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A technology of empagliflozin and synthesis process, applied in the field of medicinal chemistry, can solve the problems of high cost and expensive raw materials, and achieve the effects of less impurities, improved purity and easy availability
Inactive Publication Date: 2018-02-02
IANGSU COLLEGE OF ENG & TECH
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[0011] When this route carries out Mg/I exchange, the reaction temperature is better controlled, the reaction conv...
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[0045] (1) Preparation of p-bromoacetanilide (I): Dissolve p-bromoacetaniline in water, add dropwise methanol solution of acetic anhydride under ice bath, after the dropwise addition, react at room temperature for 3-5h to prepare p-bromoacetanilide ( I); Concrete reaction is as follows:
[0046]
[0047] (2) Preparation of p-fluorobenzyl bromide (II): Dissolve 4-fluorotoluene and NBS in a solvent, and prepare p-fluorobenzyl bromide (II) in the presence of an initiator; among them, the solvent can be carbon tetrachloride or chloroform Any one of them, preferred toxicity is weaker chloroform as solvent; Initiator can select any one in BPO or AIBN, preferred toxicity is weaker BPO; Concrete reaction is as follows:
[0048]
[0049] (3) Preparation of 4-bromo-2-(4-fluorobenzyl)acetanilide (III): Dissolve p-fluorobenzyl bromide and p-bromoacetanilide in a solvent, catalyzed by Lewis acid, and synthesize 4 -Bromo-2-(4-fluorobenzyl)acetanilide (III); wherein, the solvent can b...
Embodiment 1
[0062] The preparation of embodiment 1 p-bromoacetanilide (I)
[0063] Take 171kg of p-bromoaniline, dissolve it in 300kg of water, stir in ice bath for 30min, add dropwise the methanol solution of acetic anhydride (102kg of acetic anhydride + methanol 200kg), drop it in 30min, after the dropwise addition, stir in ice bath for 1h, then raise the temperature to Continue to react at room temperature for 2 h. After the reaction, filter, wash the filter cake until neutral, and dry to obtain 210 kg of light yellow solid, with a yield of 99%.
Embodiment 2
[0064] Embodiment 2 Preparation of p-fluorobenzyl bromide (II)
[0065] Take 110kg of 4-fluorotoluene, dissolve it in 500kg of chloroform, add 180kg of NBS, add 12kg of BPO, heat up to 70°C for reflux reaction, and react for 6h. After the reaction, cool to room temperature, filter, and recover chloroform from the filtrate under reduced pressure, and distill the residue under reduced pressure 177kg of light yellow liquid was obtained, with a yield of 95%.
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Abstract
The invention relates to a synthesis process for empagliflozin. The synthesis process for empagliflozin comprises the following steps: taking 4-fluorotoluene as a starting material; carrying out radical bromo reaction, Friedel-Crafts alkylation reaction, deprotection, diazotization chlorination and alkylation reaction to obtain an intermediate which is (S)-3-(4-(5-bromo-2-chlorobenzyl) phenoxyl) tetrahydrofuran; and then carrying out condensation, etherification and methoxyl removal on the intermediate and 2,3,4,6-quadri-O-trimethylsilyl-D-glucolactone to obtain the empagliflozin as a hypoglycemic drug. The synthesis process for empagliflozin has the advantages that compared with an existing synthesis process, the synthesis process for the empagliflozin takes the 4-fluorotoluene as the starting material, raw materials are cheap and easy to obtain, industrialization is easy to implement in the process, the synthesis route is short, and the process is easy to operate; in a preparation process, various temperature conditions are easy to control, reaction conversion rate is high, and the total yield can be 70% or above; and moreover, by the synthesis process, the product cannot be isomerized easily, impurities are fewer, the purity of the product can be improved, and the purity can be 99% or above.
Description
technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to an empagliflozin (2S,3R,4R,5S,6R)-2-[3-[4-[(3S)-tetrahydrofuran]-3-hydroxyphenyl] The synthesis process of methyl]-4-chlorophenyl-6-hydroxymethyloxyhexane-3,4,5-triol. Background technique [0002] Empagliflozin, chemical name: (2S,3R,4R,5S,6R)-2-[3-[4-[(3S)-tetrahydrofuran]-3-hydroxyphenyl]methyl]-4 -Chlorophenyl-6-hydroxymethyloxyhexane-3,4,5-triol, a type 2 sodium glucose cotransporter inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly and Company. SGLT-2 inhibitors are a new type of hypoglycemic drugs, mainly by inhibiting the expression of SGLT-2 in the kidney, reducing the reabsorption of glucose by the kidney, increasing the excretion of glucose in the urine, thereby reducing the plasma glucose level, and its hypoglycemic effect is not good. depends on β Cellular function and insulin resistance. This product was first approved for marketing by the Euro...
Claims
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