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Preparation method of Minodronic acid hydrate

A technology of minodronic acid and hydrate, applied in the field of medicine and chemical industry, can solve the problems of unsuitability for large-scale industrial production, difficult removal of by-products, low reaction yield and the like, and achieves easy industrial production, low cost and simple post-processing. Effect

Active Publication Date: 2015-05-20
JIANGSU SHENLONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the preparation process of this method, there are many by-products (mainly 2-(imidazo[1,2-a]pyridin-2-yl) ethyl acetate) during the cyclization reaction, the reaction yield is low, and the by-products are not easy to remove, so it is not suitable industrialized production

Method used

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  • Preparation method of Minodronic acid hydrate
  • Preparation method of Minodronic acid hydrate
  • Preparation method of Minodronic acid hydrate

Examples

Experimental program
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Effect test

Embodiment 1

[0068] 1. Preparation of Compound (Ⅵ)

[0069] Add 165.0g (1.0mol) of ethyl 4-chloroacetoacetate to 112ml ethylene glycol (2.0mol) and mix well, add 1.375g (0.5%) of activated carbon-loaded phosphotungstic acid, add 1000ml cyclohexane, and heat to reflux. After reacting for 2 hours, filtering, and distilling off the solvent under reduced pressure, 181.4 g of oil was obtained, with a yield of 86.8%, namely compound (VI) (2-chloromethyl-[1,3]-dioxolan-2-yl) ethyl acetate.

[0070] 2. Preparation of Compound (Ⅳ)

[0071] Dissolve 180.0g of compound (Ⅵ) 2-chloromethyl-[1,3]-dioxolan-2-yl and 120.0g 2-aminopyridine in 1000ml of tetrahydrofuran, stir well, and slowly add 150.0g of triethylamine dropwise , heating to reflux reaction, TLC detection (ethyl acetate: methanol = 70:30) until the spot of compound (Ⅵ) disappears in the reaction solution, add 1000ml of water, then adjust the pH value of the reaction solution to 3.0 with 1N hydrochloric acid, and stir at room temperature fo...

Embodiment 2

[0079] 1. Preparation of Compound (Ⅵ)

[0080] Add 165.0g (1.0mol) of ethyl 4-chloroacetoacetate to 160ml of methanol (2.0mol) and mix well, add 1.465g (0.5%) of activated carbon-loaded phosphotungstic acid, add 1000ml of cyclohexane, heat to reflux, and react 2 hours, filtered, and the solvent was distilled off under reduced pressure to obtain 173.7 g of an oily substance with a yield of 82.3%, namely compound (Ⅵ) 4-chloro-3,3-dimethoxy-butyric acid ethyl ester.

[0081] 2. Preparation of Compound (Ⅳ)

[0082] Dissolve 170.0g of compound (VI) 4-chloro-3,3-dimethoxy-butyric acid ethyl ester and 113.0g of 2-aminopyridine in 1000ml of tetrahydrofuran, stir well, slowly add 142.0g of triethylamine dropwise, and heat to reflux Reaction, TLC detection (ethyl acetate: methanol = 70: 30) until the spot of compound (Ⅵ) disappears in the reaction solution, add 1000ml of water, then adjust the pH value of the reaction solution to 3.0 with 1N hydrochloric acid, stir the reaction at room...

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Abstract

The invention discloses a preparation method of Minodronic acid hydrate, which comprises the following steps: carrying out ketonic group protection on a compound (VII) to obtain a compound (VI), carrying out nucleophilic substitution reaction on the compound (VI) and 2-aminopyridine to obtain a compound (V), carrying out ketonic group deprotection on the compound (V), and carrying out cyclization reaction to obtain a compound (IV); and hydrolyzing the compound (IV) to obtain a compound (III), carrying out diphosphorylation on the compound (III) to obtain a compound (II), and recrystallizing the compound (II) to obtain the Minodronic acid hydrate (I). The synthetic route disclosed by the invention has the advantages of sufficient initial raw material sources, low cost, environment-friendly reagents used in the reaction process, safe industrial production, mild reaction conditions, fewer side reaction, simple after-treatment and no need of special or complex reaction equipment, is convenient to operate, and can easily implement industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a minodronic acid hydrate [1-hydroxyl-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene]1,1-bisphosphoric acid Synthesis method of monohydrate. Background technique [0002] Minodronic Acid Hydrate, chemical name [1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene]1,1-bisphosphoric acid monohydrate , the structural formula is as follows: [0003] [0004] Minodronic acid is a new type of heterocyclic bisphosphonic acid compound, developed by Japan Yamanouchi Pharmaceutical Company, for the treatment of osteoporosis and hypercalcemia caused by osteoporosis and malignant tumors, pharmacological experiments show that it inhibits bone The absorption activity is 2, 10, and 100 times that of disodium incadronate, alendronate, and disodium pamidronate, respectively, and can antagonize myeloma and tumors induced osteolysis. This product has significant benefits in the incidenc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
Inventor 苏晋秦勇金春周超张超王莎莎沈平平
Owner JIANGSU SHENLONG PHARMA
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