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Preparation method for diphosphonic acid compound

A compound and bisphosphonic acid technology, applied in the field of preparation of bisphosphonic acid compounds, can solve the problems of complex reaction conditions, toxic solvents, corrosiveness and the like, and achieve the effects of simple reaction conditions, convenient industrialization and non-corrosiveness

Active Publication Date: 2012-09-26
JILIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 1) The yields of most reactions are low (less than 80%), such as: literature 2, 3, 5-7, 10-12, 14-19, 21, 23, 24, 26, 28-31;
As a result, the reaction cannot be fully stirred, and sometimes even cannot be stirred, such as: Documents 2, 3, 12, 14, 15, 17, 24, 26, 28;
[0011] 3) All the above methods (References 1-32) require the application of two phosphorus-containing reagents, resulting in complex reaction conditions;
[0012] 4) The solvents used in some reactions are toxic (such as chlorobenzene, toluene, fluorobenzene, methanesulfonic acid and p-cresol in literature 3, 5, 12, 13, 14-18, 24, 26, 28, 31, 32 ), corrosive (such as methanesulfonic acid and p-cresol in Documents 13 and 32), or controlled solvents (such as toluene in Documents 5, 16, 18, 31), which are not conducive to safe production;
[0014] 6) Some reaction solvents are expensive, such as: Document 4;
[0018] 1) Most of the methods reported so far have significantly low yields (such as literature 33-35), less than 60%;
[0020] The above shortcomings seriously restrict the further promotion and application of this synthesis strategy in industrial production, and it does not conform to the development trend of green chemistry today.

Method used

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  • Preparation method for diphosphonic acid compound
  • Preparation method for diphosphonic acid compound
  • Preparation method for diphosphonic acid compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042]Take n-hexane (200 mL) and water (1.1 mL), put them in a double-neck flask, -20°C, under stirring, add PCl dropwise 3 (20.0 mmol), stirred for 0.5 h. At -20°C, add 2-(1 H -1-imidazolyl)-acetic acid (20.0 mmol). to be 2-(1 H -1-imidazolyl)-acetic acid is completely dissolved, at -20 ℃, drop into PCl 3 (30.0 mmol), warmed up to 50°C, and stirred for 8 h. Add 0.1mol / L hydrochloric acid (200 mL), and react at 80°C for 8 h. After cooling to room temperature, the organic layer was decanted. After the aqueous layer was concentrated under reduced pressure, it was dripped into 12.6 mL of acetone at -20°C, left to stand for crystallization at -20°C for 1 h, and filtered with suction. The filter cake was dried at 20°C for 5 h to obtain the target compound—zoledronic acid monohydrate (16.2 mmol, yield 81%, purity 99.5% by HPLC normalization method).

Embodiment 2

[0044] Take n-decane (50 mL) and water (3.0 mL), put them in a double-neck flask, 0 ° C, under stirring, add PCl dropwise 3 (50.0 mmol), stirred for 2 h. At 25°C, add 2-(1 H -1-imidazolyl)-acetic acid (20.0 mmol). to be 2-(1 H -1-imidazolyl)-acetic acid is completely dissolved, at 0 ℃, drop into PCl 3 (80.0 mmol), heated to 70°C and stirred for 18 h. Concentrated hydrochloric acid (10 mL) was added and reacted at 95°C for 18 h. After cooling to room temperature, the organic layer was decanted. After the aqueous layer was concentrated under reduced pressure, it was dropped into 60 mL of methanol at 0°C, and allowed to stand for crystallization at -10°C for 8 hours, and then suction filtered. The filter cake was dried at 60°C for 5 h to obtain the target compound—zoledronic acid monohydrate (18.2 mmol, yield 91%, purity 99.8% by HPLC normalization method).

Embodiment 3

[0046] Take n-tetradecane (2.0 L) and water (4.8 mL), put them in a double-neck flask, 50 ° C, under stirring, drop PCl 3 (100.0 mmol), stirred for 24 h. At 100°C, add 2-(1 H -1-imidazolyl)-acetic acid (20.0 mmol). to be 2-(1 H -1-imidazolyl)-acetic acid is completely dissolved, at 80 ℃, drop into PCl 3 (160.0 mmol), stirred at 80°C for 24 h. Add 0.4mol / L hydrochloric acid (0.5 L), and react at 100°C for 24 h. After cooling to room temperature, the organic layer was decanted. After the aqueous layer was concentrated under reduced pressure, it was dropped into 250 mL of n-butanol at 50°C, and left to stand for crystallization at 20°C for 24 h, then filtered with suction. The filter cake was dried at 70°C for 5 h to obtain the target compound—zoledronic acid monohydrate (16.6 mmol, yield 83%, purity 99.7% by HPLC normalization method).

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Abstract

The invention relates to a preparation method for a diphosphonic acid compound, and belongs to preparation methods for compounds. According to the method, a carboxylic acid compound used as a raw material is subjected to diphosphonic acid reaction in an environment-friendly commercially available low-price aliphatic hydrocarbon solvent in the presence of water by using a single phosphorus-containing reagent PCl3; and hydrolysis reaction is performed, and is combined with recrystallization operation. The method has the advantages that the diphosphonic acid compound is high in yield and purity; only the single phosphorus-containing reagent is used, and the diphosphonic acid reaction can be performed in the presence of water; reaction conditions are simple and mild; and the method is easy to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to a preparation method of a compound, in particular to a convenient and efficient preparation method of bisphosphonic acid compounds. Background technique [0002] Bisphosphonic acid compounds are a class of pharmaceutically active substances used in the treatment of bone diseases and calcium metabolism dysfunction, and are suitable for the treatment of diseases such as osteoporosis, Paget's disease and osteolytic metastasis. [0003] The endogenous substance pyrophosphate is a natural bone resorption inhibitor. However, the P-O-P bond it contains can undergo rapid enzymatic hydrolysis in the body, resulting in a short half-life in vivo, so it cannot be used as a therapeutic drug for bone resorption. Bisphosphonic acid compounds (shown in formula I) have P-C-P bonds and can be regarded as synthetic analogs of pyrophosphate. It has a long half-life in the body, enough to affect bone metabolism. Therefore, bisphosphonic acid comp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38C07F9/6506C07F9/6561
Inventor 孙凯贾妍成焕吉宗智慧冯亭亭王小禹李杰
Owner JILIN UNIV
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