CN110655542A - Crystal form of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate - Google Patents
Crystal form of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate Download PDFInfo
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- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a medicine for treating chronic hepatitis B, which comprises 2,3: crystalline form a of 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose chlorosulfonate. The invention also relates to a preparation method and application thereof in preparing topiramate. 2,3: crystalline form a of 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose chlorosulfonate, high in purity, single hetero 2,3: less than 0.11% of 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose, consisting of 2,3: the yield of topiramate prepared from the 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A is more than 92%, the HPLC purity is more than 99.90%, and the ratio of single impurity 2,3: less than 0.03 percent of 4, 5-bis-O- (1-methylethylidene) -beta-D-pyranose fructose and less than 0.05 percent of condensate single impurity.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthetic method of 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose chlorosulfonate.
Background
Topiramate (Topiramate) is a sulfamate substituted monosaccharide antiepileptic drug which blocks an action potential repeatedly excited by continuous depolarization of neurons in a time-dependent manner, increases the frequency of gamma aminobutyric acid (GABA) activated receptors, enhances the GABA induced chloride ion influx capacity, and enhances the action of inhibitory neurotransmitters. The traditional Chinese medicine composition is clinically used for the additive treatment of children partial epileptic seizure and the preventive treatment of adult migraine.
Topiramate was first marketed in the United kingdom by the Progress of America in 1995, was approved by the FDA in the United states in 1996, and is currently marketed in the United states, Europe, and Japan. Topiramate entered China in 2001 under the trade name "Tuotai". Topiramate is popular in the market, and is one of the best-selling medicines in the world in short years, the world market is represented by Topamax (Topamax) which is a topiramate product of Qiangsheng corporation, and occupies about 13 percent of the world market of antiepileptic medicines, and Toutai (Toutai) products of Sian Yang Sen corporation monopolize the market in China. The sales volume of the national antiepileptic drug market in 2004 is increased by nearly 50% compared with 2003, and in the total sales volume of the national antiepileptic drug market in 2005, the share of topiramate accounts for more than 30%, so that the method has wide market prospects.
Topiramate is chemically known by the name 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl sulfamate
The structural formula is as follows:
2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl sulfamate
Wherein, 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate is an important intermediate for preparing topiramate, and the structure of the intermediate is shown as formula I:
the journal of Chinese medicine technology 1999, 30(11), page 486-: reacting 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose with sulfonyl chloride in a toluene solvent to give an intermediate 2,3: the 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate is light yellow syrup (yield: 75%), and is dissolved in THF, ammonia gas is introduced at normal pressure, the mixture is concentrated, diethyl ether is added for grinding, and the topiramate is obtained by recrystallization with ethanol-water, the total ammoniation yield is 73.2%, and the yield is low.
Journal of pharmaceutical chemistry of china 2013, 23(1), pages 39-41, reported the use of 2,3: reacting 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose with sulfonyl chloride in a toluene solvent to give an intermediate 2,3: the 45-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate is colorless oily matter, 22.8g and the yield is 90 percent, and then the colorless oily matter is prepared by reacting with 25 percent by volume of methylamine aqueous solution, the yield is 88.2 percent, the total yield is 77.4 percent, the HPLC purity is 95.2 percent, and the impurities are more and the purity is low, which cannot meet the industrial application of medicines.
Patent CN106632530A reports the preparation of intermediate 2,3 by reacting fructose diproprionone with sulfonyl chloride in toluene solvent: 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate is a light yellow oily substance and is directly synthesized into a crude product in the next step, and the obtained crude product needs to be refined for many times, and has the advantages of many refining times, low yield and high cost.
Zhoujing, study of the synthesis and glycosylation reactions of the saccharide drugs topiramate, MDP and GMDP intermediates [ D ]. shanghai university of east china, 2012, reported 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-pyranose fructose and sulfonyl chloride react with sulfonyl chloride in toluene or 1, 2-dichloroethane to obtain a liquid product which is not suitable for recrystallization and is directly used for preparing topiramate in the next step of amination reaction, and the product is oily due to the existence of T-2 (namely 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-pyranose fructose), and the topiramate is obtained by three times of recrystallization, wherein the yield of amination reaction is 71%, the purity is more than 98%, the recrystallization times are more, the total yield is low, and the industrial production is not suitable.
The process has been reported to prepare 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose chlorosulfonate was an oil, unreacted 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose reacts with the generated topiramate to remove one molecule of water in the next reaction, and the formed condensation compound has high content and is not easy to remove. The condensate is:
disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for processing a data packet, which relates to the following steps of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A and a preparation method and application thereof.
The specific technical scheme of the invention is as follows:
a crystalline form a of a compound of formula I having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ positions using Cu-ka radiation: 7.5 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 12.8 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.6 +/-0.2 degrees;
preferably, Cu-K α radiation is used, which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 θ positions: 7.5 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 11.4 +/-0.2 degrees, 12.4 +/-0.2 degrees, 12.8 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.8 +/-0.2 degrees, 18.0 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.6 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.4 +/-0.2 degrees and 22.4 +/-0.2 degrees.
Preferably, Cu-K α radiation is used, which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 θ positions: 7.5 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 11.4 +/-0.2 degrees, 12.4 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.4 +/-0.2 degrees, 14.1 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.4 +/-0.2 degrees, 15.8 +/-0.2 degrees, 17.2 +/-0.2 degrees, 18.7 +/-0.2 degrees, 18.0 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.6 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.4 +/-0.2 degrees, 22.4 +/-0.2 degrees, 24.0 +/-0.2 degrees.
Preferably, it is irradiated with Cu-K alpha, which has a powder X-ray diffraction pattern as shown in FIG. 1.
The invention also provides a method for preparing the compound of 2,3: a method for preparing 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate form a, comprising the steps of:
(1)2,3: reacting 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose with sulfonyl chloride in a mixed solvent of dichloromethane and toluene to prepare a crude product of the compound shown in the formula I;
(2) dissolving the crude product of the compound of the formula I by using an organic solvent, and cooling and crystallizing to obtain the crystal form A of the compound of the formula I.
Preferably, the volume ratio of the dichloromethane in the mixed solvent of the dichloromethane and the toluene in the step 1 is higher than that of the toluene; more preferably, the volume ratio of dichloromethane to toluene is: 60-100: 40-0.
Preferably, in step 2, the crude compound of formula I: the organic solvent is 1: 3-8, wherein the mass is g, and the volume is mL.
Preferably, the crystallization temperature in step 2 is-25 to-5 ℃.
Preferably, the organic solvent in step 2 is selected from one of alkanes and ethers.
More preferably, the organic solvent in step 2 is selected from one of n-pentane, n-hexane, n-heptane, cyclohexane, cyclopentane, cycloheptane, methyl tert-butyl ether, diethyl ether, isopropyl ether, dipropylene glycol dimethyl ether, petroleum ether, diethylene glycol monomethyl ether, ethylene glycol dimethyl ether and butyl ether; preferably petroleum ether, isopropyl ether, n-heptane and cycloheptane; further preferred are n-heptane and cycloheptane.
The present invention also provides 2,3: use of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A in the preparation of topiramate.
Preferably, the specific preparation method comprises the following steps: mixing 2,3: dissolving the 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A in a mixed solvent C, introducing ammonia gas, reacting at room temperature, filtering, concentrating under reduced pressure, cooling, crystallizing, filtering and drying to obtain topiramate solid.
Further preferably, the mixed solvent C is composed of tetrahydrofuran and a solvent D; more preferably, the solvent D is selected from n-hexane or petroleum ether with a boiling range specification of 60-90 ℃.
Preferably, the volume ratio of tetrahydrofuran to solvent D is: 20-40: 80-60.
Compared with the prior art, the invention has the following beneficial effects:
(1) reacting topiramate intermediate 2,3: the 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate is prepared into a solid product from an oily substance, is convenient to store, sample and remove impurities, and is suitable for industrial production.
(2) Intermediate 2,3 prepared: crystalline form a of 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranosyl chlorosulfonate is more pure than its oil, monohetero 2,3: less than 0.11% of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose.
(3) The method comprises the following steps of 2,3: the process for preparing topiramate from the 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A is simple, and the content of the single impurity is 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose is low in content and therefore the 2,3: the content of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose is low, and the prepared topiramate can reach higher purity without refining.
(4) The method comprises the following steps of 2,3: the yield of topiramate prepared from the 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A is more than 92%, the HPLC purity is more than 99.90%, and the ratio of single impurity 2,3: less than 0.03 percent of 4, 5-bis-O- (1-methylethylidene) -beta-D-pyranose fructose and less than 0.05 percent of condensate single impurity.
Drawings
Figure 1 XRD spectrum of form a of the present invention.
Figure 2 diffraction peak data for form a of the present invention.
Figure 3 XRD spectrum of form B of the present invention.
Figure 4 diffraction peak data for form B of the invention.
Figure 5 XRD overlay of form a and form B of the present invention.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.
2,3: the synthesis reaction equation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate is as follows:
example one, 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A
75mL of mixed solvent (dichloromethane: toluene: 90: 10) is added into a 250mL three-necked bottle, 10.03g of sulfonyl chloride is added, the temperature is reduced to-5 to-10 ℃ by stirring, and 15g of 2,3: dissolving 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose in 75mL of mixed solvent (dichloromethane: toluene is 90: 10) and 5.88g of pyridine, continuously stirring for 5-10 min after the dropwise addition, stirring for reaction at room temperature for 3h, adding 75mL of water, stirring for dissolution, standing for layering, collecting an organic phase, washing with 75mL of 10% citric acid, 75mL of distilled water, 75mL of 8% sodium bicarbonate solution and 75mL of 26.5% saline solution in sequence, standing, collecting the organic phase, adding anhydrous sodium sulfate, stirring and drying. And (3) filtering out a drying agent after drying is finished, concentrating the filtrate under reduced pressure to obtain 20.98g of colorless oily matter after concentration is finished, adding 100mL of isopropyl ether into a single-neck bottle, controlling the temperature to be-10 to-15 ℃, stirring, cooling, crystallizing for 1-2 h, performing suction filtration, performing vacuum drying for 1h at the temperature of 45 ℃, and weighing to obtain 2,3: 18.6g of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate is crystal form A, the yield is 90.1%, and the HPLC purity is as follows: 99.88 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.05 percent.
Examples two 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A
75mL of mixed solvent (dichloromethane: toluene 80: 20) is added into a 250mL three-necked bottle, 10.03g of sulfonyl chloride is added, the temperature is reduced to-5 to-10 ℃ by stirring, and 15g of 2,3: dissolving 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose in 75mL of mixed solvent (dichloromethane: toluene is 80: 20) and 5.88g of pyridine, continuing stirring for 5-10 min after the dropwise addition, stirring at room temperature for 3h, adding 75mL of water, stirring for dissolution, standing for layering, collecting an organic phase, washing with 75mL of 10% citric acid, 75mL of distilled water, 75mL of 8% sodium bicarbonate solution and 75mL of 26.5% saline solution in turn, standing, collecting the organic phase, adding anhydrous sodium sulfate, and stirring for drying. And after drying, filtering out a drying agent, concentrating the filtrate under reduced pressure to obtain 20.18g of colorless oily substance, adding 160mL of cyclohexane into a single-mouth bottle, controlling the temperature to be-25 to-20 ℃, stirring, cooling, crystallizing for 1-2 h, performing suction filtration, performing vacuum drying for 1h at 45 ℃, weighing to obtain 2,3: 18.9g of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate is in a form A, the yield is 91.3%, and the HPLC purity is as follows: 99.82 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.06 percent.
Example three 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A
75mL of mixed solvent (dichloromethane: toluene: 70: 30) is added into a 250mL three-necked bottle, 10.03g of sulfonyl chloride is added, the temperature is reduced to-5 to-10 ℃ by stirring, and 15g of 2,3: dissolving 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose in 75mL of mixed solvent (dichloromethane: toluene is 70: 30) and 5.88g of pyridine, continuously stirring for 5-10 min after the dropwise addition, stirring for reaction at room temperature for 3h, adding 75mL of water, stirring for dissolution, standing for layering, collecting an organic phase, washing with 75mL of 10% citric acid, 75mL of distilled water, 75mL of 8% sodium bicarbonate solution and 75mL of 26.5% saline solution in sequence, standing, collecting the organic phase, adding anhydrous sodium sulfate, stirring and drying. And after drying, filtering out a drying agent, concentrating the filtrate under reduced pressure to obtain 20.67g of colorless oily substance, adding 62mL of methyl tert-butyl ether into a single-mouth bottle, controlling the temperature to be-10 to-5 ℃, stirring, cooling, crystallizing for 1-2 h, performing suction filtration, performing vacuum drying for 1h at 45 ℃, weighing to obtain 2,3: 19.4g of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate, which is crystal form A, is in a yield of 93.7%, and the HPLC purity is as follows: 99.73 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.08 percent.
Table 1 preparation 2,3: comparison of effects of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate crystal form A
EXAMPLE preparation of Tetratopiramate
17.3g of 2,3: dissolving the crystal form A of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate in 300mL of mixed solvent (tetrahydrofuran: n-hexane: 20: 80), introducing ammonia gas, reacting at room temperature for 3h, filtering, concentrating under reduced pressure until the residual filtrate is about 40mL, cooling to-5-0 ℃ for crystallization, filtering and drying to obtain 15.8g of white solid (namely: topiramate), wherein the yield is 96.7%, and the HPLC purity is as follows: 99.93 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.02 percent; condensation product: 0.03 percent.
EXAMPLE preparation of pentatopiramate
18.1g of 2,3: dissolving the crystal form A of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate in 300mL of mixed solvent (tetrahydrofuran: petroleum ether with a boiling range of 60-90 ℃), introducing ammonia gas, reacting at room temperature for 3h, filtering, concentrating under reduced pressure until the residual filtrate is about 40mL, cooling to-5 ℃ -0 ℃ for crystallization, filtering and drying to obtain 16.2g of white solid (namely, topiramate), wherein the yield is 94.6%, and the HPLC purity is as follows: 99.91 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.03 percent; condensation product: 0.05 percent.
EXAMPLE preparation of hexatopiramate
18.0g of 2,3 prepared in example three: dissolving the crystal form A of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate in 300mL of mixed solvent (tetrahydrofuran: n-hexane: 40: 60), introducing ammonia gas, reacting at room temperature for 3h, filtering, concentrating under reduced pressure until the residual filtrate is about 40mL, cooling to-5-0 ℃ for crystallization, filtering and drying to obtain 15.8g of white solid (namely: topiramate), wherein the yield is 92.8%, and the HPLC purity is as follows: 99.90 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.02 percent; condensation product: 0.04 percent.
EXAMPLE preparation of heptatopiramate
1. 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate oil
75mL of mixed solvent (dichloromethane: toluene ═ 90: 10) is added into a 250mL three-necked bottle, 10.03g of sulfonyl chloride is added, the temperature is reduced to-5 to-10 ℃ by stirring, and 15g of 2,3: dissolving 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose in 75mL of mixed solvent (dichloromethane: toluene is 90: 10) and 5.88g of pyridine, continuously stirring for 5-10 min after the dropwise addition, stirring for reaction at room temperature for 3h, adding 75mL of water, stirring for dissolution, standing for layering, collecting an organic phase, washing with 75mL of 10% citric acid, 75mL of distilled water, 75mL of 8% sodium bicarbonate solution and 75mL of 26.5% saline solution in sequence, standing, collecting the organic phase, adding anhydrous sodium sulfate, stirring and drying. After the completion of the drying, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain 21.8g of a colorless oil, yield 105.8%, and solvent residue 6.7%. Controlling the temperature to be-10 to-15 ℃, cooling and crystallizing for 1 to 2 hours, wherein a solid product or an oily substance is not precipitated, and the yield is corrected: 98.7%, HPLC purity: 98.37%, 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 1.13 percent.
2. Ammoniation
And (3) mixing the 2,3: dissolving 20g of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate in 300mL of a mixed solvent (tetrahydrofuran: n-hexane: 20: 80), introducing ammonia gas, reacting at room temperature for 3h, filtering, concentrating under reduced pressure until the residual filtrate is about 40mL, cooling to-5 ℃ -0 ℃ to obtain an oily substance, and concentrating under reduced pressure until the oily substance is dried to obtain 16.5g of oily substance (namely: topiramate), wherein the yield is 93.7%, and the HPLC purity: 98.61 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.72 percent; condensation product: 0.60 percent.
EXAMPLE preparation of octatopiramate
1. 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form B
75mL of mixed solvent (dichloromethane: toluene 80: 20) is added into a 250mL three-necked bottle, 10.03g of sulfonyl chloride is added, the temperature is reduced to-15 to-10 ℃ by stirring, and 15g of 2,3: dissolving 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose in 75mL of mixed solvent (dichloromethane: toluene is 90: 10) and 5.88g of pyridine, continuously stirring for 5-10 min after the dropwise addition, stirring for reaction at room temperature for 3h, adding 75mL of water, stirring for dissolution, standing for layering, collecting an organic phase, washing with 75mL of 10% citric acid, 75mL of distilled water, 75mL of 8% sodium bicarbonate solution and 75mL of 26.5% saline solution in sequence, standing, collecting the organic phase, adding anhydrous sodium sulfate, stirring and drying. And after drying, filtering out a drying agent, concentrating the filtrate under reduced pressure to obtain 20.98g of colorless oily matter, adding 100mL of ethylene glycol dimethyl ether into a single-neck bottle, controlling the temperature to be 10-15 ℃, stirring, cooling, crystallizing for 1-2 h, performing suction filtration, performing vacuum drying for 1h at 45 ℃, and weighing to obtain 2,3: 17.8g of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate, 86.3% yield, purity: 98.97% as form B; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.42 percent.
2. Ammoniation
Mixing 17.1g2, 3: dissolving the crystal form B of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate in 300mL of mixed solvent (tetrahydrofuran: n-hexane: 20: 80), introducing ammonia gas, reacting at room temperature for 3h, filtering, concentrating under reduced pressure until the residual filtrate is about 40mL, cooling to-5-0 ℃ for crystallization, filtering and drying to obtain 14.5g of white solid (namely: topiramate), wherein the yield is 90.1%, and the HPLC purity is as follows: 99.40 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.21 percent; condensation product: 0.27 percent.
Comparative example preparation of topiramate
1. 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose
Acetone (144.0L, 113.0Kg, 1946moL) was cooled to 0 deg.C-10 deg.C under nitrogen, and concentrated sulfuric acid (7.2L, 13.2Kg, 135.6moL) was slowly added (about 0.5 hours) while stirring so that the temperature did not exceed 20 deg.C (-15 deg.C jacket temperature). The external cooling was stopped and D-fructose (12.0Kg, 66.6moL) was added slowly (2.0 Kg each) over a period of not less than 2 hours while maintaining the temperature at 8-15 ℃. When all fructose is dissolved, the suspension is stirred at room temperature for 2-3 hours. The solution was then cooled to 5 ℃ and 50% sodium hydroxide (24.0Kg, 297.6moL) was added at such a rate that the temperature of the solution was maintained below 20 ℃ (jacket temperature-15 ℃ over 1 hour), and the resulting slurry was centrifuged to remove precipitated salts (sodium sulfate). The solvent was removed from the filtrate by rectification in vacuo and the residue was stored at room temperature. This half of the solid reaction product was dissolved in t-butyl methyl ether (48.8Kg, 66.4L). The solution was washed with distilled water (2X 9.0L) and concentrated to give an oil. The oil was dissolved in hexane (24.0L)/isopropyl alcohol (3.5L) and slowly warmed to 60 ℃. The product was cooled to crystallize and the solid was isolated by centrifugation and dried under vacuum at 38 ℃ for 8.0 hours to give 9.04Kg of a white solid in 52.1% yield and HPLC purity: 96.96 percent and the melting point is 95-96 ℃.
2.2, 3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate (chlorosulfonate)
A solution of sulfonyl chloride (486.9g, 3.60moL) and toluene (4.0L) was cooled to-10 ℃. A solution of the alcohol of step 1 (782.4g, 3.00moL) and pyridine (285.3g, 3.60moL) in toluene (4.0L) was added to the cooled sulfonyl chloride solution. The rate of addition was adjusted so that the reaction temperature was maintained between-10 ℃ and 5 ℃ (1.5 hours). A white solid precipitate was obtained immediately from the reaction. When the solution addition was complete, the cooling bath was removed and the mixture was stirred for 2 hours. The reaction mixture was diluted with distilled water (4.0L), and the resultant was separated into layers. The organic layer was then washed with 10% citric acid solution (2.6L), distilled water (2.6L), saturated sodium bicarbonate solution (2.6L), saturated sodium chloride solution (2.6L), respectively. The solvent was removed by vacuum rectification (in a bath at 45 ℃ and a pressure of less than 5 mm). An almost colorless oily chlorosulfate (1023.4g, 94.9%) was obtained in a corrected yield of 89.2% with 5.7% toluene remaining. The HPLC purity of the product was 95.44%, 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 2.8 percent.
3.2, 3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl sulfamate (ammonolysis at 30 psi)
The solution of the chlorosulfonate (1016.4g) from step 2 in tetrahydrofuran (8.0L) was charged to a 12.0L stainless steel autoclave, pressurized to 30psi with anhydrous ammonia at room temperature, and stirred (400rpm) for 24.0 hours. After 2 hours, a moderately exothermic reaction (25 ℃ C. to 38 ℃ C.) was observed. The valve is opened to be emptied, and the autoclave is depressurized. The pale yellow solution containing the white particulate solid was filtered and the filter cake was washed with tetrahydrofuran (400 mL). Tetrahydrofuran was removed under vacuum (50 ℃, house vacuum) to give a product as a pale yellow oil (822.2g, 90.7% yield) the resulting oil was slurried in n-hexane (2.1L) and heated in a steam bath for 0.5 h, the oil becoming a white paste and crystallizing. After cooling to room temperature, the title compound was filtered and dried in air for 24.0 hours (650.8g, 71.8% yield, 93.15% HPLC purity).
A sample (650g) was recrystallized by adding distilled water (1300mL) to 95% ethanol (650mL) and adjusting the pH to 8-8.5 with 50% NaOH. The solid was collected by vacuum filtration and air dried (72.0 h) to give 519.4g of the title compound as a white solid in 79.9% refined yield and 98.32% HPLC purity; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.31 percent; condensation product: 0.52 percent. The melting point is 123-124 ℃.
Comparative example preparation of ditopipride
1. 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate
100mL of toluene and 8mL of sulfuryl chloride (0.09moL) were added to a reaction flask, stirred, and added dropwise slowly at-10 ℃ to a reaction flask containing 2,3: a mixed solution of 4, 5-bis-O- (1-methylethylidene) -D-fructopyranose (20g, 0.077moL) in 100mL of toluene and 8mL of pyridine was reacted at room temperature for 3 hours, and then 100mL of water was added to dilute the reaction solution, followed by separation of several layers by dilute hydrochloric acid, dilute aqueous sodium hydroxide solution and water, drying over anhydrous sodium sulfate, filtration and removal of toluene under reduced pressure to obtain pale yellow syrup (2, 3:4, 5-bis-O- (1-methylethylidene) -D-fructopyranose chlorosulfonate) in an amount of 25.8g, a yield of 93.5%, and a corrected yield: 88.7%, the HPLC purity of the product was: 95.12%, 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 3.20 percent.
2.2, 3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl sulfamate
Mixing 2,3:4, 5-bis-O- (1-methylethylidene) -D-fructopyranosyl sulfamate (20g, 0.056moL) is dissolved in 200mL of cyclohexane, 38mL (0.725moL) of concentrated ammonia water is added, the reaction is completed after 5 hours of reaction, standing and liquid separation are carried out, an organic layer is washed by dilute alkali liquor and water respectively, dried by sodium sulfate and concentrated under reduced pressure to obtain 1.7g of oily substance, and the yield is 9.2 percent after drying at 50 ℃. No product peak was analyzed by HPLC.
Comparative example preparation of Tritopiramate
1. 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate oil
196g of sulfonyl chloride and 1600mL of toluene/dichloromethane (9: 1) are sequentially added into a 5000mL three-neck flask provided with a stirring device, a thermometer, a nitrogen protection device and a tail gas absorption device, the temperature is reduced to-5-0 ℃ under the protection of flowing nitrogen, 313.2g of diacetone fructose and 116g of pyridine in 1600mL of toluene/dichloromethane (9: 1) solution are dropwise added, the dropwise adding temperature is controlled to be-5-0 ℃, the dropwise adding is completed within about 2.0 hours, and the tail gas is absorbed by alkaline water. After dripping, naturally heating and stirring, after about 1 hour, raising the temperature to 12-15 ℃, starting timing reaction, and controlling the reaction temperature to 15-20 ℃. After 3 hours of reaction, the nitrogen blanket was stopped, and the reaction solution was washed once with 800mL of an aqueous solution containing 96g of citric acid, twice with 1600mL of an aqueous solution containing 48g of citric acid and 38.4g of trisodium citrate, and twice with 800mL of purified water. The washed organic layer was concentrated to dryness under reduced pressure to give 414.0g of chlorosulfonate as an oil in 95.9% yield, corrected yield: 92.6%, HPLC purity: 96.81%, 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 1.72 percent.
2. Ammoniation
The chlorosulfonate obtained in the previous step was put into a 5L reactor, 3200ml of tetrahydrofuran/dichloromethane (9: 1) was added, the reactor was closed, and stirring was started. And externally connecting a low-temperature cooling cycle, reducing the internal temperature to be below 10, starting to slowly and intermittently introduce ammonia gas, keeping the internal temperature below 10 ℃ and the internal pressure within 0.5atm, closing the external cooling cycle after about 2 hours, naturally heating, and keeping the internal pressure within 0.5 atm. The time is started until the internal temperature is 20 ℃, the internal temperature is kept at 20 +/-2 ℃, and the reaction is carried out for more than 6 hours. After the reaction is finished, discharging ammonia, opening the kettle, filtering the reaction liquid, concentrating the mother liquid under reduced pressure to be nearly dry, adding 400mL of 95% ethanol into the obtained solid, heating at the external temperature of 70 ℃, dropwise adding 400mL of purified water after the solid is dissolved, and keeping the internal temperature at 65-70 ℃. After dripping, 20g of activated carbon is added, the internal temperature is kept at 65-70 ℃, and after decoloring is carried out for 30 minutes, the mixture is filtered while hot and washed by 40mL of hot ethanol. Keeping the mother liquor at 45 +/-3 ℃, adjusting the pH value to be approximately equal to 7-8 by using 20% sodium hydroxide solution, slowly dropwise adding 200mL of purified water, and naturally cooling and crystallizing after dropwise adding. Cooling to 25 +/-5 ℃ for crystallization for 2 hours, carrying out ice bath, cooling to 0-5 ℃, carrying out heat preservation and crystallization for 1 hour, filtering, and washing with 500mL of purified water. The obtained wet product is dried under reduced pressure at 45 ℃ for about 6 hours. After baking, 274.5g of crude product (yield: 72.6%) was obtained, which had an HPLC purity: 93.68 percent.
3. Refining:
and (3) taking 100g of crude product, adding 100mL of absolute ethyl alcohol, dissolving at 70 ℃, keeping the internal temperature of 67 +/-3 ℃, dropwise adding 150mL of cyclohexane, naturally cooling to crystallize after dropwise adding, slowly cooling to about 25 ℃, keeping the temperature of 25 +/-5 ℃ for crystallizing for 2 hours, carrying out ice bath, crystallizing for 1 hour at 0-5 ℃, filtering, and washing with 100mL of purified water. The obtained wet product is decompressed and dried for 6 hours at the temperature of 45 ℃ to obtain 784.3g (yield: 78.4%) of topiramate refined product, the HPLC purity: 98.67 percent; 2,3: HPLC purity of 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.42 percent; content of condensate: 0.47 percent.
Comparative example preparation of Tetratopiramate
1. 2,3: preparation of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate oil
75mL of mixed solvent (dichloromethane: toluene: 90: 10) is added into a 250mL three-necked bottle, 10.03g of sulfonyl chloride is added, the temperature is reduced to-5 to-10 ℃ by stirring, and 15g of 2,3: dissolving 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose in 75mL of mixed solvent (dichloromethane: toluene is 90: 10) and 5.88g of pyridine, continuously stirring for 5-10 min after the dropwise addition, stirring for reaction at room temperature for 3h, adding 75mL of water, stirring for dissolution, standing for layering, collecting an organic phase, washing with 75mL of 10% citric acid, 75mL of distilled water, 75mL of 8% sodium bicarbonate solution and 75mL of 26.5% saline solution in sequence, standing, collecting the organic phase, adding anhydrous sodium sulfate, stirring and drying. After the completion of the drying, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain 20.0g of a colorless oil, yield 96.7%, corrected yield: 93.8%, purity of HPL C: 98.36%, 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 1.03 percent.
2. Ammoniation
The chlorosulfonate (17.5g, 67mmoL) solution of step 2 in tetrahydrofuran (8.0L) was charged to a 12.0L stainless steel autoclave, pressurized to 30psi with anhydrous ammonia at room temperature, and stirred (400rpm) for 24.0 hours. After 2 hours, a moderately exothermic reaction (25 ℃ C. to 38 ℃ C.) was observed. The valve is opened to be emptied, and the autoclave is depressurized. The pale yellow solution containing the white particulate solid was filtered and the filter cake was washed with tetrahydrofuran (400 mL). Tetrahydrofuran was removed under vacuum (50 ℃, field vacuum (housevac)) to give a product as a pale yellow oil (15.7g, 95.2% yield) the resulting oil was slurried in n-hexane (2.1L) and heated in a steam bath for 0.5 h, the oil becoming a white paste and crystallizing. After cooling to room temperature, the title compound was filtered and dried in air for 24.0 hours (12.9g, 77.9% yield, 95.02% HPLC purity).
Distilled water (240mL) was added to 95% ethanol (120mL), and the pH was adjusted to 8-8.5 with 50% NaOH to recrystallize a sample (12.0 g). The solid was collected by vacuum filtration and air dried (72.0 hours) to give the title compound as a white solid 9.8g with a refined yield of 81.3% and an HPLC purity of 98.70%, 2,3: HPLC purity of 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.37 percent; content of condensate: 0.42 percent. The melting point is 123-124 ℃.
Comparative example preparation of pentatopiramate
Preparation of 2,3: a total of 18.7g of 4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose chlorosulphonate form a, HPLC purity: 99.87%, 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.06 percent.
17.3g of the above 2,3: dissolving the crystal form A of 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate in 300mL of mixed solvent (tetrahydrofuran: n-hexane: 80: 20), introducing ammonia gas, reacting at room temperature for 3h, filtering, concentrating under reduced pressure until the residual filtrate is about 40mL, cooling to-5-0 ℃ for crystallization, filtering and drying to obtain 15.0g of white solid (namely: topiramate), wherein the yield is 92.1%, and the HPLC purity is as follows: 99.46 percent; 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose: 0.23 percent; condensation product: 0.25 percent.
Claims (10)
1. A crystalline form a of a compound of formula I having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ positions using Cu-ka radiation: 7.5 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 12.8 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.6 +/-0.2 degrees;
2. form a according to claim 1, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks in the following 2 Θ positions using Cu-ka radiation: 7.5 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 11.4 +/-0.2 degrees, 12.4 +/-0.2 degrees, 12.8 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.8 +/-0.2 degrees, 18.0 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.6 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.4 +/-0.2 degrees and 22.4 +/-0.2 degrees.
3. Form a according to claim 2, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks in the following 2 Θ positions using Cu-ka radiation: 7.5 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 11.4 +/-0.2 degrees, 12.4 +/-0.2 degrees, 12.8 +/-0.2 degrees, 13.4 +/-0.2 degrees, 14.1 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.4 +/-0.2 degrees, 15.8 +/-0.2 degrees, 17.2 +/-0.2 degrees, 18.7 +/-0.2 degrees, 18.0 +/-0.2 degrees, 19.0 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.6 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.4 +/-0.2 degrees, 22.4 +/-0.2 degrees, 24.0 +/-0.2 degrees.
4. Form a according to claim 3, characterized in that Cu-ka radiation is used, which has the X-ray diffraction pattern as shown in figure 1.
5. A process for preparing form a according to claim 1, comprising the steps of: :
(1)2,3: reacting 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose with sulfonyl chloride in a mixed solvent of dichloromethane and toluene to prepare a crude product of the compound shown in the formula I;
(2) dissolving the crude product of the compound of the formula I by using an organic solvent, and cooling and crystallizing to obtain the crystal form A of the compound of the formula I.
6. The preparation method of the crystal form A according to claim 5, wherein the volume ratio of dichloromethane in the mixed solvent of dichloromethane and toluene in the step 1 is higher than that of toluene; preferably, the volume ratio of dichloromethane to toluene is: 60-100: 40-0.
7. The preparation method of the crystal form A as claimed in claim 5, characterized in that, in the step 2, the mass volume ratio of the crude compound of the formula I: the organic solvent is 1: 3-8, wherein the mass is g, and the volume is mL; the crystallization temperature is-25 to-5 ℃.
8. The method for preparing the crystal form A according to claim 5, wherein the organic solvent in the step 2 is selected from one of alkanes and ethers.
9. The method for preparing the crystal form a according to claim 8, wherein the organic solvent in the step 2 is one selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, cyclopentane, cycloheptane, methyl tert-butyl ether, diethyl ether, isopropyl ether, dipropylene glycol dimethyl ether, petroleum ether, diethylene glycol monomethyl ether, ethylene glycol dimethyl ether, and butyl ether.
10. Use of the compound of claim 1 in crystalline form a for the preparation of topiramate; preferably, the specific preparation method comprises the following steps: mixing 2,3: dissolving the 4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl chlorosulfonate crystal form A in a mixed solvent C, introducing ammonia gas, reacting at room temperature, filtering, concentrating under reduced pressure, cooling, crystallizing, filtering and drying to obtain topiramate solid; preferably, the mixed solvent C consists of tetrahydrofuran and a solvent D, and the solvent D is selected from normal hexane or petroleum ether with a boiling range specification of 60-90 ℃; preferably, the volume ratio of tetrahydrofuran to solvent D is: 20-40: 80-60.
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