- METHOD FOR PRODUCING 5-BROMO-2-ALKYLBENZOIC ACID
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PROBLEM TO BE SOLVED: To provide a method for producing 5-bromo-2-alkylbenzoic acid, which is useful as a synthetic intermediate of a drug substance such as an antidiabetic, in an industrially inexpensive and efficient manner. SOLUTION: The present disclosure provides a method for producing 5-bromo-2-alkylbenzoic acid by bringing 2-alkylbenzoic acid and bromine into contact with each other, in the presence of sulfuric acid. Particularly if 2-alkylbenzoic acid is 2-methylbenzoic acid, the inventive production method enables efficient production of 5-bromo-2-methylbenzoic acid to be a raw material for producing canagliflozin, one of antidiabetics. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0068; 0072-0074
(2021/09/03)
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- Synthesis method of canagliflozin intermediate
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The invention discloses a synthesis method of a canagliflozin intermediate. The method comprises the following steps: 4-bromotoluene and ethyl 5-bromolevulinate which are used as initial raw materialsundergo a Friedel-Crafts reaction under the catalysis of aluminum trichloride to obtain a compound 3; the compound 3 undergo a hydrolysis reaction under an alkaline condition to obtain a compound 4;the compound 4 reacts with dimethyl sulfoxide to produce acyl chloride, and then the acyl chloride and fluorobenzene undergo the Friedel-Crafts acylation reaction under the catalysis of aluminum trichloride to obtain a compound 5; and the compound 5 is cyclized at 150-200 DEG C by adopting thiophosphoryl trisulfide to obtain 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene. The synthesis method has the advantages of simple raw materials, simple operation steps, high purity and high yield of the product, and suitableness for industrial production.
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Paragraph 0037-0039
(2020/02/14)
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- Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene
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The invention belongs to the field of chemistry, and particularly relates to a novel synthesis method of a key intermediate 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene for preparinga medicine canagliflozin for treating type 2 diabetes mellitus. Cheap and easily available 2-methylthiophene used as an initial raw material undergoes five steps of halogenation, p-nitrotoluene alkylation, coupling, nitro reduction and a Sandmeyer reaction to prepare the product. The method has the characteristics of simplicity in operation, high reaction selectivity, few byproducts and high product quality.
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Paragraph 0037; 0046-0049; 0058-0059; 0068
(2020/04/17)
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- Preparation method of intermediate
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The invention discloses a preparation method for a Canagliflozin intermediate. The preparation method comprises the steps that substituted bromobenzene as a starting material is reacted with bisdiboron to prepare a boride, and then the Canagliflozin intermediate is prepared through a Suzuki coupling reaction, a Friedel-Crafts acylation reaction and a reduction reaction. The preparation method hasthe advantages that the intermediate product CZ-2 is prepared through the Suzuki coupling reaction, the conditions are mild and easy to operate and control, and the product yield and the product purity are high; aryl methyl is introduced through the Friedel-Crafts acylation reaction, a main chain is built, by means of the route, the yield is high, technological conditions are easy to control, andthe preparation method is suitable for large-scale industrial production.
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- Preparation method for canagliflozin intermediate
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The invention relates to a preparation method for a canagliflozin intermediate. The canagliflozin key intermediate, namely 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene is obtained through a three-step reaction of coupling, N-halogenated succinimide halogenation and p-bromotoluene alkylation by using easily-available 2-bromo-5-methylthiophene as a starting raw material. The preparation method provided by the invention has the characteristics of easily-available raw materials, short production steps, simple operation, stable process, high yield and good product quality.
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- Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene
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The invention relates to the technical field of medicine synthesis, and particularly discloses a preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene. The preparation method comprises the following steps: by taking a nitrogen-doped carbon material loaded with transition metal as a catalyst, introducing hydrogen, and performing hydrogenation reduction on 2-methyl-5-bromophenyl-2-(4-fluorophenyl)thiophene ketone at 50-180 DEG C, thereby obtaining 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene. The preparation method provided by the invention has the characteristics of the high product yield, high purity, the low cost, no toxicity and no pollution, and overcomes the defects in the traditional preparation process of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene.
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Paragraph 0033; 0039-0040; 0042; 0046-0048; 0052-0054; 0058
(2020/06/17)
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- Preparation method of canagliflozin
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The invention relates to a synthesis method of canagliflozin. According to the synthesis method, 4-fluorophenylboronic acid is taken as an initial raw material to be coupled with 5-bromo-thiophene-2-formaldehyde to synthesize 5-(4-fluorophenyl)thiophene-2-formaldehyde, the 5-(4-fluorophenyl)thiophene-2-formaldehyde undergoes reduction and chlorination and then undergoes Friedel-Crafts alkylation reaction with 4-bromotoluene to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, and the 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene undergoes condensation, etherificationand methoxyl removal with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain the hypoglycemic drug canagliflozin. The preparation method has the following advantages: compared with the conventional preparation methods, the synthesis process takes the 4-fluorobenzeneboronic acid as an initial raw material, so that the raw material is cheap and easy to get, the process is easy to realize industrialization, the synthesis route is short and the operation is easy; in the synthesis process, bromine is not used or butyl lithium does not need to be used twice, so that the risk of the process can be reduced; in addition, the preparation method is capable of improving the yield of canagliflozin products to 70% or more.
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Paragraph 0017
(2019/02/27)
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- 5 - (5 - Bromo - 2 - methyl phenyl) - 1 - (4 - fluorophenyl) pentane - 1, 4 - dione and its preparation method and application
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The invention discloses a compound 5-(5-bromo-2methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione represented by the formula I, a preparation method and applications thereof. The compound represented by the formula I can be taken as the raw material to carry out reactions in the presence of a vulcanizer so as to obtain an intermediate compound represented by the formula X of a drug Canagliflozin for treating diabetes II. The raw materials and reagents required in the preparation method are relatively cheap, and the preparation method has the advantages of low cost, convenient and safe operation, high yield, little environmental pollution, good economic profits, and suitability for industrial production.
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- Synthesis method of canagliflozin intermediate
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The invention relates to a synthesis method of a canagliflozin intermediate. Concretely, succinyl oxide and fluorobenzene are used as starting raw materials to be prepared into the canagliflozin crucial intermediate of 2-(4-fluorophenyl)-5-[(5-halogen-2-methyl phenyl)methyl]thiophene through the steps of Friedel-Crafts acylation ring opening, thiophene ring preparation, Friedel-Crafts acylation coupling, reduction and the like. The cheap succinyl oxide is used for preparing the thiophene ring, so that the Suzuki coupling reaction and Grignard reaction are avoided; the use of heavy metal reagents of palladium and the like is avoided; the production process is simplified; the product yield and the quality are improved; the environment pollution is reduced; the production cost is reduced.
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- Preparation method of 2-[(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene
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The invention provides a preparation method of 2-[(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene. The preparation method comprises the following steps: reacting 4-bromotoluene used as an initial raw material with paraformaldehyde and concentrated hydrochloric acid under the catalysis of zinc chloride to prepare 2-methyl-5-bromobenzyl chloride, dissolving the 2-methyl-5-bromobenzyl chloride and 2-p-fluorophenylthiophene in ethyl acetate, and carrying out a reaction at 80 DEG C under the catalysis of zinc chloride to synthesize the 2-[(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene. The preparation method has the advantages of low price and easy obtaining of raw materials, diversified selection of the raw materials, easiness in realization, easiness in control, high purity of the final product, no dangerous processes, simple device, novel synthesis route, short synthesis route, increase of the productivity, and reduction of the production processing cost.
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Paragraph 0006; 0013; 0015
(2017/08/31)
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- METHOD FOR PREPARING CANAGLIFLOZIN INTERMEDIATE 2-(2-METHYL-5-BROMOBENZYL)-5-(4-FLUOROPHENYL)THIOPHENE
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Provide in the present invention is a method for preparing canagliflozin intermediate 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene. The method comprises a compound, shown as formula (II), of (5-bromo-2-methylphenyl)[5-(p-fluorophenyl)thiophene-2-yl]ketone being reduced under the action of a directly used borane solution or borane locally produced by reacting alkali metal borohydride with a Lewis acid in a suitable solvent and at a suitable temperature, so as to obtain the compound of formula (I) of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorobenzene)thiophene. The preparation method avoids the use of expensive reductive agents and guarantees the complete conversion of raw materials, wherein the post-treatment is simple, the purity of product obtained is high, the reaction yield is high, in the preparation method is simple and convenient, and can easily be used in industry.
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Paragraph 0013-0024
(2017/04/11)
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- 2 - (4-fluoro phenyl) - 5 - [(5-bromo-2-methyl-phenyl) methyl] thiophene preparation method
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The invention discloses a preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl) methyl] thiophene. The 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl) methyl] thiophene is prepared by performing twice Suzuki cross-coupling reactions between 5-nitro-2-methyl-benzoyl chloride and 5-bromothiophene-2-boronic acid first and then between a reaction product and 4-fluorophenylboronic acid, a reducing reaction and a Sandmeyer reaction. The preparation method belongs to the field of preparation of medicine intermediates. The preparation method can be used for preparing a medicine Invokana for treating type-II diabetes. The preparation method has the characteristics of simple operation, good process stability, high yield, few solid, liquid and gas wastes, low production cost and good product quality.
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Paragraph 0041; 0042
(2016/12/01)
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- PROCESS FOR THE PURIFICATION OF CANAGLIFLOZIN
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The present invention provides a process for the preparation of (1S)-2,3,4,6-tetra- O-acetyl-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D- glucitol of Formula III. The invention also provides a process for the purification of canagliflozin using (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-5 thienyl]methyl]-4-methylphenyl]-D-glucitol of Formula III.
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- Synthesis of 2-arylmethyl-5-aryl-thiophene
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The present invention provides a new synthetic process for the production of 2-arylmethyl-5-aryl-thiophene, an intermediate in the synthesis of C-aryl glycosides.
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- FAMILY OF ARYL, HETEROARYL, O-ARYL AND O-HETEROARYL CARBASUGARS
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The present invention relates to a compound of the following formula (I): as well as its process of preparation, pharmaceutical and cosmetics composition comprising it and use thereof, notably as an inhibitor of the sodium-dependent glucose co-transporter, such as SGLTl, SGLT2 and SGLT3, in particular in the treatment or prevention of diabetes, and more particularly type-II diabetes, diabetes-related complications, such as arthritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for its use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti- inflammatory drug, or for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin.
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- Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus (1)
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We discovered that C-glucosides 4 bearing a heteroaromatic ring formed metabolically more stable inhibitors for sodium-dependent glucose cotransporter 2 (SGLT2) than the O-glucoside, 2 (T-1095). A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
- Nomura, Sumihiro,Sakamaki, Shigeki,Hongu, Mitsuya,Kawanishi, Eiji,Koga, Yuichi,Sakamoto, Toshiaki,Yamamoto, Yasuo,Ueta, Kiichiro,Kimata, Hirotaka,Nakayama, Keiko,Tsuda-Tsukimoto, Minoru
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experimental part
p. 6355 - 6360
(2010/11/03)
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- PROCESS FOR THE PREPARATION OF COMPOUNDS USEFUL AS INHIBITORS OF SGLT
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The present invention is directed to a novel process for the preparation of compounds having inhibitory activity against sodium-dependent glucose transporter (SGLT) being present in the intestine or kidney.
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Page/Page column 76-77
(2009/04/25)
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