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Crystal form of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate
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A technology of crystal form and topiramate, applied in the field of chemical synthesis, can solve the problems of high cost, difficult to remove, many impurities, etc., and achieve the effect of convenient storage
Pending Publication Date: 2020-01-07
LUNAN PHARMA GROUP CORPORATION
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[0010] "Chinese Journal of Medicinal Chemistry" 2013, 23(1), pages 39-41 reported the use of 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose Reaction with sulfonylchloride in toluenesolvent gave intermediate 2,3: 45-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonate as colorless oil, 22.8 g, the yield is 90%, and then reacted with an aqueous solution of methylamine with a volume fraction of 25% to obtain a colorless oil, with a yield of 88.2%, a total yield of 77.4%, and a HPLC purity of 95.2%, with many impurities and low purity that cannot meet the industrialization of medicine application
[0011] Patent CN106632530A reports the preparation of intermediate 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose chlorosulfonic acid by reacting fructose diacetone and sulfonylchloride in toluenesolvent Ester is a light yellow oily substance, and the crude product is directly synthesized in the next step, and the obtained crude product needs to be refined many times, the yield is low, and the cost is high
[0012] Zhou Jing, Synthesis and glycosylation of sugar drugs topiramate, MDP and GMDP intermediates [D]. Shanghai. East China Normal University, 2012. Reported 2,3:4,5-bis-O-(1-methyl Ethylene)-β-D-fructopyranose 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 the next step of ammoniation reaction preparation Topiramate, due to the presence of T-2 (i.e. 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose), resulted in an oily product obtained through three recrystallizations Topiramate, the ammoniation reaction yield is 71%, the purity is greater than 98%, the recrystallization times are many, the total yield is low, and it is not suitable for industrial production
[0013] The 2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate prepared by the reported process is all oily, and the unreacted 2,3 : 4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose, in the next step reaction, reacts with the generated topiramate to remove a molecule of water, and the condensate formed has a high content, not easy to remove
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Embodiment 1
[0043] Example 1 2,3: Preparation of 4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate crystal form I
[0044]2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate (state is colorless oil, solvent residue is 3.50%) 20.0g was dissolved in 100mL petroleumether, controlled temperature at 0-5°C, cooled and crystallized for 4-5h, filtered with suction, dried in vacuum at 45°C for 1h, weighed to obtain 2,3:4,5-bis-O- (1-methylethylidene)-β-D-fructopyranose chlorosulfonate 17.5g, crystal form I, yield 90.6%, HPLC purity: 99.85%; 2,3:4,5-bis- O-(1-methylethylene)-β-D-fructopyranose: 0.10%.
Embodiment 2
[0045] Example 2 2,3: Preparation of 4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate crystal form I
[0046] 2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate (state is colorless oil, solvent residue is 3.50%) 20.0g was dissolved in 160mL n-hexane, controlled temperature 0-5°C, cooled and crystallized for 4-5h, filtered with suction, dried in vacuum at 45°C for 1h, weighed to obtain 2,3:4,5-bis-O- (1-methylethylidene)-β-D-fructopyranose chlorosulfonate 17.8g, crystal form I, yield 92.1%, HPLC purity: 99.71%; 2,3:4,5-bis- O-(1-methylethylene)-β-D-fructopyranose: 0.12%.
Embodiment 3
[0047] Example 3 2,3: Preparation of 4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate crystal form I
[0048] 2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate (state is colorless oil, solvent residue is 3.50%) 20.0g was dissolved in 60mL diethyl ether, the temperature was controlled at 0-5°C, the temperature was lowered and crystallized for 4-5h, suction filtered, vacuum-dried at 45°C for 1h, and weighed to obtain 2,3:4,5-bis-O-( 1-methylethylidene)-β-D-fructopyranose chlorosulfonate 18.1g, crystal form I, yield 93.7%, HPLC purity: 99.61%; 2,3:4,5-bis-O -(1-methylethylene)-β-D-fructopyranose: 0.15%.
[0049] Table 1 Preparation of 2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate crystal form I effect comparison
[0050]
[0051]
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Abstract
The invention belongs to the technical field of medicines and in particular relates to a crystal form I of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate. The invention further relates to a preparation method and application of the crystal form in preparing topiramate. The crystal form I of the 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate, whichis provided by the invention, is high in purity, the content of a single impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose is less than 0.15%, the yield of topiramate prepared from thecrystal form I of 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose chlorosulfonate is 92% or greater, the HPLC (high performance liquid chromatography) purity is greater than 99.85%, the content of the single impurity 2,3:4,5-di-O-(1-methylethylidene)-beta-D-pyranofructose is less than 0.06%, and the content of a single impurity of a condensation compound is smaller than 0.08%.
Description
technical field [0001] The invention belongs to the field of chemical synthesis, in particular to the crystal form of 2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate. Background technique [0002] Topiramate is a sulfamate-substituted monosaccharideantiepileptic drug, which blocks the action potential repeatedly excited by the continuous depolarization of neurons in a time-dependent manner, and increases the activation of γ-aminobutyric acid (GABA). Increase the frequency of the body, strengthen the ability of GABA to induce chlorideion influx, and enhance the effect of inhibitory neurotransmitters. It is clinically used for the adjunctive treatment of partial epileptic seizures in children and the preventive treatment of migraine in adults. [0003] Topiramate was originally developed by Johnson & Johnson in the United States. It was first launched in the UK in 1995 and was approved by the US FDA in 1996. It is currently on the market in the United St...
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