizures), adjunctive (generalized tonicclonic seizures, focal seizures, myoclonic seizures), on referral to tertiary care (tonic/ atonic seizures, absence seizures).
Epilepsy types: first line (juvenile myoclonic epilepsy, idiopathic generalized epilepsy, Dravet), adjunctive (juvenile myoclonic epilepsy, epilepsy with generalized tonic- clonic seizures only, idiopathic generalized epilepsy, benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late- onset childhood occipital epilepsy), on referral to tertiary care (absence syndromes), contraindicated (Lennox– Gastaut syndrome).
Neurology: migraine prophylaxis
Pharmacological effects
The major mechanism of Topiramate is through blocking the dispersion of epileptic seizures rather than preventing its occurrence. It has been also found that TPM can exert its efficacy in treating epilepsy through various kinds of mechanisms including:
1, blocking the voltage-dependent sodium channels and thereby reducing the duration of epileptic discharges and the number of action potentials generated during each discharge.
2, antagonizing kainate/AMPA--glutamate receptors.
3, enhancing the GABA activity in the non-benzodiazepine position of the GABA receptor.
4, mildly inhibiting carbonic anhydrase.
5, blocking the T-type calcium channels.
6, block the activity of the excitatory neurotransmitter of the central nervous AMPA glutamate receptor.
Recent studies have shown that blocking L-type high-voltage-dependent calcium channels may be one of the most important mechanisms of the action of antiepileptic topiramate.
Topiramate (TPM) can be used to prevent the animal epileptic seizures induced by maximum electroshock seizure test (MES) but has no effect on the chemical drug-induced epileptic seizure as well as can’t be used to prevent the occurrence of the epileptic seizures.
Electrode physiological studies on the cultured hippocampal neurons have shown that 10μmol/ml topiramate can reduce the incidence of neural ignited spontaneously epileptic seizures and action potentials while 20μmol/ml of TPM can reduce the frequency of action potential firing. The antiepileptic effect of topiramate may also be related to its effect on increasing the GABA-induced influx of the chloride ions. Similar to benzodiazepine, TPM is also capable of increasing the GABA induced penetration of chloride particles through the cultured cell membrane. In addition to affecting the flow of chloride ions, TPM also increase the frequency of CABA’s activation of GABAA receptor. However, the activation is not through the interaction of the GABA binding site or benzodiazepine binding site. Topiramate has also been found to have mild inhibitory effect on the two carbonic anhydrase isozymes: carbonic anhydrase II and carbonic anhydrase IV.
The above information is edited by the lookchem of Dai Xiongfeng.
Pharmacokinetics
Topiramate is a white crystalline powder with bitter taste and is easily soluble in alkaline solution. Its saturated solution has a pH of 6.3. It can be rapidly absorbed after oral administration with achieving the average Cmax = 1.5 μg/ml within 2 to 3 hours (Tmax). Food had no significant effect on the bioavailability of topiramate with the oral absorption averaged on about 81%. There is 13% to 17% of topiramate binding to the plasma proteins with the average volume of distribution being 0.55~0.80L/kg. Upon single oral administration of a dosage of 100~400mg, it exhibits a linear drug-metabolism property. Patients with normal renal function can have it reach steady-state plasma concentrations in 4 to 8 days. Oral administration of 50 mg and 100 mg 2 times per day has the average T1/2 of approximately 21 hours. Oral administration of 100~400mg with 2 times per day together with taking phenytoin or carbamazepine can increase the plasma concentrations of the latter two drugs in positive dose-dependent relationship. Therefore, such patients should be subject to close observation on the adverse reactions and monitoring of the drug plasma concentrations when necessary. Instead, carbamazepine and phenytoin sodium can reduce the plasma concentration of topiramate. Therefore we need to adjust the dose based on efficacy and adverse reactions. Valproate doesn’t significantly affect the plasma concentration of topiramate.
Only about 20% of the topiramate can be subject to metabolism in its prototype. When used in combination with antiepileptic drug for treatment, about 50% of the topiramate is converted by metabolic enzymes. The six kinds of topiramate metabolites produced by the body all have no obvious anticonvulsant activity. 80% of the prototype topiramate in the body as well as its metabolites are subject to renal clearance. Oral administration of 50~100mg for 2 times per day gives the average renal clearance rate being about 18ml/min. Patients of renal impairment or hepatic injury has a decreased plasma clearance and renal clearance rate and the time for reaching steady state plasma concentration may take 10 to 15 days. Usually elderly patients have their plasma clearance rate be unchanged.
Pharmacokinetics
Topiramate is rapidly absorbed, with at least an 80 to 95% oral bioavailability that is unaffected by food. Following an oral dose
of topiramate, peak plasma concentration is reached in 1 to 4 hours, exhibiting linear pharmacokinetics. Protein binding is
minimal (<20%), and the usual elimination half-life is 20 to 30 hours, allowing a twice-daily dosing regimen. In the absence of
enzyme-inducing drugs, approximately 70 to 80% of the drug is excreted unchanged in the urine, with the remainder as
metabolites resulting from oxidation and hydrolysis. Enzyme-inducing AEDs alter the pharmacokinetics of topiramate by
reducing its plasma levels and increasing its rate of elimination.
In children from 4 to 17 years of age, topiramate exhibits linear pharmacokinetics, with a 50% increase in clearance rate
compared to adults. Topiramate may require up to a 50% dose reduction in patients with renal insufficiency, and a replacement dose may be needed after renal dialysis. Topiramate has demonstrated teratogenicity in animal studies.
Dosage
It acts as adjuvant drugs for the treatment of partial epileptic seizure with or without secondary systemic seizure. It is preferably to start administrating it from a low dose and gradually increase to the effective dose. Do not crush the tablets. For adults, it is recommended to take 50 mg per night during the first wee; take 50 mg at both day and night during the second week; take 50 mg in the morning and 100 mg in the evening; take 100 mg at both day and night during the fourth week; take 100 mg at day and take 150 mg at night in the fifth week; take 150 mg at both day and night during the sixth week; take 150 mg at day and 200 mg at night during the seventh week; take 200 mg at both day and night at the eighth week. Maintenance dose: 400mg/d. For children of 2 to 16 years old, the recommended dosage is 5~9mg/kg daily and divided into 2 times. The dose should be adjusted to 25mg (day 1~3 mg/kg) at night during the first week and then add 1~3mg/kg every day at the interval of 1 to 2 weeks with administration in 2 times until reaching the optimal clinical efficacy.
Dose titration
Epilepsy
Monotherapy
25 mg nocte for 7 days, then increased by 25– 50 mg every 7– 14 days; usual maintenance 100– 200 mg daily divided into two doses (max 500 mg daily, although doses of 1000 mg daily have been used for refractory epilepsy).
Adjunctive therapy
25– 50 mg nocte for 7 days then increased by 25– 50 mg every 7– 14 days; usual maintenance 200– 400 mg daily divided into two doses (max 400 mg daily). In case of a missed dose, take the next dose; do not take an extra tablet to make up for the missed one.
Clinical evaluation
33 cases of patients of epilepsy apply monotherapy or combination treatment with other antiepileptic drugs with the initial dose of 25mg, qd; the other 40 patients were subject to carbamazepine treatment as control. The effective rate of the topiramate treatment group was 93.9% which is significantly higher than that of the carbamazepine treatment group 77.5% (P <0.05); topiramate monotherapy has a better efficacy than combination therapy.
In preclinical tests of the AEDs development of the National Institutes of Health (NIH), researchers had studied the efficacy of topiramate as adjuvant therapy in the treatment of adult epilepsy patients. 41% of patients treated with topiramate had their seizure times decreased> 50% while the value in the placebo group was only 10%; 19% of patients treated with topiramate get the seizure times decreased> 75% (the value is only 3% in the placebo group).
Cautions
Patients with acute porphyrias.
Patients with risk factors for metabolic acidosis.
Patients with risk factors for nephrolithiasis (ensure adequate hydration).
Adverse reactions and precautions
1, since topiramate is often used in combination with other anti-epileptic drugs, it is therefore difficult to distinguish which drug or several drugs are related to the adverse reactions. The most frequently reported adverse reactions drug are symptoms associated with the central nervous system including ataxia, impaired attention, confusion, dizziness, fatigue, paresthesia, somnolence and abnormal thinking. This is potential risk factors for patient in driving or operating machinery. Common adverse reactions include anxiety, forgetting, loss of appetite, aphasia, depression, diplopia, mood swings, nausea, nystagmus, verbal expression disorder, taste perversion, abnormal vision and weight loss. Occasionally there are reports of renal stone disease. Drinking lots of water during the treatment can reduce the risk factors. Patients known allergic to the chemicals should be disabled.
2, similar to other anti-epileptic drugs, we should discontinue it gradually so that the possibility of increased seizure frequency can be reduced to minimum. In clinical trials, the reduced amount weekly is 100mg/day.
3, same as with other antiepileptic drugs, animal experiments confirmed that topiramate has teratogenic effects.
4, upon acute overdose, if ingested just now, you should immediately adopt gastric tube induced gastric emptying or induced vomiting for gastric emptying for rescue. Activated carbon does not adsorb topiramate, therefore it is not recommended to apply it upon overdose. Apply hemodialysis if necessary.
5, when using in combination phenytoin, we should monitor with the phenytoin plasma concentrations. Phenytoin and carbamazepine can reduce the plasma concentration of this product. For patients taking digoxin, when adding or discontinuing this product, pay attention to monitoring the digoxin plasma concentration. When topiramate is used in combination with oral contraceptives, the efficacy of the contraceptive may be reduced. You may need to adjust the dose of this product when added with hydrochlorothiazide. It is not recommended to administer together with alcohol or other central nervous system depressants. For patients being subject to metformin treatment, if increasing or stopping the treatment of this product, it should be closely monitored of the diabetic condition. Upon being used combination with pioglitazone, we should pay attention to the control of the diabetes disease. Being used in combination with other drugs which can lead to kidney stones can increase the risk of kidney stones. Overdose may cause convulsions, drowsiness, speech disorder, blurred vision, diplopia, mental impairment, lethargy, ataxia, stupor, hypotension, abdominal pain, dizziness and depression. Topiramate could result in severe metabolic acidosis.
Interactions
With AEDs
Carbamazepine and phenytoin decrease the plasma concentration of topimarate. Therefore, the addition or withdrawal of carbamazepine and phenytoin to topiramate therapy may require an adjustment in dosage of the latter: this should be done by titrating to clinical effect.
The addition of topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin, possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C9). Therefore, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.
With other drugs
Nil.
With alcohol/food
Concomitant administration of topiramate and alcohol (or other CNS depressant drugs) has not been evaluated in clinical studies. it is recommended that topiramate not be used concomitantly with alcohol or other CNS depressant drugs.
There are no specific foods that must be excluded from diet when taking topiramate.
Special populations
Hepatic impairment
Use with caution in moderate to severe impairment, as topiramate clearance may be reduced.
Renal impairment
In patients with impaired renal function topiramate should be administered with caution as the plasma and renal clearance of topiramate are decreased. Subjects with known renal impairment may require a longer time to reach steady- state at each dose. Half of the usual starting and maintenance dose is recommended.
Pregnancy
Clinical data from pregnancy registries indicate that infants exposed to topiramate monotherapy have an increased risk (three- fold for topiramate monotherapy) of major congenital malformations (particularly cleft lip/ palate, hypospadias, and anomalies involving various body systems) following exposure during the first trimester (increased risk of teratogenic effects associated with the use of AEDs in combination therapy).
Clinical data from pregnancy registries indicate that infants exposed to topiramate monotherapy have a higher prevalence of low birth weight (<2500 g) compared with a reference group.
It is therefore recommended that women of child- bearing age use highly effective contraception and consider alternative therapeutic options. In case of administration during the first trimester, careful prenatal monitoring should be performed. The dose of topiramate should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis. It is recommended that the foetal growth is monitored.
Although the excretion of topiramate in human milk has not been evaluated in controlled studies, limited observations in patients suggest an extensive excretion of topiramate into breast milk. Therefore, the options of suspending breastfeeding or discontinuing/ abstaining from topiramate therapy should be carefully weighed up.
Psychiatric use
There is some evidence that topirmate may be effective in the treatment of depression, either as monotherapy or as adjunctive treatment. The findings of initial reports suggesting that topiramate can be effective in the treatment of bipolar disorder and post- traumatic stress disorders have not been confirmed by the results of randomized controlled trials. Preliminary data suggest some efficacy in Tourette syndrome, obsessive- compulsive disorder, eating disorders (binge eating), behavioural and psychological symptoms of dementia, alcohol and cocaine dependence. In late 2012, topiramate was approved by the USA FDA in combination with phentermine for weight loss: this is a clinically significant effect in patients with behavioural problems, as psychopharmacological treatment is often associated with metabolic dysfunction and weight gain.
Manufacturing Process
To a cold solution (-4°C) of 2,3:4,5-di-O-isopropylidene-β-fructopyranose (75
g, 0.29 mol) in DMF (725 ml) was added 50% oily sodium hydride (16.34 g,0.34 mol). After stirring for 90 min, sulfamoyl chloride (54.9 g, 0.48 mol) was
added and the stirring continued for an additional 3.5 h at that temperature.
The reaction mixture was poured into cold water and extracted with toluene.
The organic layer was dried (Na2SO4) and the solvents removed under
vacuum to give a syrup which crystallized immediately. Recrystallization from
ethylacetate/hexane gave pure 2,3:4,5-bis-O-(1-methylethylidene)-β-D_x0002_fructopyranose sulfamate, melting point 125°-126°C.
Biological Functions
Topiramate is most useful in patients with generalized
tonic–clonic seizures and those with partial complex
seizures. Topiramate causes a higher incidence of CNSrelated
side effects (primarily cognitive slowing and
confusion) than other AEDs. It does not appear to
cause a significant incidence of rashes or other hypersensitivity
reactions; however, a significantly higher incidence
of kidney stones has been observed in persons
receiving topiramate than in a similar untreated population.
Biological Activity
Anticonvulsant. Antagonizes GluR5 kainate receptors (IC 50 = 0.46 μ M), acts as a positive allosteric modulator of GABA A receptor-mediated currents, inhibits Na v channels (IC 50 = 48.9 μ M) and inhibits L-type Ca 2+ channels. Also inhibits carbonic anhydrase (CA) (K i values are 0.1 and 0.2 μ M at rat CA II and CA IV respectively), which lowers intracellular neuronal pH.
Biochem/physiol Actions
Kainate GluR5 receptor antagonist; anticonvulsant.
Mechanism of action
The mechanism of action for topiramate is unknown, but several actions are thought to contribute to its AED activity. It
blocks repetitive firing by acting on sodium channels, may enhance GABAA-mediated chloride flux, and appears to be an
antagonist at the AMPA and KA receptors, thus blocking the effect of glutamate. In addition, recent evidence
suggests inhibition of L-type calcium currents.
Clinical Use
Topiramate is a sulfamate-substituted monosaccharide derived from fructose with a broad spectrum of AED activity. It is
approved for monotherapy or as an adjunct drug for partial or primary generalized tonic-clonic seizures in patients older than
10 years, as adjunct therapy in children aged from 2 to 10 years with partial-onset seizures, and in persons older than 2 years
with Lennox-Gastaut syndrome. Topiramate also is approved for the prophylaxis of migraine headaches.
Side effects
Common CNS side effects associated with topiramate therapy include drowsiness, dizziness, impaired concentration and
memory, speech and language difficulties, and confusion. These effects develop during the first weeks of therapy and may
decline over time. Acute closed-angle glaucoma caused by topiramate requires immediate evaluation. Only rare hepatic or
bone marrow effects have been noted thus far; however, an increased incidence of renal stones is troublesome and probably
related to the drug's activity as a carbonic anhydrase inhibitor, reducing citrate excretion and increasing urinary pH. Use of
additional carbonic anhydrase inhibitors, a ketogenic diet, or a family history of nephrolithiasis may be considered as
contraindications for using topiramate.
Topiramate is not devoid of potential interaction properties: It induces CYP3A4 and inhibits CYP2C19, thus significantly increasing plasma phenytoin levels. Topiramate also may decrease the effectiveness of oral contraceptives.
Veterinary Drugs and Treatments
Topiramate may be useful for treating seizures in dogs, particularly
partial seizure activity. It may also be of benefit in treating cats, but
little information is available.
in vitro
in principal neurons of the rat basolateral amygdala, low concentrations of topiramate selectively inhibited pharmacologically isolated excitatory synaptic currents mediated by kainate receptors with the glur5 subunit with an ic50 value of 0.5 μm. topiramate also partially depressed predominantly ampa-receptor-mediated epscs with lower efficacy [1]. in dissociated neocortical slices, low concentrations of tpm (25–30 μm) slightly inhibited the persistent fraction of na+ current and reduced the na+-dependent long-lasting action potential shoulders evoked in layer v pyramidal neurons after ca2+ and k+ current blockade. tpm (100 μm) had no effects on the voltage dependence of activation but induced a leftward shift of the steady-state inaf inactivation curve [3].
in vivo
tpm treatment significantly improved the 24-h neurological deficit scores (high dose, 1.17 ± 0.41; low dose, 1.75 ± 0.5; p < 0.05 for both doses). the percentage of infarct volume (low dose, 22.9 ± 8.9%, p = 0.002; high dose 7.6 ± 3.4%, p < 0.001) reduced when compared with the controls (infarct size, 54.2 ± 9.0%; neurobehavior score, 2. 67 ± 0.52). higher dose of tpm induced more neuroprotection than that of lower dose (p < 0.05). in a rat model of focal ischemia, treatment with tpm 2 h after mca embolization resulted in neuroprotective effect in a dose- and use-dependent manner [2]. topiramate (25-100 mg/kg, i.p.) dose-dependently elevated the threshold for clonic seizures induced by infusion of a selective agonist of glur5 kainate receptors atpa [4]. topiramate (i.p) effectively suppressed acute seizures induced by perinatal hypoxia in a dose-dependent manner with an ed50 of 2.1 mg/kg [5]. topiramate (20 and 40 mg/kg i.p.) dose-dependently inhibited both tonic and absence-like seizures. in dba/2 mice, topiramate inhibited sound-induced seizures with ed50 of 8.6 mg/kg (p.o) [6].
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: antagonism of anticonvulsant
effect; avoid with St John’s wort.
Antiepileptics: concentration reduced by
fosphenytoin, phenytoin, carbamazepine and possibly
phenobarbital; increases fosphenytoin and phenytoin
concentration; reduces concentration of perampanel;
hyperammonaemia and CNS toxicity reported with
valproate.
Antimalarials: mefloquine antagonises
anticonvulsant effect.
Antipsychotics: anticonvulsant effect antagonised.
Oestrogens and progestogens: reduced contraceptive
effect.
Orlistat: possibly increased risk of convulsions.
Ulipristal: reduced contraceptive effect - avoid.
Metabolism
Topiramate is not extensively metabolised (~20%) in
healthy volunteers. It is metabolised up to 50% in patients
receiving enzyme-inducing drugs. Six metabolites formed
through hydroxylation, hydrolysis and glucuronidation
have been identified but have little activity. It is eliminated
chiefly in urine, as unchanged drug and metabolites.
references
[1] gryder d s, rogawski m a. selective antagonism of glur5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons[j]. the journal of neuroscience, 2003, 23(18): 7069-7074.[2] yang y, shuaib a, li q, et al. neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization[j]. brain research, 1998, 804(2): 169-176.[3] taverna s, sancini g, mantegazza m, et al. inhibition of transient and persistent na+ current fractions by the new anticonvulsant topiramate[j]. journal of pharmacology and experimental therapeutics, 1999, 288(3): 960-968.[4] kaminski r m, banerjee m, rogawski m a. topiramate selectively protects against seizures induced by atpa, a glur5 kainate receptor agonist[j]. neuropharmacology, 2004, 46(8): 1097-1104.[5] koh s, jensen f e. topiramate blocks perinatal hypoxia‐induced seizures in rat pups[j]. annals of neurology, 2001, 50(3): 366-372.[6] nakamura j, tamura s, kanda t, et al. inhibition by topiramate of seizures in spontaneously epileptic rats and dba/2 mice[j]. european journal of pharmacology, 1994, 254(1-2): 83-89.
Check Digit Verification of cas no
The CAS Registry Mumber 97240-79-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 9,7,2,4 and 0 respectively; the second part has 2 digits, 7 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 97240-79:
(7*9)+(6*7)+(5*2)+(4*4)+(3*0)+(2*7)+(1*9)=154
154 % 10 = 4
So 97240-79-4 is a valid CAS Registry Number.
InChI:InChI=1/C12H21NO8S/c1-10(2)18-7-5-16-12(6-17-22(13,14)15)9(8(7)19-10)20-11(3,4)21-12/h7-9H,5-6H2,1-4H3,(H2,13,14,15)/t7-,8-,9?,12+/m0/s1
97240-79-4Relevant articles and documents
Hexafluoroisopropyl sulfamate: A useful reagent for the synthesis of sulfamates and sulfamides
Sguazzin, Matthew A.,Johnson, Jarrod W.,Magolan, Jakob
supporting information, p. 3373 - 3378 (2021/05/10)
Sulfamates and sulfamides are most often synthesized from alcohols and amines with sulfamoyl chloride, which is an unstable reagent. We have identified hexafluoroisopropyl sulfamate (HFIPS) as a bench-stable solid that reacts readily with a wide variety of alcohols, amines, phenols, and anilines under mild reaction conditions. The sole byproduct of the reaction is hexafluoroisopropanol (HFIP) and reaction products can often be isolated in high purity after an aqueous workup (optional) and removal of solvents by evaporation.
Crystal form of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate
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Paragraph 0057-0062; 0063; 0066-0068; 0071; 0072; 0078; 0079, (2020/01/25)
The invention belongs to the technical field of pharmaceuticals, and particularly relates to a crystal form A of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate. The invention further relates to a preparation method of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate and the purpose of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate to preparation of Topiramate. The crystal form A of the prepared 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphate is high in purity, single-impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose is smaller than 0.11%, the yield of the Topiramate prepared from the crystal form A of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose chlorosulphateis 92% or above, the HPLC purity is greater than 99.90%, the single-impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-fructopyranose is smaller than 0.03%, and single impurities of a condensation compound are smaller than 0.05%.
Crystal form of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate
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Paragraph 0052-0058; 0061-0062; 0063; 0066-0068; 0071-0074, (2020/01/25)
The invention belongs to the technical field of medicines and in particular relates to a crystal form I of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate. The invention further relates to a preparation method and application of the crystal form in preparing topiramate. The crystal form I of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate, whichis provided by the invention, is high in purity, the content of a single impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose is less than 0.15%, the yield of topiramate prepared from thecrystal form I of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate is 92% or greater, the HPLC (high performance liquid chromatography) purity is greater than 99.85%, the content of the single impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose is less than 0.06%, and the content of a single impurity of a condensation compound is smaller than 0.08%.
Preparation method of high-purity topiramate
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Paragraph 0023; 0026; 0027; 0028; 0031; 0032; 0033; 0036, (2018/09/08)
The invention discloses a preparation method of high-purity topiramate. The preparation method comprises the following steps: (1) performing reflux reaction on D-fructose and acetone in a dehydratingagent, centrifuging, then performing low-temperature reaction under a 4A molecular sieve-sulfuryl chloride-acid binding agent system, filtering and performing organic layer vacuum distillation; (2) dissolving a reaction product obtained in the step (1) by using a solvent, then introducing ammonia gas, stirring for 4-8 hours at a room temperature, vacuum-pumping for 0.5 h, increasing the temperature of reaction liquid, refluxing for 1 h, then slowly reducing the temperature to below 10 DEG C, crystallizing for 4 h, centrifuging and washing a filter cake with a solvent; (3) pressurizing a reaction product obtained in the step (2), increasing the temperature and dissolving, reducing the temperature to 65 DEG C, adding a small amount of topiramate seed crystals with a respective purity of morethan 99 percent, continuously reducing the temperature to 5 DEG C, crystallizing for 6 h, centrifuging and washing a filter cake with a low-temperature solvent to obtain the high-purity topiramate. The topiramate produced by the preparation method disclosed by the invention has the advantages of being abundant and cheap in raw material, low in cost, high in yield, high in purity, great in industrial value, low in pollution and the like.
Preparation method of high-purity topiramate
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Paragraph 0012; 0071; 0072, (2017/08/29)
The invention discloses a preparation method of high-purity topiramate. Under the condition of dissolving the topiramate into an organic solvent, a proper concentration of alkali is added, so that the topiramate slat forms solid to be separated out in the solvent; the solid is dissolved into water, and is acidified into a weak acidic state; the solid is a topiramate coarse product; the topiramate coarse product is recrystallized to obtain the high-purity topiramate. The preparation method of the high-purity topiramate has the advantages that the purity reaches 99.90 percent or higher; under the condition that the product purity reaches 99.9 percent or higher, the yield of the product keeps unchanged; no additional excessive cost is added. The operation is convenient; the process is safe; the industrial production is easy.
Synthesis technology of topiramate
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Paragraph 0021-0022; 0024-0027; 0029-0032; 0034-0035, (2017/08/27)
The invention provides a synthesis technology of topiramate and relates to the technical field of drug synthesis. The synthesis technology of the topiramate comprises the following steps that (1) diacetone fructose and sulfonyl chloride are esterified under the alkalescence environment to obtain chlorosulfonate ester; (2) the chlorosulfonate ester is aminated in a mixed solvent of tetrahydrofuran/dichloromethane, and a crude topiramate product is obtained; (3) refining is conducted: the crude topiramate product is subjected to recrystallization, and refined topiramate is obtained; the method for preparing the topiramate is safe and easy to operate, multistep recrystallization is avoided, the cost is reduced, the production technology is simplified, and the method is suitable for industrial large scale production.
A method for preparing topiramate and the method involved in the intermediate crystal form and its preparation method
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, (2017/04/27)
The invention belongs to the pharmaceutical chemistry field, and more specifically relates to a synthetic method of an antiepileptic drug topiramate, and an alkali metal salt new crystal form of a key intermediate compound N-benzyloxycarbonyl-2,3: 4,5-di-O-(1-methyl ethylidene)-beta-D-fructopyranose sulfamate related in the synthetic method, and a preparation method of the new crystal form, and a method for preparing topiramate.
Efficient synthesis of N-oxysulfonyl formamidines through thionyl chloride-promoted reaction of sulfamates with formamides
Wusiman, Abudureheman,Hudabaierdi, Ruzeahong
supporting information, p. 2015 - 2021 (2017/10/13)
N-Oxysulfonyl formamidine derivatives have been efficiently synthesized under mild conditions through direct condensation of various sulfamates and formamides in the presence of thionyl chloride. The scope of this reaction was investigated, and a plausible mechanism was proposed. The resulting N-oxysulfonyl formamidines can be converted to sulfamates through appropriate deprotection.
Preparation method of high-purity topiramate
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Paragraph 0027; 0028; 0029, (2016/10/31)
The invention discloses a preparation method of high-purity topiramate. The topiramate is obtained by using 2,3,4,5-bis-O-(1-methylethylene)-beta-D-pyran fructose chlorosulfonate as a raw material and tetrahydrofuran and acetonitrile as solvents, adding ammonia-source ammonium acetate and performing amination under a heating condition, wherein the purity of the topiramate is not lower than 99.5%. The preparation method is low in cost, easy and convenient to operate, safe and efficient, and is suitable for large-scale industrial production.
The first general protocol for N-monoalkylation of sulfamate esters: Benign synthesis of N-alkyl Topiramate (anticonvulsant drug) derivatives
Saeidian, Hamid,Abdoli, Morteza
, p. 463 - 470 (2015/10/19)
A novel protocol for the highly selective N-monoalkylation of the sulfamate ester moiety has been developed. This reaction proceeded efficiently using alkyl halides, benzyl halides and -halo ketones as the electrophile in the presence of KF-Al2O3 as a cost-effective and robust catalyst. This approach provides new access to N-monoalkylated Topiramate (anticonvulsant drug) derivatives which are potentially of great importance in medicinal chemistry.