CN103910770A - Preparation method of topiramate, intermediate crystal form related in method thereof and its preparation method - Google Patents
Preparation method of topiramate, intermediate crystal form related in method thereof and its preparation method Download PDFInfo
- Publication number
- CN103910770A CN103910770A CN201410102754.8A CN201410102754A CN103910770A CN 103910770 A CN103910770 A CN 103910770A CN 201410102754 A CN201410102754 A CN 201410102754A CN 103910770 A CN103910770 A CN 103910770A
- Authority
- CN
- China
- Prior art keywords
- beta
- carbobenzoxy
- cbz
- pair
- methyl ethylidene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *S(NC(OCc1ccccc1)=O)(=O)=O Chemical compound *S(NC(OCc1ccccc1)=O)(=O)=O 0.000 description 1
Abstract
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.
Description
Technical field
The invention belongs to that medicine and intermediate thereof are synthetic, crystal formation chemical field, be specifically related to a kind of antiepileptic drug topiramate midbody compound
N-carbobenzoxy-(Cbz)-2,3:4, an alkali metal salt new crystal of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate and preparation method thereof, and they are for the preparation of topiramate.
Background technology
An alkali metal salt: described in the application, an alkali metal salt refers to sodium salt and sylvite.
Basic metal: basic metal described in the application refers to sodium and potassium.
Alkaline alkali metal salt: described in the application, alkaline alkali metal salt refers to sodium carbonate, sodium bicarbonate, sodium phosphate, salt of wormwood, saleratus, potassiumphosphate.
Alkaline sodium salt: described in the application, alkaline sodium salt refers to sodium carbonate, sodium bicarbonate, sodium phosphate.
Alkaline potassium salt: described in the application, alkaline potassium salt refers to salt of wormwood, saleratus, potassiumphosphate.
U.S. Patent number 4,513,006 discloses the novel anti-epileptic compound of a class.Wherein a kind of compound 2,3:4,5-bis--O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate (being known as topiramate), in the clinical experiment of people's epilepsy, has been proved to be effective adjuvant therapy medicaments or single therapy medicine into simple form and complexity partial seizures and Secondary cases generalized seizure.
Topiramate is from nineteen ninety-five assisting therapy mainly as other antiepileptic drug since Britain's listing.Nowadays, be widely used clinically, topiramate has retardance Na
+passage, strengthens the restraining effect that GABA mediates, and the innervation of blocked glutamic acid mediation, affects Cl
-film running and Ca
2+the multiple action mechanism that passage stops.Within 1999, start to use in China, curative effect is high, untoward reaction is few, and except finding can to cause while share with Phenytoin Sodium Salt in only a few patient Concentration of Phenytoin increases, topiramate does not affect the Plasma Concentration of other conventional antiepileptic drug.In recent years, along with the progress to its pharmaceutical research and clinical observation, found that there is many new purposes, and obtained clinically satisfied curative effect.Therefore still it is being carried out to multidirectional research at field of medicaments.
Chinese patent CN03815991.0 discloses a kind of optimization route of synthetic topiramate, and this route steps is simply convenient to suitability for industrialized production.Specific as follows:
Step 1: chlorosulfonic acid isocyanate, be again CSI, structural formula is
react with benzylalcohol
generate
Step 2:
with fructose two acetone
reaction generates N-carbobenzoxy-(Cbz)-2,3:4, and 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is for No. CAS 627537-93-3, structural formula is
refer to more specifically embodiment 4 parts of this piece of patent documentation: "
Embodiment 4
N-benzyloxycarbonyl-2,3:4,5-bis--O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate (compound #15)
Steps A: preparation
-[[[(chlorosulfonyl) amino] carbonyl] oxygen base]-benzene
The reaction flask exporting to outfit stirring rod, thermopair and the N2 of 250mL adds isocyanic acid chlorine sulfonyl ester (10.0mL, 115mmol) and methylene dichloride (20mL).After cooling reaction flask to 0 ℃, add benzylalcohol (11.9mL, 115mmol) through feed hopper in 30 minutes.Internal temperature keeps below 10 ℃.After having added, reaction mixture is warming up to room temperature, stirs 15 minutes, then vacuum concentration obtains white solid.With sherwood oil (100mL) grinding white solid.Solid collected by filtration, rinses final vacuum with sherwood oil (2x50mL) dry, obtains final product white fine powder end.
Step B:
To outfit stirring rod and the N of 100mL
2the reaction flask of outlet adds [[[(chlorosulfonyl) amino] carbonyl] oxygen base]-benzene (5.0g, 21mmol) and acetonitrile (20mL).Then add the pyridine (2.4mL, 30mmol) containing diacetone fructose (5.2g, 20mmol) through feed hopper, reaction stirred is spent the night.Then concentrated this material is to the dry oil that obtains.This oil is dissolved in to DCM (100mL), with 0.5NHCl (2x50mL) and salt solution (1x50mL) flushing.After being separated, organic layer Na
2sO
4(150g) dry, filter final vacuum concentrated, obtain sticky white solid (9.3g).Its application of sample, in silica gel, with ethyl acetate and hexane (50%) wash-out, is obtained to title compound viscous oil.”
Step 3:
generate topiramate through hydrogenation.
Although Chinese patent CN03815991.0 embodiment 4 is routes that after being suitable for most in currently available technology, hydrogenation generates topiramate, also there are easy other advantages that are suitable for industrialized production of method, need improved shortcoming badly but still have, that is exactly topiramate midbody compound N-carbobenzoxy-(Cbz)-2 that obtain, 3:4, 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is oily matter, the residual reaction solvent in the inside is more, impurity is many and complicated, so can cause that the purity of the finished product topiramate is low and yield is low does not say, and yield and purity unstable, wayward.Experimental results show that N-carbobenzoxy-(Cbz)-2 that utilize the method for patent CN03815991.0 embodiment 4 to make, 3:4, the yield of 5-pair-O-(1-methyl the ethylidene)-topiramate that Beta-D-Fructopyranose sulfamate obtains after over hydrogenation waves between 50%-70%.This is all because N-carbobenzoxy-(Cbz)-2,3:4, in 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate oily matter, the uncertainty of impurity causes, uncertain being not easy of impurity wherein controlled, just can not design what a fixing method of removing impurity according to prior charging capacity, this just causes and need to repeat removal of impurities or strengthen the input amount of removal of impurities just to reach medicinal standard, and the result of doing is like this exactly that time-consuming, effort, cost increase.
The embodiment 23 of Chinese patent CN03815991.0 is N-carbobenzoxy-(Cbz)-2 in addition, 3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose thionamic acid ester sodium salt, but this synthetic method condition is very harsh, sodium hydride used is extremely unstable, is more unsuitable for scale operation.
Summary of the invention
For above shortcoming, the present invention improves CN03815991.0 embodiment 4 and topiramate synthetic route.
First, the present invention relates to a kind of compound N-carbobenzoxy-(Cbz)-2,3:4, an alkali metal salt new crystal of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate, an alkali metal salt here refers to its sodium salt and sylvite.This alkali metal salt crystal formation compound detects gained collection of illustrative plates through X-ray powder diffraction and has following characteristic peak: 7.1 °, and 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, 22 °; An alkali metal salt crystal formation compound has absorption peak through determine with dsc method (DSC mensuration) gained collection of illustrative plates within the scope of 248.7 ℃ ± 5 ℃.
Product purity is high, and crystallization purity is more than 96%; Yield is more than 90%.
Secondly, the invention still further relates to one and prepare N-carbobenzoxy-(Cbz)-2,3:4, the method for 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt crystallization
N-carbobenzoxy-(Cbz)-2,3:4, an alkali metal salt crystallization of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate obtains by the following method:
Steps A adopts synthetic method synthetic compound N-of the prior art carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
This step illustrates a kind of synthetic N-carbobenzoxy-(Cbz)-2,3:4, the synthetic method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate, but this be never limited to, only illustrate that this step is all to synthesize based on existing known technology.
In 500mL reaction flask, add Sulfuryl chloride isocyanate (CSI) 20g of 1 equivalent and methylene dichloride 200mL to cool to below-20 ℃, drip the benzylalcohol 16.1g of 1.05 equivalents, in dropping process, temperature temperature control is below-10 ℃.Be added dropwise to complete rear stirring 1～2 hour.Add 35 grams, fructose two acetone of 0.95 equivalent.Greenhouse cooling is arrived below-20 ℃, 17.1 grams of the triethylamines of dropping 1.2 equivalents, after being added dropwise to complete again.Naturally be raised to room temperature (25 ℃), stir 4 hours.Whether tlc monitoring reaction completes.
Step B is after thin-layer chromatography detection reaction completes, directly add the sodium hydroxide or potassium hydroxide or the washing of alkaline alkali metal salt brine solution that are no less than 0.2 equivalent, described alkaline alkali metal salt comprises: sodium carbonate or salt of wormwood, sodium bicarbonate or saleratus and sodium phosphate or potassiumphosphate.Stir 30 minutes to reacting completely, static 30 minutes, point water-yielding stratum, retained organic layer.Organic layer is concentrated obtains white solid, and the nuclear magnetic data of this white solid is
1hNMR d
6-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] C
20h
26nO
10s, calculated value, 472.1277; Measured value, 472.1397.
As shown in Figure 1, the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is at 7.1 ° for the X-ray powder diffraction collection of illustrative plates of this white solid, and 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, locate indicating characteristic peak for 22 °.
This white solid locates to have absorption peak through determine with dsc method (DSC mensuration) gained collection of illustrative plates (as shown in Figure 2) at 248.7 ℃ ± 5 ℃.
Therefore, N-carbobenzoxy-(Cbz)-2 that steps A obtains, 3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate obtains N-carbobenzoxy-(Cbz)-2 after step B processes, 3:4, an alkali metal salt crystallization of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate.
The inventive method is easy and simple to handle, and sodium carbonate used or salt of wormwood, sodium bicarbonate or saleratus, sodium hydroxide or potassium hydroxide, sodium phosphate or the potassiumphosphate aqueous solution are cheap and easy to get, nontoxic, and aftertreatment is simple; Minimum stable yield is more than 90%, and its stable yield of optimal conditions is more than 95%.The purity of this alkali metal salt crystallization is stabilized in more than 96%.The hydrogenation being directly used in is below produced topiramate.
Again, summary of the invention 3N-carbobenzoxy-(Cbz)-2,3:4, an alkali metal salt crystallization of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate and preparation method thereof is for the preparation of topiramate
Steps A adopts synthetic method synthetic compound N-of the prior art carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
This step illustrates a kind of synthetic N-carbobenzoxy-(Cbz)-2,3:4, and the synthetic method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate, but be never limited to this, only explanation is all to synthesize based on existing known technology.
In 500mL reaction flask, add Sulfuryl chloride isocyanate (CSI) 20g of 1 equivalent and methylene dichloride 200mL to cool to below-20 ℃, drip the benzylalcohol 16.1g of 1.05 equivalents, in dropping process, temperature temperature control is below-10 ℃.Be added dropwise to complete rear stirring 1～2 hour.Add 35 grams, fructose two acetone of 0.95 equivalent.Greenhouse cooling is arrived below-20 ℃, 17.1 grams of the triethylamines of dropping 1.2 equivalents, after being added dropwise to complete again.Naturally be raised to room temperature (25 ℃), stir 4 hours.Whether tlc monitoring reaction completes.
N-carbobenzoxy-(Cbz)-2 that step B makes through steps A, 3:4,5-is two-and O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate processes preparation N-carbobenzoxy-(Cbz)-2 with sodium hydroxide or potassium hydroxide or aqueous solution of alkali metal salt, 3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt crystallization
After thin-layer chromatography detection reaction completes, directly add the sodium hydroxide or potassium hydroxide or the washing of alkaline alkali metal salt brine solution that are no less than 0.2 equivalent, described alkaline alkali metal salt comprises: sodium carbonate or salt of wormwood, sodium bicarbonate or saleratus and sodium phosphate or potassiumphosphate.Stir 30 minutes to reacting completely, static 30 minutes, point water-yielding stratum, retained organic layer.The concentrated white solid that obtains of organic layer.
Step C N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt crystallization is prepared topiramate through hydrogenation
The white solid that step B is obtained, add methyl alcohol 260ml, humidification palladium carbon (amounting to butt weight is 7.0g), room temperature high-pressure hydrogenation (1.2MPa) is stirred 3 hours, point plate detection reaction completes, and crosses and filters out palladium carbon, leaches the drip washing of palladium carbon 50ml methyl alcohol, filtrate decompression is concentrated into surplus 90ml, and ice bath is cooled to 0 ℃ of insulation one hour.Filtration drying obtains topiramate.
It is easy and simple to handle that the present invention prepares the synthetic method of topiramate, after processing by sodium carbonate or salt of wormwood, sodium bicarbonate or saleratus, sodium hydroxide or potassium hydroxide, sodium phosphate or the potassiumphosphate aqueous solution in step B, by N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt hydrogenation obtains topiramate, not only step is simple, raw materials used cheap and easy to get, nontoxic, after this portion processes, the purifying process process stabilization of topiramate, easy to operate; With regard to the average purity of gained topiramate crude product, all more than 95%, yield is also stabilized in more than 80%, under optimal conditions, is stabilized in more than 90%.
Accompanying drawing explanation
Illustrate: the application's gained N-carbobenzoxy-(Cbz)-2,3:4, powder diffraction spectrum, DSC collection of illustrative plates and the thermogravimetric analysis collection of illustrative plates of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose thionamic acid ester sodium salt and sylvite are extremely similar, in line with concisely, clearly principle only provides and has represented collection of illustrative plates, explanation hereby.
Fig. 1-1 is N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose thionamic acid ester sodium salt X powder diffraction collection of illustrative plates
Fig. 1-2 is N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate sylvite X powder diffraction collection of illustrative plates
Fig. 2-1 is determine with dsc method (DSC mensuration) gained N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose thionamic acid ester sodium salt collection of illustrative plates
Fig. 2-2 are thermogravimetry mensuration (TGA mensuration) gained N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate sylvite collection of illustrative plates
Embodiment
Illustrate: the amount of each reactive material is all take the mole number of Sulfuryl chloride isocyanate as 1 reaction reference equivalent, that is to say that hypothesis Sulfuryl chloride isocyanate institute consumption is 1 equivalent, for example benzylalcohol of the amount of other reactive material is 1.05 equivalents, just refers to that the consumption of benzylalcohol is 1.05 times of Sulfuryl chloride isocyanate reaction equivalent.
In addition, if synthetic N-carbobenzoxy-(Cbz)-2,3:4, the method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is not the method described in the application who adopts, so in preparation N-carbobenzoxy-(Cbz)-2,3:4, in the step of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt, add the amount of sodium hydroxide or potassium hydroxide or alkaline alkali metal salt with N-carbobenzoxy-(Cbz)-2,3:4, the amount of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is reference equivalent.This is because the consumption of all synthesis materials is that hypothesis Sulfuryl chloride isocyanate reacts completely in the application, and has entered next step reaction.
Embodiment 1 prepares N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose thionamic acid ester sodium salt
Steps A adopts synthetic method synthetic compound N-of the prior art carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
This step illustrates a kind of synthetic N-carbobenzoxy-(Cbz)-2,3:4, and the synthetic method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate, but be never limited to this, but be all to synthesize based on existing known technology.
In 500mL reaction flask, add Sulfuryl chloride isocyanate (CSI) 20g of 1 equivalent and methylene dichloride 200mL to cool to below-20 ℃, drip the benzylalcohol 16.1g of 1.05 equivalents, in dropping process, temperature temperature control is below-10 ℃.Be added dropwise to complete rear stirring 1～2 hour.Add 35 grams, fructose two acetone of 0.95 equivalent.Greenhouse cooling is arrived below-20 ℃, 17.1 grams of the triethylamines of dropping 1.2 equivalents, after being added dropwise to complete again.Naturally be raised to room temperature (25 ℃ of left and right), stir 4 hours.Whether tlc monitoring reaction completes.
Step B, after thin-layer chromatography detection reaction completes, directly adds the aqueous sodium carbonate (7.5g sodium carbonate, 100ml water) that is no less than 0.2 equivalent, stirs 30 minutes to reacting completely, and static 30 minutes, point water-yielding stratum, retained organic layer.Concentrated 65 grams of white solids, the yield 94% of obtaining of organic layer.
The nuclear magnetic data of this white solid
1hNMR d
6-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] C
20h
26nO
10s, calculated value, 472.1277; Measured value, 472.1397.
As shown in Figure 1, the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is at 7.1 ° for the X-ray powder diffraction collection of illustrative plates of this white solid, and 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, locate indicating characteristic peak for 22 °.
This white solid locates to have absorption peak through determine with dsc method (DSC mensuration) gained collection of illustrative plates (as shown in Figure 2) at 248.7 ℃.
Other steps are identical, just aqueous sodium carbonate is changed and done after sodium hydroxide or other alkaline sodium salt aqueous solution, preparation N-carbobenzoxy-(Cbz)-2,3:4, concrete yield and the purity of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose thionamic acid ester sodium salt are as shown in table 1.Each data are the mean value of test of many times.
Sodium hydroxide or other alkaline sodium salt aqueous solution preparation preparation N-carbobenzoxy-(Cbz)-2,3:4, yield and the purity of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose thionamic acid ester sodium salt for table 1
Embodiment 2 prepares N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate sylvite
Steps A adopts synthetic method synthetic compound N-of the prior art carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
This step illustrates a kind of synthetic N-carbobenzoxy-(Cbz)-2,3:4, the synthetic method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate, but this be never limited to, only illustrate that this step is all to synthesize based on existing known technology.
In 500mL reaction flask, add Sulfuryl chloride isocyanate (CSI) 20g of 1 equivalent and methylene dichloride 200mL to cool to below-20 ℃, drip the benzylalcohol 16.1g of 1.05 equivalents, in dropping process, temperature temperature control is below-10 ℃.Be added dropwise to complete rear stirring 1～2 hour.Add 35 grams, fructose two acetone of 0.95 equivalent.Greenhouse cooling is arrived below-20 ℃, 17.1 grams of the triethylamines of dropping 1.2 equivalents, after being added dropwise to complete again.Naturally be raised to room temperature (25 ℃ of left and right), stir 4 hours.Whether tlc monitoring reaction completes.
Step B, after thin-layer chromatography detection reaction completes, directly adds the wet chemical (9.8g salt of wormwood, 100ml water) that is no less than 0.2 equivalent, stirs 30 minutes to reacting completely, and static 30 minutes, point water-yielding stratum, retained organic layer.Concentrated 68 grams of white solids, the yield 91% of obtaining of organic layer.
The nuclear magnetic data of this white solid
1hNMR d
6-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] C
20h
26nO
10s, calculated value, 472.1277; Measured value, 472.1397.
As shown in Figure 1, the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is at 7.1 ° for the X-ray powder diffraction collection of illustrative plates of this white solid, and 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, locate indicating characteristic peak for 22 °.
This white solid locates to have absorption peak through determine with dsc method (DSC mensuration) gained collection of illustrative plates (as shown in Figure 2) at 245.7 ℃.
Other steps are identical, just wet chemical is changed and done after potassium hydroxide aqueous solution or other alkaline potassium salt aqueous solution, preparation N-carbobenzoxy-(Cbz)-2,3:4, concrete yield and the purity of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate sylvite are as shown in table 2.
Table 2 is prepared N-carbobenzoxy-(Cbz)-2 with potassium hydroxide or other alkaline potassium salt aqueous solution, 3:4, yield and the purity of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate sylvite
The preparation method of embodiment 3 topiramates
Steps A adopts synthetic method synthetic compound N-of the prior art carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
This step just illustrates a kind of synthetic N-carbobenzoxy-(Cbz)-2,3:4, the synthetic method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate, but this be never limited to, and only explanation is all to synthesize based on existing known technology.
In 500mL reaction flask, add Sulfuryl chloride isocyanate (CSI) 20g of 1 equivalent and methylene dichloride 200mL to cool to below-20 ℃, drip the benzylalcohol 16.1g of 1.05 equivalents, in dropping process, temperature temperature control is below-10 ℃.Be added dropwise to complete rear stirring 1～2 hour.Add 35 grams, fructose two acetone of 0.95 equivalent.Greenhouse cooling is arrived below-20 ℃, 17.1 grams of the triethylamines of dropping 1.2 equivalents, after being added dropwise to complete again.Naturally be raised to room temperature (25 ℃), stir 4 hours.Whether tlc monitoring reaction completes.
Step B, after thin-layer chromatography detection reaction completes, adds the sodium bicarbonate aqueous solution (12g sodium bicarbonate, 100ml water) that is no less than 0.2 equivalent, stirs 30 minutes, and static 30 minutes, point water-yielding stratum, retained organic layer.Concentrated 63 grams of white solids, the yield 94% of obtaining of organic layer;
Step C N-carbobenzoxy-(Cbz)-2,3:4, the hydrogenation of the amino sulphur an alkali metal salt of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose obtains topiramate
By gained solid in embodiment 2, N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose thionamic acid ester sodium salt adds methyl alcohol 260ml, humidification palladium charcoal, amounting to butt weight is 7.0g, and room temperature high pressure 1.2MPa hydrogenation is stirred 3 hours, and tlc detection reaction completes, cross and filter out palladium carbon, leach the drip washing of palladium carbon 50ml methyl alcohol, filtrate decompression is concentrated into surplus 90ml, and ice bath is cooled to 0 ℃ of insulation one hour.Filtration drying obtains topiramate 37g, yield 83%.
Other steps are identical, just sodium bicarbonate aqueous solution used in step B changed and done after potassium hydroxide or sodium hydroxide or other alkaline alkali metal salt brine solutions, and concrete yield and the purity of preparing topiramate are as shown in table 3.Each data are the mean value of test of many times.
Table 3 is prepared N-carbobenzoxy-(Cbz)-2 by sodium hydroxide or potassium hydroxide or different alkaline alkali metal salt brine solutions, 3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt hydrogenation obtains yield and the purity of topiramate.
Claims (13)
1. prepare the method for compound topiramate for one kind, it is characterized in that the method necessarily comprises the steps: N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is used the sodium hydroxide or potassium hydroxide or alkaline alkali metal salt brine solution processing generation N-carbobenzoxy-(Cbz)-2 that are no less than 0.2 equivalent, 3:4, the step of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt
Described alkaline alkali metal salt brine solution is sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium phosphate, the potassiumphosphate aqueous solution, described equivalent is with N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is reference equivalent.
2. a kind of method of preparing compound topiramate as claimed in claim 1, is characterized in that the method also comprises the steps:
A. Sulfuryl chloride isocyanate reacts generation with benzylalcohol
B.
with fructose two acetone
reaction generates N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
3. a kind of method of preparing compound topiramate as described in claim 1 or 2 any one, it is characterized in that the method also comprises with N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt obtains topiramate through hydrogenation.
4. prepare N-carbobenzoxy-(Cbz)-2 for one kind, 3:4, the method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt, it is characterized in that the method necessarily comprises: by N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is used the sodium hydroxide or potassium hydroxide or alkaline alkali metal salt brine solution processing generation N-carbobenzoxy-(Cbz)-2 that are no less than 0.2 equivalent, 3:4, the step of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt;
Described alkaline alkali metal salt is sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium phosphate, potassiumphosphate;
Described equivalent is with N-carbobenzoxy-(Cbz)-2,3:4, and the consumption of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is a reference equivalent.
5. one as claimed in claim 4 is prepared N-carbobenzoxy-(Cbz)-2,3:4, and the method for 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt, is characterized in that the method also comprises the steps:
A. Sulfuryl chloride isocyanate reacts generation with benzylalcohol
B.
with fructose two acetone
reaction generates N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
6. the one as described in claim 4 or 5 any one is prepared N-carbobenzoxy-(Cbz)-2,3:4, the method for 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt, it is characterized in that the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle with the method gained compound is at 7.1 °, 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, locate indicating characteristic peak for 22 °.
7. the one as described in claim 4 or 5 any one is prepared N-carbobenzoxy-(Cbz)-2,3:4, the method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt, is characterized in that within the scope of 248.7 ℃ ± 5 ℃, having absorption peak through determine with dsc method or thermogravimetric analysis detection with the method gained compound.
8. the one as described in claim 4 or 5 any one is prepared N-carbobenzoxy-(Cbz)-2,3:4, and the method for 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt, is characterized in that the method is for the preparation of topiramate.
9. N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt crystal formation compound, it is characterized in that X-ray powder diffraction collection of illustrative plates that this compound represents with 2 θ ± 0.2 ° diffraction angle is at 7.1 °, 8.8 °, 10.5 °, 11.0 °, 13.2 °, 14.7 °, 15.1 °, 17.2 °, 18 °, 18.5 °, 21 °, locate indicating characteristic peak for 22 °;
Described N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt refers to N-carbobenzoxy-(Cbz)-2,3:4, sodium salt and the sylvite of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate.
10. N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt crystal formation compound, it is characterized in that this compound has absorption peak through determine with dsc method or thermogravimetric analysis detection within the scope of 248.7 ℃ ± 5 ℃;
Described N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt refers to N-carbobenzoxy-(Cbz)-2,3:4, sodium salt and the sylvite of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate.
11. a kind of N-carbobenzoxy-(Cbz)-2 as described in claim 9 or 10 any one, 3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt crystal formation compound, it is characterized in that this compound is for the preparation of topiramate.
A kind of N-carbobenzoxy-(Cbz)-2 described in 12. preparation claim 9 or 10 any one, 3:4, the method of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt crystal formation compound, it is characterized in that the method necessarily comprises carbobenzoxy-(Cbz)-2 by N-, 3:4, 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is used the sodium hydroxide or potassium hydroxide or alkaline alkali metal salt brine solution processing generation N-carbobenzoxy-(Cbz)-2 that are no less than 0.2 equivalent, 3:4, the step of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate an alkali metal salt,
Described alkaline alkali metal salt is sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium phosphate, potassiumphosphate;
Described equivalent is with N-carbobenzoxy-(Cbz)-2,3:4, and the consumption of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate is a reference equivalent.
13. methods as claimed in claim 12, is characterized in that the method also comprises the steps:
A. Sulfuryl chloride isocyanate reacts generation with benzylalcohol
B.
with fructose two acetone
reaction generates N-carbobenzoxy-(Cbz)-2,3:4,5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410102754.8A CN103910770B (en) | 2014-03-14 | 2014-03-14 | A kind of intermediate crystal form involved in the preparation method of topiramate and the method and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410102754.8A CN103910770B (en) | 2014-03-14 | 2014-03-14 | A kind of intermediate crystal form involved in the preparation method of topiramate and the method and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103910770A true CN103910770A (en) | 2014-07-09 |
| CN103910770B CN103910770B (en) | 2017-01-04 |
Family
ID=51036819
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410102754.8A Expired - Fee Related CN103910770B (en) | 2014-03-14 | 2014-03-14 | A kind of intermediate crystal form involved in the preparation method of topiramate and the method and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103910770B (en) |
Citations (4)
| 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 |
| WO2007099388A1 (en) * | 2006-03-01 | 2007-09-07 | Glade Organics Private Limited | An improved process for the manufacture of topiramate |
| 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 |
-
2014
- 2014-03-14 CN CN201410102754.8A patent/CN103910770B/en not_active Expired - Fee Related
Patent Citations (4)
| 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 |
| WO2007099388A1 (en) * | 2006-03-01 | 2007-09-07 | Glade Organics Private Limited | An improved process for the manufacture of topiramate |
| 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 |
|---|
| 苗宇等，: "托吡酯的合成研究进展.", 《中国现代应用药学》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103910770B (en) | 2017-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106279074B (en) | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized | |
| CN102127092B (en) | Preparation of Everolimus | |
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| CN108368132A (en) | It is double（Fluorosulfonyl）The novel manufacturing method of imide li | |
| CN101007812A (en) | Antibacterial drugs cefoxitin preparation process | |
| CN105452256A (en) | Method for preparing a pyripyropene compound | |
| CN110878084A (en) | Preparation method of nicosulfuron original drug | |
| CN104045602A (en) | Improved method for preparing tetrazole for valsartan | |
| CN104003981A (en) | Synthesis method of avanafil | |
| CN103012300A (en) | Novel method for preparing valsartan | |
| CN101302207A (en) | Preparation of 3-o-alkyl-5,6-o-(1-methyl ethylidine)-l-ascorbic acid and preparation of 5,6-o-(1- methyl ethylidine)-l- ascorbic acid | |
| CN103304550A (en) | Preparation method of Olmesartan Medoxomil | |
| CN104744390A (en) | Preparation method of ezetimibe internmediate ketone | |
| CN103980120A (en) | Synthesis method of D,L-danshensu isopropyl ester | |
| CN103910770A (en) | Preparation method of topiramate, intermediate crystal form related in method thereof and its preparation method | |
| CN106674281B (en) | A kind of Rosuvastatin midbody compound, preparation method and its usage | |
| CN107001250B (en) | A method of Ao Dangka is prepared for intermediate | |
| CN106946724B (en) | The synthetic method of monoamine base inhibitor class intermediate 2- acetylaminohydroxyphenylarsonic acid 2- benzyl malonic acid mono ethyl ester | |
| CN102276442B (en) | Synthetic method of dichloroacetate | |
| CN110016029A (en) | A kind of preparation method of fluoro- 1H- pyrrolo- [2,3-b] pyridine-2-carboxylic acids of 3- | |
| WO2012103105A1 (en) | Processes for preparing raltegravir and intermediates in the processes | |
| CN111303045A (en) | Production process of 2-ethoxy-4, 6-difluoropyrimidine | |
| CN104817482A (en) | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin | |
| CN109053585A (en) | A kind of synthetic method of Triclabendazole | |
| CN104447567B (en) | A kind of preparation method of 1 substituted benzimidazole derivant |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: Tianjin City, Nankai District road 300384 yuan Huayuan new technology industrial park, 5 block D No. 9 Applicant after: Nankai Yungong Pharmaceutical Science-Technology Co., Ltd., Tianjin Applicant after: Tongliao Huabang Pharmaceutical Co Ltd Applicant after: Tibet Linzhi Baisheng Pharmaceutical Co., Ltd. Address before: Tianjin City, Nankai District road 300384 yuan Huayuan new technology industrial park, 5 block D No. 9 Applicant before: Nankai Yungong Pharmaceutical Science-Technology Co., Ltd., Tianjin Applicant before: Naikai Share Pharmaceutical Co., Ltd. Applicant before: Tibet Linzhi Baisheng Pharmaceutical Co., Ltd. |
|
| COR | Change of bibliographic data | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190520 Address after: 028100 Tiedong, Ganqika Town, Kezuo Houqi, Tongliao City, Inner Mongolia Autonomous Region Co-patentee after: Tibet Linzhi Baisheng Pharmaceutical Co., Ltd. Patentee after: Tongliao Huabang Pharmaceutical Co Ltd Address before: 300384 9/F, Block D, No. 5 Lanyuan Road, Huayuan New Technology Industrial Park, Nankai District, Tianjin Co-patentee before: Tongliao Huabang Pharmaceutical Co Ltd Patentee before: Nankai Yungong Pharmaceutical Science-Technology Co., Ltd., Tianjin Co-patentee before: Tibet Linzhi Baisheng Pharmaceutical Co., Ltd. |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170104 Termination date: 20200314 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |