CN103910770B - A kind of intermediate crystal form involved in the preparation method of topiramate and the method and preparation method thereof - Google Patents
A kind of intermediate crystal form involved in the preparation method of topiramate and the method and preparation method thereof Download PDFInfo
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- CN103910770B CN103910770B CN201410102754.8A CN201410102754A CN103910770B CN 103910770 B CN103910770 B CN 103910770B CN 201410102754 A CN201410102754 A CN 201410102754A CN 103910770 B CN103910770 B CN 103910770B
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- DRZGKVFICWIAST-UHFFFAOYSA-N N=S(NC(OCc1ccccc1)=O)(Cl)=O Chemical compound N=S(NC(OCc1ccccc1)=O)(Cl)=O DRZGKVFICWIAST-UHFFFAOYSA-N 0.000 description 1
- BCSYQDOKTDVISP-UHFFFAOYSA-N O=C(NS(Cl)(=O)=O)OCc1ccccc1 Chemical compound O=C(NS(Cl)(=O)=O)OCc1ccccc1 BCSYQDOKTDVISP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to medicinal chemistry art, it is specifically related to the synthetic method of a kind of antiepileptic topiramate, and the key intermediate compound N benzyloxycarbonyl group 2 related in this synthetic method, 3:4, alkali metal salt novel crystal forms of 5 pairs of O (1 methyl ethylidene) β D fructopyranose sulfamates and preparation method thereof, and they are used for preparing topiramate.
Description
Technical field
The invention belongs to medicine and intermediate synthesis, crystal formation chemical field, be specifically related to a kind of antiepileptic torr pyrrole
Ester midbody compound
N-benzyloxycarbonyl group-2, the alkali metal of double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-
Salt novel crystal forms and preparation method thereof, and they are used for preparing topiramate.
Background technology
Alkali metal salt: herein described alkali metal salt refers to sodium salt and potassium salt.
Alkali metal: alkali metal described herein refers to sodium and potassium.
Alkaline alkali metal salt: herein described alkaline alkali metal salt refer to sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate,
Potassium bicarbonate, potassium phosphate.
Alkaline sodium salt: herein described alkaline sodium salt refers to sodium carbonate, sodium bicarbonate, sodium phosphate.
Alkaline potassium salt: herein described alkaline potassium salt refers to potassium carbonate, potassium bicarbonate, potassium phosphate.
U.S. Patent number 4,513,006 discloses a class novel anti-epileptic compounds.One of which compound 2,3:4,5-
Two-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate (being known as topiramate) is in people's epilepsy clinical experiment,
It is certified as simple type and complexity partial seizures and effective adjuvant therapy medicaments of Secondary cases generalized seizure or single
Medicine.
Topiramate is from nineteen ninety-five auxiliary treatment mainly as other antuepileptic since Britain lists.Nowadays, facing
Being widely used on bed, topiramate has retardance Na+Passage, strengthens the inhibitory action of GABA mediation, blocked glutamic acid
The innervation of mediation, affects Cl-Film operating and Ca2+The multiple action mechanism that passage stops.1999 start in China
Using, curative effect is high, untoward reaction is few, except may result in Concentration of Phenytoin when finding and share with phenytoin in only a few patient
Outside increasing, topiramate does not affect the blood drug level of other conventional antiepileptic.In recent years, along with its pharmaceutical research is entered
Exhibition and clinical observation, be found to have many new application, and obtain satisfied curative effect clinically.Therefore at field of medicaments still to it
Carry out multidirectional research.
Chinese patent CN03815991.0 discloses a kind of optimization route synthesizing topiramate, and this route steps is simple just
In industrialized production.Specific as follows:
Step 1: chlorosulfonic acid isocyanate, is again CSI, and structural formula isReact with benzylalcoholGenerate
Step 2:With fructose two acetoneReaction generation N-benzyloxycarbonyl group-
Double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 2,3:4,5-, No. CAS is 627537-93-3, structural formula
ForMore specifically refer to embodiment 4 part of this patent documentation: "
Embodiment 4
N-benzyloxycarbonyl-2,3:4,5-bis--O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate (chemical combination
Thing #15)
Step A: preparation-[[[(chlorosulfonyl) amino] carbonyl] epoxide]-benzene
To the outfit stirring rod of 250mL, thermocouple and N2 outlet reaction bulb add Carbimide. chlorine sulfonyl ester (10.0mL,
115mmol) with dichloromethane (20mL).Cooling reaction bulb to after 0 DEG C, through charging hopper add in 30 minutes benzylalcohol (11.9mL,
115mmol).Internal temperature keeps below 10 DEG C.After having added, reactant mixture is warming up to room temperature, stirs 15 minutes, so
Final vacuum concentrates and obtains white solid.White solid is ground with petroleum ether (100mL).Solid is collected by filtration, uses petroleum ether
(2x50mL) rinse final vacuum to be dried, it is thus achieved that end product white fine powder end.
Step B:
To outfit stirring rod and the N of 100mL2Reaction bulb addition [[[(chlorosulfonyl) amino] carbonyl] epoxide] of outlet-
Benzene (5.0g, 21mmol) and acetonitrile (20mL).Then the pyridine containing diacetone fructose (5.2g, 20mmol) is added through charging hopper
(2.4mL, 30mmol), reaction stirred is overnight.Then concentrate this material and obtain oil to dry.By this oil soluble in DCM (100mL),
Rinse with 0.5NHCl (2x50mL) and saline (1x50mL).After Xiang Fenliing, organic layer Na2SO4(150g) it is dried, true after filtration
Empty concentration, it is thus achieved that sticky white solid (9.3g).It is loaded onto silica gel, with ethyl acetate and hexane (50%) eluting, it is thus achieved that
Title compound viscous oil.”
Step 3:Topiramate is generated through hydrogenation.
Although Chinese patent CN03815991.0 embodiment 4 is that after being most suitable in currently available technology, hydrogenation generates
The route of topiramate, it may have other advantages that method simplicity is suitable for industrialized large-scaled production, but still have and need lacking of improvement badly
Point, that is, topiramate midbody compound N-benzyloxycarbonyl group-2 obtained, double-O-(the 1-methyl ethylidene)-β-D-of 3:4,5-
Fructopyranose sulfamate is grease, and the reaction dissolvent of the inside residual is more, and impurity is many and complicated, so can cause
The purity of final products topiramate is low and yield is low does not says, and yield and purity are unstable, wayward.Experiment proves to utilize
N-benzyloxycarbonyl group-2 that the method for patent CN03815991.0 embodiment 4 prepares, double-O-(1-methyl the ethylidene)-β of 3:4,5--
The yield of the topiramate that D-fructopyranose sulfamate obtains after over hydrogenation waves between 50%-70%.This be all because of
For N-benzyloxycarbonyl group-2, impurity in double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate grease of 3:4,5-
Uncertainty causes, and impurity therein is uncertain to be not easily controlled, and what a cannot design according to prior inventory solid
The fixed method removing impurity, this results in the input amount needing to repeat remove impurity or increasing remove impurity just can reach medicinal standard,
Result of this is that time-consuming, laborious, cost increases.
Additionally the embodiment 23 of Chinese patent CN03815991.0 is N-benzyloxycarbonyl group-2, and (1-methyl is sub-for the double-O-of 3:4,5-
Ethyl)-Beta-D-Fructopyranose sulfamic acid ester sodium salt, but this synthetic method condition is the harshest, and sodium hydride used is the most not
Stable, it is less suitable for large-scale production.
Summary of the invention
For disadvantage mentioned above, CN03815991.0 embodiment 4 and topiramate synthetic route are improved by the present invention.
First, the present invention relates to a kind of compound N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-of 3:4,5-
The alkali metal salt novel crystal forms of fructopyranose sulfamate, alkali metal salt here refers to its sodium salt and potassium salt.This alkali metal salt
Crystal-form compound has a following characteristic peak through X-ray powder diffraction detection gained collection of illustrative plates: 7.1 °, 8.8 °, 10.5 °, 11.0 °,
13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, 22 °；Alkali metal salt crystal-form compound is through differential scanning calorimetry
Measure (DSC mensuration) gained collection of illustrative plates, in the range of 248.7 DEG C ± 5 DEG C, there is absworption peak.
Product purity is high, crystallization purity more than 96%；Yield more than 90%.
Secondly, the invention still further relates to one and prepare N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-of 3:4,5-
The method of fructopyranose sulfamate alkali metal salt crystallization
N-benzyloxycarbonyl group-2, the alkali metal of double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-
Salt-pepper noise obtains by the following method:
Step A uses synthetic method of the prior art synthesis compound N-benzyloxycarbonyl group-2, double-O-(the 1-first of 3:4,5-
Base ethylidene)-Beta-D-Fructopyranose sulfamate
This step illustrates one synthesis N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-pyrans of 3:4,5-
The synthetic method of fructose sulfamate, but it is never limited to this, only illustrate that this step is all based on existing known technology and carries out
Synthesis.
N-Chlorosulfonyl isocyanate (CSI) 20g and the dichloromethane 200mL cooling of 1 equivalent is added in 500mL reaction bulb
To less than-20 DEG C, dripping the benzylalcohol 16.1g of 1.05 equivalents, during dropping, temperature temperature control is below-10 DEG C.After being added dropwise to complete
Stir 1～2 hour.Add 35 grams of fructose two acetone of 0.95 equivalent.Again by below greenhouse cooling to-20 DEG C, drip 1.2 equivalents
Triethylamine 17.1 grams, after being added dropwise to complete.Naturally it is raised to room temperature (25 DEG C), stirs 4 hours.Whether thin layer chromatography monitoring reaction
Complete.
Step B, after thin layer chromatography detection reaction completes, is directly added into the sodium hydroxide no less than 0.2 equivalent or hydroxide
Potassium or the washing of alkaline alkali metal saline solution, described alkaline alkali metal salt includes: sodium carbonate or potassium carbonate, sodium bicarbonate or carbon
Potassium hydrogen phthalate and sodium phosphate or potassium phosphate.Stir extremely reaction in 30 minutes completely, static 30 minutes, to separate water layer, retain organic layer.
Organic layer is concentrated to give white solid, and the nuclear magnetic data of this white solid is1HNMR d6-DMSO, δ 7.35～7.25 (m, 5H), δ
(4.86 d, 2H), δ 4.9～4.5 (dd, 1H), δ 4.36 (d, 1H), δ 4.2 (d, 1H), δ 3.90～3.80 (dd, 2H), δ 3.75～
3.3 (dd, 2H), δ 2.5 (s, 1H), δ 1.43 (s, 3H), δ 1.32 (d, 6H), δ 1.24 (s, 3H).
The mass spectrometric data of this white solid, MS (ESI) [M-H] C20H26NO10S, value of calculation, 472.1277；Measured value,
472.1397。
The X-ray powder diffraction pattern of this white solid as shown in Figure 1, the X-ray represented with the 2 θ ± 0.2 ° angles of diffraction
Powder diffraction spectrum at 7.1 °, 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, 22 °
Place's display characteristic peak.
This white solid measures (DSC mensuration) gained collection of illustrative plates (as shown in Figure 2) at 248.7 DEG C through differential scanning calorimetry
At ± 5 DEG C, there is absworption peak.
Therefore, N-benzyloxycarbonyl group-2 that step A obtains, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose ammonia of 3:4,5-
Base sulphonic acid ester obtains N-benzyloxycarbonyl group-2 after step B processes, 3:4,5-double-O-(1-methyl ethylidene)-β-D-pyrans fruit
The alkali metal salt crystallization of sugar sulfamate.
The inventive method is easy and simple to handle, sodium carbonate used or potassium carbonate, sodium bicarbonate or potassium bicarbonate, sodium hydroxide or
Potassium hydroxide, sodium phosphate or aqueous potassium phosphate solution are cheap and easy to get, nontoxic, and post processing is simple；Minimum stable yield is 90%
Above, its stable yield of optimal conditions is more than 95%.The degree of purity of this alkali metal salt crystallization is stable more than 96%.Directly use
Hydrogenation later produces topiramate.
Again, summary of the invention 3N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose amino of 3:4,5-
Alkali metal salt crystallization of sulphonic acid ester and preparation method thereof is used for preparing topiramate
Step A uses synthetic method of the prior art synthesis compound N-benzyloxycarbonyl group-2, double-O-(the 1-first of 3:4,5-
Base ethylidene)-Beta-D-Fructopyranose sulfamate
This step illustrates one synthesis N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-pyrans of 3:4,5-
The synthetic method of fructose sulfamate, but it is never limited to this, only illustrate that being all based on existing known technology synthesizes.
N-Chlorosulfonyl isocyanate (CSI) 20g and the dichloromethane 200mL cooling of 1 equivalent is added in 500mL reaction bulb
To less than-20 DEG C, dripping the benzylalcohol 16.1g of 1.05 equivalents, during dropping, temperature temperature control is below-10 DEG C.After being added dropwise to complete
Stir 1～2 hour.Add 35 grams of fructose two acetone of 0.95 equivalent.Again by below greenhouse cooling to-20 DEG C, drip 1.2 equivalents
Triethylamine 17.1 grams, after being added dropwise to complete.Naturally it is raised to room temperature (25 DEG C), stirs 4 hours.Whether thin layer chromatography monitoring reaction
Complete.
N-benzyloxycarbonyl group-2 that step B prepares through step A, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose of 3:4,5-
Sulfamate sodium hydroxide or potassium hydroxide or aqueous solution of alkali metal salt process prepare N-benzyloxycarbonyl group-2,3:4,5-pair-
O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate alkali metal salt crystallization
After through thin layer chromatography detection, reaction completes, be directly added into no less than the sodium hydroxide of 0.2 equivalent or potassium hydroxide or
Alkaline alkali metal saline solution is washed, and described alkaline alkali metal salt includes: sodium carbonate or potassium carbonate, sodium bicarbonate or bicarbonate
Potassium and sodium phosphate or potassium phosphate.Stir extremely reaction in 30 minutes completely, static 30 minutes, to separate water layer, retain organic layer.Organic
Layer is concentrated to give white solid.
Step C N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate alkali of 3:4,5-
Slaine crystallizes hydrogenated reaction and prepares topiramate
White solid step B obtained, adds methanol 260ml, and humidification palladium carbon (equivalent butt weight is 7.0g), room temperature is high
Pressure hydrogenation (1.2MPa) stirs 3 hours, and some plate detection reaction completes, and is removed by filtration palladium carbon, leaches palladium carbon 50ml methanol drip washing,
Filtrate reduced in volume is to surplus 90ml, and ice bath is cooled to 0 DEG C and is incubated one hour.Filtration drying obtains topiramate.
The synthetic method that the present invention prepares topiramate is easy and simple to handle, in stepb by sodium carbonate or potassium carbonate, bicarbonate
After sodium or potassium bicarbonate, sodium hydroxide or potassium hydroxide, sodium phosphate or aqueous potassium phosphate solution process, by N-benzyloxycarbonyl group-2,3:
4,5-double-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate alkali metal salt hydrogenation obtains topiramate, not only step
Simply, raw materials used cheap and easy to get, nontoxic, after this portion processes, the purification process of topiramate is stable, easily grasps
Make；For the average purity of gained topiramate crude product the most more than 95%, yield is also stabilized in more than 80%, optimizes bar
Stablize more than 90% under part.
Accompanying drawing explanation
Illustrate: the application gained N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose ammonia of 3:4,5-
Base sulphonic acid ester sodium salt is the most similar with the powder diffraction spectrum of potassium salt, DSC collection of illustrative plates and thermogravimetric analysis collection of illustrative plates, in line with simple and clear, clear
The principle of Chu only provides and represents collection of illustrative plates, hereby illustrates.
Fig. 1-1 is N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-
Sodium salt X powder diffraction collection of illustrative plates
Fig. 1-2 is N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-
Potassium salt X powder diffraction collection of illustrative plates
Fig. 2-1 measures (DSC mensuration) gained N-benzyloxycarbonyl group-2 for differential scanning calorimetry, double-O-(the 1-methyl of 3:4,5-
Ethylidene)-Beta-D-Fructopyranose sulfamic acid ester sodium salt collection of illustrative plates
Fig. 2-2 measures (TGA mensuration) gained N-benzyloxycarbonyl group-2 for thermogravimetry, double-O-(the 1-methyl Asia second of 3:4,5-
Base)-Beta-D-Fructopyranose sulfamate potassium salt collection of illustrative plates
Detailed description of the invention
Illustrate: the amount of each reacting substance is all 1 with the molal quantity of N-Chlorosulfonyl isocyanate and reacts reference equivalent, namely
Saying that hypothesis N-Chlorosulfonyl isocyanate amount used is 1 equivalent, the amount of other reacting substance such as benzylalcohol is 1.05 equivalents, it is simply that refer to
The consumption of benzylalcohol is 1.05 times of N-Chlorosulfonyl isocyanate reaction equivalent.
If it addition, synthesis N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose amino of 3:4,5-
The method of sulphonic acid ester is not the method described herein used, then in preparation N-benzyloxycarbonyl group-2, the double-O-of 3:4,5-
In the step of (1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate alkali metal salt, add sodium hydroxide or potassium hydroxide
Or the amount of alkaline alkali metal salt is with N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose amino sulphur of 3:4,5-
Equivalent on the basis of the amount of acid esters.This is because the consumption of all synthesis materials assumes that N-Chlorosulfonyl isocyanate reacts in the application
Completely, and enter next step reaction.
Embodiment 1 prepares N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose amino sulphur of 3:4,5-
Sodium salt
Step A uses synthetic method of the prior art synthesis compound N-benzyloxycarbonyl group-2, double-O-(the 1-first of 3:4,5-
Base ethylidene)-Beta-D-Fructopyranose sulfamate
This step illustrates one synthesis N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-pyrans of 3:4,5-
The synthetic method of fructose sulfamate, but it is never limited to this, but be all based on existing known technology and synthesize.
N-Chlorosulfonyl isocyanate (CSI) 20g and the dichloromethane 200mL cooling of 1 equivalent is added in 500mL reaction bulb
To less than-20 DEG C, dripping the benzylalcohol 16.1g of 1.05 equivalents, during dropping, temperature temperature control is below-10 DEG C.After being added dropwise to complete
Stir 1～2 hour.Add 35 grams of fructose two acetone of 0.95 equivalent.Again by below greenhouse cooling to-20 DEG C, drip 1.2 equivalents
Triethylamine 17.1 grams, after being added dropwise to complete.Naturally it is raised to room temperature (about 25 DEG C), stirs 4 hours.Thin layer chromatography monitoring reaction
Whether complete.
Step B, after thin layer chromatography detection reaction completes, is directly added into the aqueous sodium carbonate no less than 0.2 equivalent
(7.5g sodium carbonate, 100ml water), stirs extremely reaction in 30 minutes and completely, static 30 minutes, separates water layer, retain organic layer.Organic
Layer is concentrated to give 65 grams of white solids, yield 94%.
The nuclear magnetic data of this white solid1HNMR d6-DMSO, δ 7.35～7.25 (m, 5H), δ 4.86 (d, 2H), δ 4.9～
4.5 (dd, 1H), δ 4.36 (d, 1H), δ 4.2 (d, 1H), δ 3.90～3.80 (dd, 2H), δ 3.75～3.3 (dd, 2H), δ 2.5
(s, 1H), δ 1.43 (s, 3H), δ 1.32 (d, 6H), δ 1.24 (s, 3H).
The mass spectrometric data of this white solid, MS (ESI) [M-H] C20H26NO10S, value of calculation, 472.1277；Measured value,
472.1397。
The X-ray powder diffraction pattern of this white solid as shown in Figure 1, the X-ray represented with the 2 θ ± 0.2 ° angles of diffraction
Powder diffraction spectrum at 7.1 °, 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, 22 °
Place's display characteristic peak.
This white solid measures (DSC mensuration) gained collection of illustrative plates (as shown in Figure 2) at 248.7 DEG C through differential scanning calorimetry
Place has absworption peak.
Other steps are identical, simply changed by aqueous sodium carbonate after doing sodium hydroxide or other alkaline sodium salt aqueous solutions, system
Standby N-benzyloxycarbonyl group-2, the concrete yield of double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamic acid ester sodium salt of 3:4,5-
As shown in table 1 with purity.Each data are the meansigma methods of test of many times.
Table 1 sodium hydroxide or other alkaline sodium salt aqueous solutions prepare N-benzyloxycarbonyl group-2, the double-O-(1-of 3:4,5-
Methyl ethylidene) yield of-Beta-D-Fructopyranose sulfamic acid ester sodium salt and purity
Embodiment 2 prepares N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose amino sulphur of 3:4,5-
Acid esters potassium salt
Step A uses synthetic method of the prior art synthesis compound N-benzyloxycarbonyl group-2, double-O-(the 1-first of 3:4,5-
Base ethylidene)-Beta-D-Fructopyranose sulfamate
This step illustrates one synthesis N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-pyrans of 3:4,5-
The synthetic method of fructose sulfamate, but it is never limited to this, only illustrate that this step is all based on existing known technology and carries out
Synthesis.
N-Chlorosulfonyl isocyanate (CSI) 20g and the dichloromethane 200mL cooling of 1 equivalent is added in 500mL reaction bulb
To less than-20 DEG C, dripping the benzylalcohol 16.1g of 1.05 equivalents, during dropping, temperature temperature control is below-10 DEG C.After being added dropwise to complete
Stir 1～2 hour.Add 35 grams of fructose two acetone of 0.95 equivalent.Again by below greenhouse cooling to-20 DEG C, drip 1.2 equivalents
Triethylamine 17.1 grams, after being added dropwise to complete.Naturally it is raised to room temperature (about 25 DEG C), stirs 4 hours.Thin layer chromatography monitoring reaction
Whether complete.
Step B, after thin layer chromatography detection reaction completes, is directly added into the wet chemical no less than 0.2 equivalent
(9.8g potassium carbonate, 100ml water), stirs extremely reaction in 30 minutes and completely, static 30 minutes, separates water layer, retain organic layer.Organic
Layer is concentrated to give 68 grams of white solids, yield 91%.
The nuclear magnetic data of this white solid1HNMR d6-DMSO, δ 7.35～7.25 (m, 5H), δ 4.86 (d, 2H), δ 4.9～
(4.5 dd, 1H), δ 4.36 (d, 1H), δ 4.2 (d, 1H), δ 3.90～3.80 (dd, 2H), δ 3.75～3.3 (dd, 2H), δ 2.5
(s, 1H), δ 1.43 (s, 3H), δ 1.32 (d, 6H), δ 1.24 (s, 3H).
The mass spectrometric data of this white solid, MS (ESI) [M-H] C20H26NO10S, value of calculation, 472.1277；Measured value,
472.1397。
The X-ray powder diffraction pattern of this white solid as shown in Figure 1, the X-ray represented with the 2 θ ± 0.2 ° angles of diffraction
Powder diffraction spectrum at 7.1 °, 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, 22 °
Place's display characteristic peak.
This white solid measures (DSC mensuration) gained collection of illustrative plates (as shown in Figure 2) at 245.7 DEG C through differential scanning calorimetry
Place has absworption peak.
Other steps are identical, simply changed by wet chemical and do potassium hydroxide aqueous solution or other alkaline potassium salt aqueous solutions
After, prepare N-benzyloxycarbonyl group-2, the tool of double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate potassium salt of 3:4,5-
Body yield and purity are as shown in table 2.
Table 2 potassium hydroxide or other alkaline potassium salt aqueous solutions prepare N-benzyloxycarbonyl group-2, double-O-(the 1-methyl of 3:4,5-
Ethylidene) yield of-Beta-D-Fructopyranose sulfamate potassium salt and purity
The preparation method of embodiment 3 topiramate
Step A uses synthetic method of the prior art synthesis compound N-benzyloxycarbonyl group-2, double-O-(the 1-first of 3:4,5-
Base ethylidene)-Beta-D-Fructopyranose sulfamate
This step is merely illustrative a kind of synthesis N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-of 3:4,5-
The synthetic method of fructopyranose sulfamate, but it is never limited to this, only illustrate that being all based on existing known technology closes
Become.
N-Chlorosulfonyl isocyanate (CSI) 20g and the dichloromethane 200mL cooling of 1 equivalent is added in 500mL reaction bulb
To less than-20 DEG C, dripping the benzylalcohol 16.1g of 1.05 equivalents, during dropping, temperature temperature control is below-10 DEG C.After being added dropwise to complete
Stir 1～2 hour.Add 35 grams of fructose two acetone of 0.95 equivalent.Again by below greenhouse cooling to-20 DEG C, drip 1.2 equivalents
Triethylamine 17.1 grams, after being added dropwise to complete.Naturally it is raised to room temperature (25 DEG C), stirs 4 hours.Whether thin layer chromatography monitoring reaction
Complete.
Step B, after thin layer chromatography detection reaction completes, adds sodium bicarbonate aqueous solution (the 12g carbon no less than 0.2 equivalent
Acid hydrogen sodium, 100ml water), stir 30 minutes, static 30 minutes, separate water layer, retain organic layer.Organic layer is concentrated to give 63 grams
White solid, yield 94%；
Step C N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose amino sulphur alkali metal of 3:4,5-
Salt hydrogenates to obtain topiramate
By gained solid in embodiment 2, N-benzyloxycarbonyl group-2,3:4,5-double-O-(1-methyl ethylidene)-β-D-pyrans fruit
Sugar sulfamic acid ester sodium salt adds methanol 260ml, humidifies palladium charcoal, and equivalent butt weight is 7.0g, and room temperature high-pressure 1.2MPa hydrogenation is stirred
Mixing 3 hours, thin layer chromatography detection reaction completes, and is removed by filtration palladium carbon, leaches palladium carbon 50ml methanol drip washing, and filtrate decompression is dense
Being reduced to surplus 90ml, ice bath is cooled to 0 DEG C and is incubated one hour.Filtration drying obtains topiramate 37g, yield 83%.
Other steps are identical, simply sodium bicarbonate aqueous solution used in step B is changed do potassium hydroxide or sodium hydroxide or
After other alkaline alkali metal saline solutions, concrete yield and the purity of preparing topiramate are as shown in table 3.Each data are test of many times
Meansigma methods.
Table 3 is prepared N-benzyloxycarbonyl group-2 by sodium hydroxide or potassium hydroxide or different alkaline alkali metal saline solutions, and 3:
4,5-double-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate alkali metal salts hydrogenate topiramate yield and
Purity.
Claims (12)
1. the method preparing compound topiramate, it is characterised in that the method necessarily comprise the steps: N-benzyloxycarbonyl group-
Double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 2,3:4,5-with no less than 0.2 equivalent sodium hydroxide or
Potassium hydroxide or alkaline alkali metal saline solution process and generate N-benzyloxycarbonyl group-2, and double-O-(1-methyl the ethylidene)-β of 3:4,5--
D-fructopyranose sulfamate alkali metal salt, N-benzyloxycarbonyl group-2 generated, the double-O-(1-methyl ethylidene) of 3:4,5--
Beta-D-Fructopyranose sulfamate alkali metal salt is hydrogenated reacts to obtain topiramate；
Described alkaline alkali metal saline solution is that sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate are water-soluble
Liquid, described equivalent is with N-benzyloxycarbonyl group-2, and double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-is
Reference equivalent.
A kind of method preparing compound topiramate, it is characterised in that the method also includes as follows
Step:
A. N-Chlorosulfonyl isocyanate and benzylalcohol react generation
B.With fructose two acetoneReaction generates N-benzyloxycarbonyl group-2,3:4,5-
Double-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
3. prepare N-benzyloxycarbonyl group-2 for one kind, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate alkali of 3:4,5-
The method of slaine, it is characterised in that the method necessarily includes: by N-benzyloxycarbonyl group-2, double-O-(the 1-methyl Asia second of 3:4,5-
Base)-Beta-D-Fructopyranose sulfamate is with no less than the sodium hydroxide of 0.2 equivalent or potassium hydroxide or alkaline alkali metal saline
Solution processes and generates N-benzyloxycarbonyl group-2, the double-O-(1-methyl ethylidene) of 3:4,5--Beta-D-Fructopyranose sulfamate alkali gold
Belong to the step of salt；
Described alkaline alkali metal salt is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate；
Described equivalent is with N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-
Consumption be a reference equivalent.
4. one as claimed in claim 3 prepares N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-pyrrole of 3:4,5-
Mutter the method for fructose sulfamate alkali metal salt, it is characterised in that the method also comprises the steps:
A. N-Chlorosulfonyl isocyanate and benzylalcohol react generation
B.With fructose two acetoneReaction generates N-benzyloxycarbonyl group-2,3:4,5-
Double-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
5. the one as described in claim 3 or 4 any one prepares N-benzyloxycarbonyl group-2, double-O-(the 1-methyl Asia second of 3:4,5-
Base) method of-Beta-D-Fructopyranose sulfamate alkali metal salt, it is characterised in that with the method gained compound with 2 θ ±
The X-ray powder diffraction pattern that 0.2 ° of angle of diffraction represents at 7.1 °, 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °,
17.2 °, 18 °, 18.5 °, 21 °, at 22 °, show characteristic peak.
6. one as claimed in claim 5 prepares N-benzyloxycarbonyl group-2, double-O-(the 1-methyl ethylidene)-β-D-pyrrole of 3:4,5-
Mutter the method for fructose sulfamate alkali metal salt, it is characterised in that survey through differential scanning calorimetry with the method gained compound
Fixed or thermogravimetric analysis detection has absworption peak in the range of 248.7 DEG C ± 5 DEG C.
7. the one as described in claim 3 or 4 any one prepares N-benzyloxycarbonyl group-2, double-O-(the 1-methyl Asia second of 3:4,5-
Base) method of-Beta-D-Fructopyranose sulfamate alkali metal salt, it is characterised in that the method is used for preparing topiramate.
8. N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamic acid ester alkali metal of 3:4,5-
Salt crystal-form compound, it is characterised in that the X-ray powder diffraction pattern that this compound represents with the 2 θ ± 0.2 ° angles of diffraction at 7.1 °,
8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, at 22 °, show characteristic peak；
Described N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate alkali metal salt of 3:4,5-
Refer to N-benzyloxycarbonyl group-2, the sodium salt of double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-and potassium
Salt.
9. a kind of N-benzyloxycarbonyl group-2 as claimed in claim 8,3:4,5-double-O-(1-methyl ethylidene)-β-D-pyrans fruit
Sugar sulfamate alkali metal salt crystal-form compound, it is characterised in that this compound divides through differential scanning calorimetry mensuration or thermogravimetric
Analysis detection has absworption peak in the range of 248.7 DEG C ± 5 DEG C；
Described N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate alkali metal salt of 3:4,5-
Refer to N-benzyloxycarbonyl group-2, the sodium salt of double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-and potassium
Salt.
10. a kind of N-benzyloxycarbonyl group-2 as described in claim 8 or 9 any one, double-O-(the 1-methyl Asia second of 3:4,5-
Base)-Beta-D-Fructopyranose sulfamate alkali metal salt crystal-form compound, it is characterised in that this compound is used for preparing torr pyrrole
Ester.
11. preparations a kind of N-benzyloxycarbonyl group-2 described in claim 8 or 9 any one, double-O-(the 1-methyl Asia second of 3:4,5-
Base) method of-Beta-D-Fructopyranose sulfamate alkali metal salt crystal-form compound, it is characterised in that the method necessarily include by
N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-is with no less than 0.2 equivalent
Sodium hydroxide or potassium hydroxide or alkaline alkali metal saline solution process and generate N-benzyloxycarbonyl group-2, double-O-(the 1-first of 3:4,5-
Base ethylidene) step of-Beta-D-Fructopyranose sulfamate alkali metal salt；
Described alkaline alkali metal salt is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate；
Described equivalent is with N-benzyloxycarbonyl group-2, double-O-(1-methyl the ethylidene)-Beta-D-Fructopyranose sulfamate of 3:4,5-
Consumption be a reference equivalent.
12. methods as claimed in claim 11, it is characterised in that the method also comprises the steps:
A. N-Chlorosulfonyl isocyanate and benzylalcohol react generation
B.With fructose two acetoneReaction generates N-benzyloxycarbonyl group-2,3:4,5-
Double-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4513006A (en) * | 1983-09-26 | 1985-04-23 | Mcneil Lab., Inc. | Anticonvulsant sulfamate derivatives |
| CN1665828A (en) * | 2002-05-13 | 2005-09-07 | 奥索-麦克尼尔药品公司 | Novel substituted sulfamate anticonvulsant derivatives |
| CN101045740A (en) * | 2007-04-26 | 2007-10-03 | 杭州盛美医药科技开发有限公司 | Preparation method of topiramate |
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| WO2007099388A1 (en) * | 2006-03-01 | 2007-09-07 | Glade Organics Private Limited | An improved process for the manufacture of topiramate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4513006A (en) * | 1983-09-26 | 1985-04-23 | Mcneil Lab., Inc. | Anticonvulsant sulfamate derivatives |
| CN1665828A (en) * | 2002-05-13 | 2005-09-07 | 奥索-麦克尼尔药品公司 | Novel substituted sulfamate anticonvulsant derivatives |
| CN101045740A (en) * | 2007-04-26 | 2007-10-03 | 杭州盛美医药科技开发有限公司 | Preparation method of topiramate |
Non-Patent Citations (1)
| Title |
|---|
| 托吡酯的合成研究进展.;苗宇等，;《中国现代应用药学》;20130430;第30卷(第4期);第453-456页 * |
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