102 results about "Empagliflozin" patented technology

The present invention relates to methods for preventing or treating acute or chronic heart failure and for reducing the risk of cardiovascular death, hospitalization for heart failure and other conditions in patients with preserved or reduced ejection fraction by administering empagliflozin to the patient.

The invention provides a preparation method of an intermediate compound 7 of an SGLT-2 diabetes inhibitor dapagliflozin and an intermediate compound 8 of a SGLT-2 diabetes inhibitor empagliflozin, and new synthesis method of two final products. The preparation method comprises the following steps: carrying out carbonyl group reduction and hydroxyl group protection on a (5-halo-2-chlorophenyl)(4-ethoxyphenyl)ketone compound 1 used as an initial raw material to obtain a Grignard addition reaction key compound 4, and carrying out Grignard addition and acetylation to obtain the compound 7 and the compound 8. The dapagliflozin and the empagliflozin are respectively prepared from the compound 8. The methods have the advantages of simplicity in operation, high yield, high purity of the obtained products, and suitableness for amplified production.

The invention relates to a B crystal form of empagliflozin and a preparation method of the B crystal form. The prepared B crystal form of empagliflozin has diffraction peaks when the diffraction angle 2 theta is equal to 8.916 degrees, 10.011 degrees, 11.239 degrees, 17.567 degrees, 18.775 degrees, 19.308 degrees, 25.353 degrees and 26.000 degrees according to characterization of a powder x-ray diffraction pattern, and the powder x-ray diffraction pattern is obtained through CuK alpha rays. The preparation technology of the crystal form is simple, the stability is better, and the medicinal requirements are met.

The invention provides a preparation method of an Empagliflozin and mannitol composition. The preparation method comprises the following steps: mixing Empagliflozin and mannitol, performing hot-melting granulation, and mixing with other pharmaceutically acceptable carriers to obtain an oral solid preparation. The Empagliflozin and mannitol composition prepared by using the method is stable and controllable in quality and fast to dissolve.

The invention provides a preparation method of an empagliflozin intermediate. The preparation method comprises the following steps: 1), taking 4-fluorotoluene and (R)-3-hydroxytetrahydrofuran as raw materials, a polar solvent as a reaction solvent and inorganic alkali as a catalyst, performing a reaction to obtain (S)-3-p-cresyl tetrahydrofuran; 2), with N-chlorosuccinimide and the product obtained in the step 1) as raw materials, a non-polar solvent as a reaction solvent and dibenzoyl peroxide or azobisisobutyronitrile as an initiator, performing a reaction to obtain (S)-3- p-chlorophenol tetrahydrofuran; 3) dissolving 4-bromaniline and the product obtained in the step 2) into ethyl acetate, adding a catalyst Lewis acid, performing a reaction to obtain (S)-3-(4-(5-bromo-2-aminobenzyl)phenoxy) tetrahydrofuran; 4), performing a diazotization reaction on the product obtained in the step 3), and then reacting with cuprous chloride to synthesize (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahydrofuran. The preparation method has the advantages that the cost is low, the finished product is high in purity and the synthesis route is short.

The invention discloses a synthesis method of an Empagliflozin intermediate. The synthesis method uses 4-hydroxybenzyl chloride as a starting material to sequentially react with methanesulfonyl chloride and (S)-3-hydroxytetrahydrofuran to obtain compound III, then react with 4-iodoaniline to obtain compound IV, and finally react with cuprous chloride after diazotization to obtain (S)-3-(4-(5-iodine-2-chlorobenzyl)phenoxy) tetrahydrofuran. The raw materials used in the synthesis method are simple and easy to obtain, the operation steps are simple, the post-treatment is simple, the product yieldis high, and the method is suitable for industrial production.

The invention discloses an empagliflozin intermediate preparation method, which comprises: carrying out substitution by using p-methoxybenzyl chloride and p-iodoaniline as starting raw materials to obtain a compound IV, performing diazotization and a Sandmeyer reaction to obtain a compound III, further performing demethylation under the action of boron tribromide to obtain a compound II, and finally performing condensation with (S)-3-p-toluenesulfonyloxy tetrahydrofuran to obtain the target compound I, wherein the product purity is greater than or equal to 99.0%. According to the invention, the preparation method has advantages of simple and easily available raw materials, low cost, simple operation steps, simple post-treatment and high product yield, and is suitable for industrial production.

The invention relates to a preparation method of empagliflozin. The preparation method of empagliflozin comprises the following steps: taking 2-chlorobenzaldehyde as a starting material; carrying outbromination reaction, reduction reaction and halogenating reaction on the starting material, and carrying out Friedel-Crafts alkylation reaction on the starting material and (S)-3-phenoxyl tetrahydrofuran 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 preparation method of the empagliflozin has the advantages that compared with an existing synthesisprocess, the preparation method of the empagliflozin takes the 2-chlorobenzaldehyde as the starting material, raw materials are cheap and easy to obtain, industrialization is easy to implement in theprocess, the synthesis route is short, and the method is easy to operate; in a preparation process, various temperature conditions are easy to control, reaction conversion rate is high, and the totalyield can be 75% or above; and moreover, by the preparation method, 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.

The invention provides a synthetic method of empagliflozin. The synthetic method comprises the following steps of: by using 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranose acid-1,5-lactone and p-chloroiodobenzene as raw materials, performing a reaction so as to obtain an intermediate as shown in a formula II; performing reduction to eliminate a hydroxyl on anomeric carbon of the intermediate as shown in the formula II, so as to obtain an intermediate as shown in a formula III; by using (S)-3-phenoxy tetrahydrofuran, the intermediate as shown in the formula III, and paraform as raw materials, performing a reaction so as to obtain an intermediate as shown in a formula IV; and removing benzyl of the intermediate as shown in the formula IV, so as to obtain the empagliflozin. According to the synthetic method disclosed by the invention, firstly 1-p-chlorophenyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose is prepared, then the intermediate of the 1-p-chlorophenyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose, the (S)-3-phenoxy tetrahydrofuran and the paraform are used as the raw materials, the empagliflozin protected by intermediate benzyl is prepared, and finally a benzyl protecting group is removed, so that the empagliflozin is obtained. The synthetic route of the synthetic method disclosed by the invention is short, and the total yield is high.

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.

The present invention provides a double-layer tablet containing metformin hydrochloride and empagliflozin, wherein the metformin hydrochloride tablet layer is a sustained-release layer, the empagliflozin tablet layer is a rapid-release layer, and the metformin hydrochloride sustained-release layer is 12-24 h sustained-release layer. The invention further provides a preparation method of the double-layer tablet, and uses of the double-layer tablet in preparation of drugs for treatment and/or improvement of type 2 diabetes. According to the present invention, with the double-layer tablet containing metformin hydrochloride and empagliflozin, the sustained release property of the metformin hydrochloride and the rapid dissolution of the empagliflozin are ensured; the double-layer tablet is taken twice a day, and can provide the important significant for the improvement of the clinical treatment of diabetes patients; and the method has advantages of simple preparation process, low production cost and product stability improving, and can ensure the mixing uniformity of the two active components in the production.

The invention belongs to the technical field of organic synthesis route design and medicine and chemical engineering, particularly relates to a synthesis method of a sodium-glucose cotransporter 2(SGLT2) inhibitor, and more particularly relates to a preparation method of empagliflozin. The empagliflozin is synthesized by taking (3S)-3-[4-[(2-chloro-5-iodophenyl) methyl] phenoxy] tetrahydrofuran and glucono delta-lactone as initial raw materials through a series of substep reactions such as protection, addition, substitution, deprotection and reduction. In the synthesis steps disclosed by the invention, a staged target product does not need to be separated and purified after each step of reaction, and the target product is finally obtained by directly subjecting a high-purity reaction intermediate to subsequent steps. The preparation method is simple in process, simple and convenient to operate and good in industrial prospect.

A method for preparing empagliflozin is provided. The method includes steps of preparing a composite organometallic reagent to promote condensation of (S)-4-halogen-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl) benzene and halogenated glucose, and then removing a protecting group to obtain a product, wherein the organometallic reagent is a product by mixing a Grignard reagent or a lithium chloridepromoted Grignard reagent with a lithium reagent. The organometallic reagent can allow the temperature of a coupling reaction to be increased from -78 DEG C to -10 DEG C, thus improving process reaction conditions, making operation simple and convenient, reducing byproducts and reducing the production cost. The method reduces process steps, avoids reactions at excessively low temperatures, increases the total yield and has an industrial application prospect.

The invention provides a brand-new synthesis process of empagliflozin. According to the process, a boric acid ester is used for halogen removal, and specific reaction conditions are combined, so thatempagliflozin can be prepared with high yield and simplicity and convenience in operation. The synthesis method of empagliflozin has the advantages of mild reaction conditions, high total yield, few side reactions and convenience in operation, thereby being beneficial to industrial production and cost control.

The invention discloses a synthesizing method suitable for industrial empagliflozin production. The synthesizing method includes: subjecting a compound as shown in formula (II) to reduction reaction to obtain a compound as shown in formula (I), and removing the protecting groups of the compound as shown in formula (I) to obtain empagliflozin. The synthesizing method has the advantages that the method is simple in process, only needs one-step reduction reaction and can effectively reduce the repeated use of high-toxicity and high-risk chemicals; in addition, the intermediate purified after derivation protection, effective process control is achieved, and product quality is increased; the method is high in practical application value and suitable for industrial production.

The invention discloses an empagliflozin quick-release pellet preparation and a preparation method, and relates to the field of pharmaceutic preparation techniques and applications. An administration mode of the quick-release pellet preparation is oral administration; a blank pellet core is taken as a carrier; an empagliflozin aqueous solution containing a cosolvent and an adhesive is a drug layering solution; the dosage of empagliflozin is 0.0025-0.3wt% of the dosage of the pellet core; and the oral dosage of the empagliflozin is not higher than 50mcg. The empagliflozin quick-release pellet preparation has the characteristics of high drug layering rate, good content homogeneity, quick release, rapid effect in abirritation, good clinic compliance, high safety and the like. In addition, a blank pellet core fluidized bed drug layering method is suitable for preparing a very-low-specification oral empagliflozin preparation.

The invention provides a preparation method of an empagliflozin microcrystalline cellulose composition. The preparation method comprises the following steps: mixing empagliflozin and microcrystalline cellulose to obtain a mixture of empagliflozin and microcrystalline cellulose; heating the mixture to melt the empagliflozin, and stirring the mixture; and cooling to obtain an empagliflozin microcrystalline cellulose composition. The empagliflozin composition prepared by the method provided by the invention has stable and controllable quality and is quickly dissolved out.