CN1693308A - Process for preparing dazoline phospho acid - Google Patents
Process for preparing dazoline phospho acid Download PDFInfo
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- CN1693308A CN1693308A CN 200510038871 CN200510038871A CN1693308A CN 1693308 A CN1693308 A CN 1693308A CN 200510038871 CN200510038871 CN 200510038871 CN 200510038871 A CN200510038871 A CN 200510038871A CN 1693308 A CN1693308 A CN 1693308A
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Abstract
A process for preparing Zuolailingsuan from imidazole includes such steps as reaction between imidazole and alpha-haloacetate or alpha-haloacetonitrile in inertial solvent under catalysis of alkali, hydrolyzing in phosphoric acid solution, reacting on phosphorus trichloride (or trioxychloride), acidic hydrolyzing, and recrystallizing in distilled water.
Description
Technical field
The present invention relates to a kind of is the preparation method of starting raw material one-step synthesis Zoledronic acid with the imidazoles.
Background technology
Zoledronic acid, chemistry [1-hydroxyl-2-(1-imidazolyl) ethylidene] bisphosphate list hydrate by name, it is the bis-phosphonic acids treatment hypercalcemia medicine of the different ring-like third generation, this medicine can reduce cancer patient bone and soft tissue metastasis rate, can be used for assisting therapy metastatic carcinoma of bone disease patient, to alleviate the danger of hypercalcemia, ostalgia and fracture, also can be used for delaying the generation that bone shifts, its mechanism of action is to suppress bone resorption and the release or the anticancer that reduce the ground substance of bone somatomedin adheres to ground substance of bone.Clinical trial shows that this product is to act on the strongest bisphosphonate compound so far.Zoledronic acid was got permission listing in Canada first with trade(brand)name Zometa in 2000.
About synthesizing of Zoledronic acid, U.S. Pat 4939130 and GerardR.Kieczykowski, Ronaid B.Jobson.J.Org.Chem.1995,60,8310-8312. disclose its synthetic method, as starting raw material, warp and phosphorus trichloride and phosphoric acid is the synthetic Zoledronate of reaction posthydrolysis in the presence of a large amount of methylsulfonic acids or chlorobenzene with imidazole acetic acid hydrochloride in system.Xiao Tao, Zhang Xiaoqing etc. synthesizing of novel bone resorption inhibitor Zoledronic acid. synthetic chemistry, 2002,10 (5) 428-429.Reported with the imidazoles to be starting raw material, through in the presence of sodium hydroxide and phase-transfer catalyst, becoming 1-imidazoleacetic acid ethyl ester through capable N-alkylated reaction with ethyl bromoacetate, again through the synthetic 1-imidazole acetic acid hydrochloride of hydrolysis, salify, last in chlorobenzene with phosphorus trichloride and phosphatase reaction posthydrolysis and the method for Zoledronic acid.
In the aforesaid method, all having adopted human body and the great chlorobenzene of environmental hazard is solvent, and reported method steps such as Xiao Tao, Zhang Xiaoqing are more, operation is loaded down with trivial details, yield is lower.Thereby above-mentioned literature method haves much room for improvement.
Summary of the invention
For addressing the above problem, it is the preparation method of starting raw material one-step synthesis Zoledronic acid with the imidazoles that the present invention takes a kind of.
The preparation method of a kind of Zoledronic acid of the present invention is to be starting raw material one-step synthesis Zoledronic acid with the imidazoles, employing is in the inert solvent that does not contain reactive hydrogen, base catalysis following and alpha-halogen acetic ester or alpha-halogen acetonitrile reaction, hydrolysis in 85% phosphoric acid, again with phosphorus trichloride or phosphorus oxychloride reaction, hydrolysis under the last acidic conditions, recrystallization in the distilled water and Zoledronic acid.
The inert solvent that does not wherein contain reactive hydrogen is 1,4-dioxane, tetrahydrofuran (THF), n-butyl ether, methyl-sulphoxide etc., and especially with 1, the 4-dioxane is advisable.
Wherein the alpha-halogen acetic ester is methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, tert.-butyl acetate, jasmal of alpha-chloro or bromo etc.Especially with 3 pure formed acetic ester the bests below the carbon; The alpha-halogen acetonitrile is chloromethyl cyanide or bromoacetonitrile.
Alkaline catalysts is sodium Metal 99.5, sodium hydride, sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood, the active basic metal of saleratus and salt thereof.
The temperature of hydrolysis is a room temperature to 100 ℃ in 85% phosphoric acid, is optimum temps with 50-60 ℃ especially, and the reaction times is 3-4 hour.
The present invention is at phosphorus trichloride or phosphorus oxychloride reaction, and last acidic hydrolysis condition is the hydrochloric acid of 1.5mol/L-12mol/L, and the best is the hydrochloric acid of the hydrochloric acid of 4mol/L-8mol/L, especially 6mol/L.
The present invention on the basis of existing technology, simplified operation, avoided use human body and the great chlorobenzene of environmental hazard, reaction process steadily, have continuity and adopt one-step synthesis, have simple to operate, safe, good product quality, advantage such as cost is low.
Embodiment
Embodiment one: with 1,4-dioxane 500mL, 60% sodium hydride 40g add in the reaction flask, stir the 150mL1 that drips the 68g imidazoles down, 4-dioxane solution in the ice-water bath.Drip and finish, stirring at room 30 minutes drips ethyl chloroacetate 122.5g, drips and finishes, stirring at room reaction 3 hours.Slowly the phosphoric acid 200mL of adding 85% is warming up to 50 ℃-60 ℃ reactions 4 hours, drips phosphorus trichloride 200mL under this temperature, and the control rate of addition dripped off in about 1 hour.Be warming up to back flow reaction 4 hours, and be cooled to 50 ℃-60 ℃ hydrochloric acid 500mL that add 6mol/L, be warming up to back flow reaction 3 hours.Cooling, stirring is crystallization down, and filter to collect and separate out solid, the small amount of ethanol washing, recrystallization in the distilled water gets Zoledronic acid 93g, yield: 32.0%mp:239 ℃ (decomposition).
Ultimate analysis (C
5H
10N
2O
7P
2H
2O): theoretical value (%) is C20.70, H4.17, N9.66, P21.53; Experimental value (%) is C20.90, H4.27, N9.49, P21.49.
ESI-MS (m/z): 273.0[M+1]
+Be the molecular ion peak that anhydrates.
1HNMR (solvent: D
2O/NaOH; Interior mark: TMS): δ 4.43 (t, 2H), δ 6.84 (s, 1H), δ 7.21 (s, 1H), δ 7.70 (s, 1H).
Embodiment two: with 68g imidazoles, 120g salt of wormwood, 1,4-dioxane 700mL, 76g chloromethyl cyanide add in the reaction flask, stirring at room reaction 24 hours, remove by filter insolubles, add 200mL85% phosphoric acid in the filtrate, stir and be warming up to 50 ℃-60 ℃ reactions 4 hours, under this temperature, drip phosphorus trichloride 200mL, the control rate of addition dripped off in about 1 hour.Be warming up to back flow reaction 4 hours, and be cooled to 50 ℃-60 ℃ hydrochloric acid 500mL that add 6mol/L, be warming up to back flow reaction 3 hours.Cooling, stirring is crystallization down, and filter to collect and separate out solid, the small amount of ethanol washing, recrystallization in the distilled water gets Zoledronic acid 87g, yield: 29.9%mp:239 ℃ (decomposition).
Ultimate analysis (C
5H
10N
2O
7P
2H
2O): theoretical value (%) is C20.70, H4.17, N9.66, P21.53; Experimental value (%) is C20.80, H4.20, N9.50, P21.56.
ESI-MS (m/z): 273.0[M+1]
+Be the molecular ion peak that anhydrates.
1HNMR (solvent: D
2O/NaOH; Interior mark: TMS): δ 4.42 (t, 2H), δ 6.78 (s, 1H), δ 7.26 (s, 1H), δ 7.77 (s, 1H).
Claims (9)
1, process for preparing dazoline phospho acid is a starting raw material one-step synthesis Zoledronic acid with the imidazoles; Employing is in the inert solvent that does not contain reactive hydrogen, base catalysis following and alpha-halogen acetic ester or alpha-halogen acetonitrile reaction, hydrolysis in 85% phosphoric acid is again with phosphorus trichloride or phosphorus oxychloride reaction, hydrolysis under the last acidic conditions, recrystallization in the distilled water and Zoledronic acid.
2, according to process for preparing dazoline phospho acid described in the claim 1, the inert solvent that it is characterized in that not containing reactive hydrogen is 1,4-dioxane, tetrahydrofuran (THF), n-butyl ether, methyl-sulphoxide.
3,, it is characterized in that alkaline catalysts is sodium Metal 99.5, sodium hydride, sodium hydroxide, yellow soda ash, sodium bicarbonate, potassium hydroxide, salt of wormwood, the active basic metal of saleratus and salt thereof according to process for preparing dazoline phospho acid described in the claim 1.
4, according to the described process for preparing dazoline phospho acid of claim 1, the temperature that it is characterized in that hydrolysis in 85% phosphoric acid is a room temperature to 100 ℃, and the reaction times is 3-4 hour.
5, according to the described process for preparing dazoline phospho acid of claim 4, the temperature that it is characterized in that hydrolysis in 85% phosphoric acid is 50-60 ℃.
6,, it is characterized in that the alpha-halogen acetic ester is methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, tert.-butyl acetate, the jasmal of alpha-chloro or bromo according to the described process for preparing dazoline phospho acid of claim 1.
7,, it is characterized in that the alpha-halogen acetonitrile is chloromethyl cyanide or bromoacetonitrile according to the described process for preparing dazoline phospho acid of claim 1.
8,, it is characterized in that the acidic hydrolysis condition is the hydrochloric acid of 1.5mol/L-12mol/L according to the described process for preparing dazoline phospho acid of claim 1.
9, described according to Claim 8 process for preparing dazoline phospho acid is characterized in that the acidic hydrolysis condition is the hydrochloric acid of 4mol/L-8mol/L.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510038871 CN1693308A (en) | 2005-04-15 | 2005-04-15 | Process for preparing dazoline phospho acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510038871 CN1693308A (en) | 2005-04-15 | 2005-04-15 | Process for preparing dazoline phospho acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007125521A3 (en) * | 2006-05-02 | 2008-01-10 | Ranbaxy Lab Ltd | Polymorphic form of zoledronic acid and processes for their preparation |
| CN102070668A (en) * | 2010-12-23 | 2011-05-25 | 蚌埠丰原医药科技发展有限公司 | Method for preparing zoledronic acid and sodium salt thereof by utilizing phase transfer catalyst |
| US8882740B2 (en) | 2009-12-23 | 2014-11-11 | Stryker Trauma Gmbh | Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone |
-
2005
- 2005-04-15 CN CN 200510038871 patent/CN1693308A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007125521A3 (en) * | 2006-05-02 | 2008-01-10 | Ranbaxy Lab Ltd | Polymorphic form of zoledronic acid and processes for their preparation |
| US8882740B2 (en) | 2009-12-23 | 2014-11-11 | Stryker Trauma Gmbh | Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone |
| CN102070668A (en) * | 2010-12-23 | 2011-05-25 | 蚌埠丰原医药科技发展有限公司 | Method for preparing zoledronic acid and sodium salt thereof by utilizing phase transfer catalyst |
| CN102070668B (en) * | 2010-12-23 | 2013-07-24 | 蚌埠丰原医药科技发展有限公司 | Method for preparing zoledronic acid and sodium salt thereof by utilizing phase transfer catalyst |
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Open date: 20051109 |