CN102875602A - Preparation method of Minodronic acid hydrate - Google Patents

Preparation method of Minodronic acid hydrate Download PDF

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CN102875602A
CN102875602A CN2012104146696A CN201210414669A CN102875602A CN 102875602 A CN102875602 A CN 102875602A CN 2012104146696 A CN2012104146696 A CN 2012104146696A CN 201210414669 A CN201210414669 A CN 201210414669A CN 102875602 A CN102875602 A CN 102875602A
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acid
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ketone group
iii
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CN102875602B (en
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苏晋
秦勇
金春
周超
张超
王莎莎
沈平平
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JIANGSU SHENLONG PHARMACEUTICAL Co.,Ltd.
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Jiangsu Chengchuang Drug R & D Co ltd
JIANGSU SHENLONG PHARMACEUTICAL CO Ltd
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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

A kind of preparation method of minodronic acid hydrate
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of minodronic acid hydrate [1-hydroxyl-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene] 1, the synthetic method of 1-bis phosphoric acid monohydrate.
Background technology
Minodronic acid hydrate (Minodronic Acid Hydrate), chemical name [1-hydroxyl-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene] 1,1-bis phosphoric acid monohydrate, structural formula is as follows:
Minodronic acid is a kind of new type heterocycle bis phosphoric acid compounds, by the development of Japanese Yamanouchi drugmaker, the hypercalcemia that is used for the treatment of osteoporosis and is caused by osteoporosis and malignant tumour, pharmacological evaluation shows that its activity that suppresses bone resorption is respectively ineadronic acid disodium (disodium incadronate), alendronate sodium (alendronate), Pamidronate Disodium (disodium pamidronate) 2,10 and 100 times, and can the antagonism myelomatosis and the osteolysis effect that causes of tumour.This product is having remarkable benefit aspect the spinal fracture incidence, simultaneously very large minimizing is being arranged aspect the stomach side effect, has been defined as the novel drugs of effective osteoporosis, prevention fracture now.The development of this medicine will provide for the clinical disease patient a kind of medicine of safer, effective, aspect undoubtedly, will produce good Social benefit and economic benefit after the listing.
The preparation method of minodronic acid hydrate has report in patent EP0354806, its disclosed preparation method is:
Only have compound (VIII) to prepare the method for minodronic acid hydrate among the disclosed preparation method of EP0354806, source and the method for making of unexposed starting compound (VIII), and its yield is lower.Wherein compound (VIII) is the dihydrochloride of compound (III).
Document " Chinese Journal of Pharmaceuticals " 35(4), the 2004:193-194 Disodium Minodronate is synthetic; J Med.Chem, 1969,12(1): the disclosed syntheti c route of 122-126 is as follows:
This synthesis technique is starting raw material with imidazo [1,2-a] pyridine, obtains compound (III) 2-(imidazo [1,2-a] pyridin-3-yl through Mannich reaction, cyaniding, hydrolysis) acetic acid, bis phosphoric acid obtains compound (II).This method has been used hypertoxic sodium cyanide, operational hazards, and simultaneously side reaction is more, and product is difficult to purifying, and reactions steps is more, operates comparatively loaded down with trivial detailsly, and environmental pollution is larger.
The disclosed synthetic route of patent documentation (CN101531681) is as follows:
This route is as starting raw material take ethy succinyl chloride, become compound (IV) 2-(imidazo [1 with the PA cyclization through reduction, after the bromination, 2-a] pyridin-3-yl) ethyl acetate, after hydrolysis, obtain compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, phosphorylation obtains compound (II) minodronic acid again.This route relates to the very low temperature reaction, and synthetic starting raw material ethy succinyl chloride is expensive, and bromination has been used a large amount of bromines in the reaction process, and is unfriendly to environment, is not suitable for suitability for industrialized production.
The disclosed synthetic route of patent documentation CN102020676 is as follows:
This route is with 2; 2-dimethoxy acetaldehyde and phosphine acyl acetic acid three ethyl are starting raw material; after condensation, become compound (IV) 2-(imidazo [1 with the PA cyclization; 2-a] pyridin-3-yl) ethyl acetate; after hydrolysis, obtain compound (III) 2-(imidazo [1; 2-a] pyridin-3-yl) acetic acid, make again compound (I) minodronic acid hydrate.The starting raw material 2 of this route, the market supply of 2-dimethoxy acetaldehyde is few, and expensive, causes production cost high, is not suitable for suitability for industrialized production.
The disclosed synthetic route of patent documentation (CN101812062) is as follows:
This route is as starting raw material take trans-4-oxo-2-butylene acid esters, become compound (IV) 2-(imidazo [1 with the PA cyclization, 2-a] pyridin-3-yl) ethyl acetate, after hydrolysis, obtain compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.The starting raw material of this route is trans-and 4-oxo-2-butylene acid esters market supply is few, and also expensive, cause production cost high, also be not suitable for suitability for industrialized production.
The disclosed synthetic route of patent documentation CN102250090 is as follows:
This route is to be starting raw material with 3-bromine imidazo [1,2-a] pyridine, with after the diester malonate condensation again hydrolysis obtain compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.Starting raw material 3-bromine imidazo [1,2-a] the basic unavailability in pyridine market of this route needs customization, and needs waterless operation in this reaction process, is not suitable for suitability for industrialized production.
The disclosed synthetic route of patent documentation US5464843 and CN10234448 is as follows:
This route is take α ketoglutaric acid as starting raw material, through obtaining compound (III) 2-(imidazo [1,2-a] pyridin-3-yl behind the hydrolysis decarboxylation again behind over-churning and the bromo with after the PA condensation) acetic acid.Need to pass into saturated hydrogen chloride gas in this route in the esterification, but also need to carry out bromo, unfriendly to environment during production, be not suitable for suitability for industrialized production.
Patent documentation CN 102030752 disclosed synthetic routes are as follows:
This route is with 3-imidazo [1,2-a] pyridylaldehyde and be starting raw material to Methyl benzenesulfonyl methyl isonitrile, under the catalysis of potassium tert.-butoxide, obtain 2-(imidazo [1,2-a] pyridine-3 base) acetonitrile, this technique to product can be used for preparing compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.But not only need the very low temperature reaction during this route reaction, but also need nitrogen filled protection, production operation is extremely inconvenient, is not suitable for suitability for industrialized production.
Patent documentation CN 102093352 disclosed synthetic routes are as follows:
This route is to be starting raw material with imidazo [1,2-a] pyridine and glyoxylic ester or oxoethanoic acid, and reaction obtains 2-(3-imidazo [1,2-a] pyridine), 2-oxyacetic acid, the product that this technique obtains can be used for preparing compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.But need to need the filling with inert gas protection during this route reaction, production operation is inconvenient, and by product is many, and reaction yield is low, is not suitable for suitability for industrialized production.
Patent documentation CN 1020101860 disclosed synthetic routes are as follows:
This route is take GBL as starting raw material, through open loop, oxidation, behind the bromo with the PA cyclization after again hydrolysis obtain compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.But need the very low temperature reaction in this route, production operation is inconvenient, and has used a large amount of bromines, and is unfriendly to environment, is not suitable for suitability for industrialized production.
At patent documentation CN 102153585 and Chem Pharm Bull 1988,46(11): the operational path of 1703 reports is:
This synthetic route obtains 2-(imidazo [1,2-a] pyridin-3-yl by PA and the cyclization of 4-ethyl bromoacetoacetate by hydrolysis) acetic acid, behind bis phosphoric acid, obtain again minodronic acid.By product many (mainly being 2-(imidazo [1,2-a] pyridine-2-yl) ethyl acetate during ring-closure reaction in the method preparation process), reaction yield is low, and by product is difficult for removing, and is not suitable for industrialized production.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of minodronic acid hydrate, the easy control low for equipment requirements, easy of this method, reaction conditions gentleness, environmental friendliness, the high also suitable commercial scale production of productive rate.
Another object of the present invention provides a kind of synthetic method of minodronic acid.
Purpose of the present invention can reach by following measures:
A kind of preparation method of minodronic acid hydrate, it is: first compound (VII) is carried out the ketone group protection, obtain compound (VI), again with compound (VI) and PA generation nucleophilic substitution reaction, obtain compound (V), ring-closure reaction occurs in compound (V) after taking off the ketone group protection, obtain compound (IV); Get compound (III) after compound (IV) hydrolysis, compound (III) gets compound (II) behind bis phosphoric acid, gets minodronic acid hydrate (I) behind compound (II) recrystallization;
Wherein,
X is halogen;
R is C1~4 alkyl;
R 1Or R 2Be C independently respectively 1~4Alkyl, perhaps R 1And R 2Link to each other and consist of C 2~4Alkylidene group.
The present invention also comprises a kind of preparation method of minodronic acid, it is: first compound (VII) is carried out the ketone group protection, obtain compound (VI), again with compound (VI) and PA generation nucleophilic substitution reaction, obtain compound (V), ring-closure reaction occurs in compound (V) after taking off the ketone group protection, obtain compound (IV); Get compound (III) after compound (IV) hydrolysis, compound (III) gets compound (II) behind bis phosphoric acid.Its reaction scheme such as following formula VII are to II.
In the various compound of the present invention, described X is preferably I, Br or Cl atom, most preferably Cl atom; R is preferably methyl, ethyl, propyl group or sec.-propyl, most preferably ethyl; R 1Or R 2Preferred is methyl or ethyl, perhaps R respectively independently 1And R 2Link to each other and consist of ethylidene or propylidene.So compound (VII) preferred structure is the 4-chloroacetyl acetacetic ester.
When compound (VII) being carried out the ketone group protection, the ketone group protection reagent that uses is C 1~4Alkyl alcohol or C 2~4Alkyl diol, it is preferably methyl alcohol, ethanol, ethylene glycol or 1,3-PD, most preferably is ethylene glycol; The catalyzer of ketone group protection is activated carbon supported phospho-wolframic acid.
In the ketone group protective reaction, catalyst levels be reaction mass total mass 0.1~5%, preferred 0.5~1%, ketone group protective reaction solvent is preferably hexanaphthene, ketone group protective reaction temperature is preferably 50~85 ℃.
In the nucleophilic substitution reaction process of compound (VI) and PA, add acid binding agent; Described acid binding agent is selected from one or more of triethylamine, diethylamine, pyridine, sodium-acetate, yellow soda ash, salt of wormwood; The molar weight of acid binding agent is 1~3 times of PA.The preferred tetrahydrofuran (THF) of solvent in this reaction, temperature of reaction is 50~70 ℃.
When compound (V) took off the ketone group protection, the pH value of reaction system was 1~6, and preferred pH value is 3~4; Take off the catalyzer that uses in the ketone group protective reaction as hydrochloric acid, sulfuric acid, nitric acid, Hydrogen bromide, hydroiodic acid HI, acid or glacial acetic acid, be preferably hydrochloric acid.Take off ketone group protective reaction solvent and be preferably water; Take off ketone group protective reaction temperature and be preferably 20~30 ℃; Described ring-closure reaction temperature is preferably 90~105 ℃; The ring-closure reaction solvent is preferably water.
In compound (IV) hydrolysis reaction, its solvent is selected from one or more in acetonitrile-water, methanol-water, the ethanol-water mixed solvent; Described hydrolysis reaction is: adding sodium hydroxide or potassium hydroxide after compound (IV) dissolving are hydrolyzed, then be evaporated to dried, the residuum water dissolution, wash with ethyl acetate again, last water leaves standstill and obtains compound (III) after crystallization also filters with salt acid for adjusting pH to 6.0~7.0.
In compound (III) bis phosphoric acid reaction process, the reagent of bis phosphoric acid is phosphorous acid and phosphorus oxychloride, and this reaction solvent is preferably toluene.The process of stating the bis phosphoric acid reaction is: compound (III) is joined in the reaction solvent, be warming up to 80~90 ℃, add phosphorous acid and phosphorus oxychloride, being warming up to 95~115 ℃ reacts, inclining reaction solvent again, adds hydrochloric acid and in 90~105 ℃ of lower reactions, makes compound (II).
In compound (II) recrystallization, the solvent of selecting is hydrochloric acid, nitric acid or sulphuric acid soln, preferred hydrochloric acid; The concentration of described hydrochloric acid is 0.1~3N, preferred 0.5~1N, 20~60:1 of the consumption of recrystallization solvent and compound (II) weight ratio; The process of described recrystallization is: with compound (II) heating for dissolving in solvent, add entry in the solution, last crystallization, wherein 20~100:1 of the consumption of water and compound (II) weight ratio.
Below take ethylene glycol as the ketone group protective material as example, further specify the more specifically synthetic method of minodronic acid hydrate, comprise the steps:
(1) compound (VII) and ketone group protective material are mixed, it is an amount of to add activated carbon supported phospho-wolframic acid, adds an amount of hexanaphthene, is heated to backflow, react 2 hours, and filtration removes solvent under reduced pressure, obtains oily matter, i.e. compound (VI);
(2) compound (VI) and PA are dissolved in an amount of organic solvent, stir, slowly drip an amount of triethylamine, heating reflux reaction, (ethyl acetate: methyl alcohol=70:30) reaction solution to compound (VI) spot disappears in the TLC detection, adding suitable quantity of water, is 3.0~4.0 with 1N hydrochloric acid conditioned reaction liquid pH value then, stirring at room reaction 1 hour, then be warming up to back flow reaction 3 hours, the concentrating under reduced pressure reaction solution is to doing again, and enriched material adds an amount of acetic acid ethyl dissolution, then washs organic phase with suitable quantity of water, concentrated organic phase, enriched material refluxes with acetonitrile, and dissolving is rear filters, and 0 ℃ of crystallization gets faint yellow needle-like crystal, i.e. compound (IV);
(3) compound (IV) is dissolved in the methyl alcohol, add an amount of sodium hydroxide solution, room temperature reaction 1 hour, reaction solution is concentrated into dried, adds water dissolution, water washs with ethyl acetate, water 3N salt acid for adjusting pH to 6.0~7.0, leave standstill crystallization, suction filtration gets faint yellow solid, i.e. compound (III).
(4) compound (III) is joined in an amount of toluene, be warming up to 80~90 ℃, add an amount of phosphorous acid, stir, then drip phosphorus oxychloride, be warming up to back flow reaction 6 hours, incline again and toluene, it is an amount of to add 6N hydrochloric acid, reflux 4 hours, separatory water intaking layer, be concentrated into dried, add methyl alcohol and leave standstill crystallization, suction filtration gets white solid, i.e. compound (II).
(5) compound (II) is joined in an amount of hydrochloric acid soln, be warming up to molten clearly, filter, drip an amount of pure water in the filtrate, drip and finish, room temperature crystallization 6 hours, suction filtration gets white or little crystallization with red white, i.e. compound (I) minodronic acid hydrate.
The synthetic method of minodronic acid hydrate of the present invention has following features:
1, the sources of initial raw materials of reaction is sufficient, and cost is low, the reagent environmental friendliness of using in the reaction process, and industrial production safety.
2, reaction conditions is gentle, and easy to operate, side reaction is few, and aftertreatment is simple, does not need special or complex reaction equipment, is easy to suitability for industrialized production.
Embodiment
Following examples further specify the present invention, but do not limit the present invention.
Embodiment 1:
1, the preparation of compound (VI)
With 4-chloroacetyl acetacetic ester 165.0g(1.0mol) add 112ml ethylene glycol (2.0mol) and mix, add activated carbon supported phospho-wolframic acid 1.375g(0.5%), add the 1000ml hexanaphthene, be heated to backflow, reacted 2 hours, filter, remove solvent under reduced pressure, obtain oily matter 181.4g, yield 86.8%, it is compound (VI) (2-chloromethyl-[1,3]-dioxolane-2-yl) ethyl acetate.
2, the preparation of compound (IV)
With 180.0g compound (VI) 2-chloromethyl-[1,3]-dioxolane-2-base and 120.0g PA be dissolved in the 1000ml tetrahydrofuran (THF), stir, slowly drip the 150.0g triethylamine, heating reflux reaction, (ethyl acetate: methyl alcohol=70:30) reaction solution to compound (VI) spot disappears in the TLC detection, add 1000ml water, then be 3.0 with 1N hydrochloric acid conditioned reaction liquid pH value, stirring at room reaction 1 hour, then be warming up to back flow reaction 3 hours, the concentrating under reduced pressure reaction solution is to doing again, and enriched material adds the 500ml acetic acid ethyl dissolution, then use 500mlX3 water washing organic phase, concentrated organic phase, enriched material reflux with the 500ml acetonitrile, and dissolving is rear filters, and 0 ℃ of crystallization gets faint yellow needle-like crystal 145.8g, it is compound (IV) 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate, yield 83.0%, fusing point: 75.5~78.0 ℃.
3, the preparation of compound (III)
With 145.0g compound (IV) 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate is dissolved in the 180ml methyl alcohol, the sodium hydroxide solution 150ml of adding 30%, stirring at room reaction 1 hour, reaction solution is concentrated into dried, add the 500ml water dissolution, water washs with the 300mlX3 ethyl acetate, water leaves standstill crystallization with 3N salt acid for adjusting pH to 6.0, and suction filtration gets faint yellow solid 100.9g, it is compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, yield 80.6%, fusing point: 258.5~260.5 ℃.
4, the preparation of compound (II)
With 100.0g compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid joins in the 1000ml toluene, be warming up to 85 ℃, add 116.6g phosphorous acid, stir, then drip the 261.2g phosphorus oxychloride, be warming up to back flow reaction 6 hours, inclining toluene again, and adding 2000ml6N hydrochloric acid is an amount of, reflux 4 hours, separatory water intaking layer is concentrated into driedly, adds 3500ml methyl alcohol and leaves standstill crystallization 6 hours, suction filtration gets white solid 103.4g, be compound (II) [1-hydroxyl-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene] 1,1-bis phosphoric acid (minodronic acid), yield 56.3%, fusing point: 242.5~245.5 ℃.
5, the preparation of compound (I) minodronic acid hydrate
100.0g compound (II) minodronic acid is joined in the 1N hydrochloric acid soln of 3000ml, be warming up to molten clear, filter, drip the 3000ml pure water in the filtrate, drip and finish, room temperature crystallization 6 hours, suction filtration gets little crystallization 91.3g with red white, i.e. compound (I) minodronic acid hydrate, yield 86.5%, fusing point: 249.0~250.0 ℃.
Embodiment 2:
1, the preparation of compound (VI)
With 4-chloroacetyl acetacetic ester 165.0g(1.0mol) add 160ml methyl alcohol (2.0mol) and mix, add activated carbon supported phospho-wolframic acid 1.465g(0.5%), add the 1000ml hexanaphthene, be heated to backflow, reacted 2 hours, filter, remove solvent under reduced pressure, obtain oily matter 173.7g, yield 82.3%, be compound (VI) 4-chloro-3,3-dimethoxy-ethyl butyrate.
2, the preparation of compound (IV)
With 170.0g compound (VI) 4-chloro-3,3-dimethoxy-ethyl butyrate and 113.0g PA are dissolved in the 1000ml tetrahydrofuran (THF), stir, slowly drip the 142.0g triethylamine, heating reflux reaction, (ethyl acetate: methyl alcohol=70:30) reaction solution to compound (VI) spot disappears in the TLC detection, add 1000ml water, then be 3.0 with 1N hydrochloric acid conditioned reaction liquid pH value, stirring at room reaction 1 hour, then be warming up to back flow reaction 3 hours, the concentrating under reduced pressure reaction solution is to doing again, and enriched material adds the 500ml acetic acid ethyl dissolution, then use 500mlX3 water washing organic phase, concentrated organic phase, enriched material reflux with the 500ml acetonitrile, and dissolving is rear filters, and 0 ℃ of crystallization gets faint yellow needle-like crystal 128.3g, it is compound (IV) 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate, yield 77.3%, fusing point: 76.5~78.5 ℃.
3, the preparation of compound (III)
With 125.0g compound (IV) 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate is dissolved in the 150ml methyl alcohol, the sodium hydroxide solution 130ml of adding 30%, stirring at room reaction 1 hour, reaction solution is concentrated into dried, add the 450ml water dissolution, water washs with the 250mlX3 ethyl acetate, water leaves standstill crystallization with 3N salt acid for adjusting pH to 7.0, and suction filtration gets faint yellow solid 100.983.9g, it is compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, yield 77.7%, fusing point: 257.5~260.0 ℃.
4, the preparation of compound (II)
With 80.0g compound (III) 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid joins in the 800ml toluene, be warming up to 85 ℃, add 93.3g phosphorous acid, stir, then drip the 209.0g phosphorus oxychloride, be warming up to back flow reaction 6 hours, inclining toluene again, and adding 1600ml6N hydrochloric acid is an amount of, reflux 4 hours, separatory water intaking layer is concentrated into driedly, adds 2800ml methyl alcohol and leaves standstill crystallization 6 hours, suction filtration gets white solid 82.5g, be compound (II) [1-hydroxyl-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene] 1,1-bis phosphoric acid (minodronic acid), yield 56.1%, fusing point: 242.0~245.5 ℃.
5, the preparation of compound (I) minodronic acid hydrate
80.0g compound (II) minodronic acid is joined in the 1N hydrochloric acid soln of 3200ml, be warming up to molten clear, filter, drip the 3200ml pure water in the filtrate, drip and finish, room temperature crystallization 6 hours, suction filtration gets little crystallization 72.5g with red white, i.e. compound (I) minodronic acid hydrate, yield 85.9%, fusing point: 249.5~250.5 ℃.

Claims (10)

1. the preparation method of a minodronic acid hydrate, it is characterized in that first compound (VII) being carried out the ketone group protection, obtain compound (VI), again with compound (VI) and PA generation nucleophilic substitution reaction, obtain compound (V), ring-closure reaction occurs in compound (V) after taking off the ketone group protection, obtain compound (IV); Get compound (III) after compound (IV) hydrolysis, compound (III) gets compound (II) behind bis phosphoric acid, gets minodronic acid hydrate (I) behind compound (II) recrystallization;
Wherein,
X is halogen;
R is C1~4 alkyl;
R 1Or R 2Be C independently respectively 1~4Alkyl, perhaps R 1And R 2Link to each other and consist of C 2~4Alkylidene group.
2. method according to claim 1 is characterized in that described X is I, Br or Cl atom, preferred Cl atom; R is methyl, ethyl, propyl group or sec.-propyl, preferred ethyl; R 1Or R 2Be methyl or ethyl, perhaps R independently respectively 1And R 2Link to each other and consist of ethylidene or propylidene.
3. method according to claim 1, when it is characterized in that compound (VII) carried out the ketone group protection, the ketone group protection reagent that uses is C 1~4Alkyl alcohol or C 2~4Alkyl diol is preferably methyl alcohol, ethanol, ethylene glycol or 1,3-PD; The catalyzer of ketone group protection is activated carbon supported phospho-wolframic acid, described catalyst levels be reaction mass total mass 0.1~5%, preferred 0.5~1%, ketone group protective reaction solvent is hexanaphthene, ketone group protective reaction temperature is 50~85 ℃.
4. method according to claim 1 is characterized in that adding acid binding agent in the nucleophilic substitution reaction process of described compound (VI) and PA; Described acid binding agent is selected from one or more of triethylamine, diethylamine, pyridine, sodium-acetate, yellow soda ash, salt of wormwood; The molar weight of acid binding agent is 1~3 times of PA.
5. method according to claim 1 is characterized in that the pH value of reaction system was 1~6 when compound (V) took off the ketone group protection; Take off the catalyzer that uses in the ketone group protective reaction and be hydrochloric acid, sulfuric acid, nitric acid, Hydrogen bromide, hydroiodic acid HI, acid or glacial acetic acid.
6. method according to claim 5 is characterized in that the pH value of reaction system was 3~4 when compound (V) took off the ketone group protection; Take off the catalyzer that uses in the ketone group protective reaction and be hydrochloric acid; Taking off ketone group protective reaction solvent is water; Taking off ketone group protective reaction temperature is 20~30 ℃; Described ring-closure reaction temperature is 90~105 ℃; The ring-closure reaction solvent is water.
7. method according to claim 1 is characterized in that described compound (IV) hydrolysis reaction solvent is selected from one or more in acetonitrile-water, methanol-water, the ethanol-water mixed solvent; Described hydrolysis reaction is: adding sodium hydroxide or potassium hydroxide after compound (IV) dissolving are hydrolyzed, then be evaporated to dried, the residuum water dissolution, wash with ethyl acetate again, last water leaves standstill and obtains compound (III) after crystallization also filters with salt acid for adjusting pH to 6.0~7.0.
8. method according to claim 1, it is characterized in that: the reagent of bis phosphoric acid is phosphorous acid and phosphorus oxychloride in described compound (III) the bis phosphoric acid reaction process, and reaction solvent is toluene; The process of described bis phosphoric acid reaction is: compound (III) is joined in the reaction solvent, be warming up to 80~90 ℃, add phosphorous acid and phosphorus oxychloride, being warming up to 95~115 ℃ reacts, inclining reaction solvent again, adds hydrochloric acid and in 90~105 ℃ of lower reactions, makes compound (II).
9. method according to claim 1 is characterized in that the solvent of selecting in described compound (II) recrystallization is hydrochloric acid, nitric acid or sulphuric acid soln, preferred hydrochloric acid; The concentration of described hydrochloric acid is 0.1~3N, preferred 0.5~1N, 20~60:1 of the consumption of recrystallization solvent and compound (II) weight ratio; The process of described recrystallization is: with compound (II) heating for dissolving in solvent, add entry in the solution, last crystallization, wherein 20~100:1 of the consumption of water and compound (II) weight ratio.
10. the preparation method of a minodronic acid, it is characterized in that first compound (VII) being carried out the ketone group protection, obtain compound (VI), again with compound (VI) and PA generation nucleophilic substitution reaction, obtain compound (V), ring-closure reaction occurs in compound (V) after taking off the ketone group protection, obtain compound (IV); Get compound (III) after compound (IV) hydrolysis, compound (III) gets compound (II) behind bis phosphoric acid;
Wherein,
X is halogen,
R is C1~4 alkyl,
R 1Or R 2Be C independently respectively 1~4Alkyl, perhaps R 1And R 2Link to each other and consist of C 2~4Alkylidene group.
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Cited By (5)

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CN104945436A (en) * 2015-07-09 2015-09-30 山东罗欣药业集团股份有限公司 Minodronic acid preparing method
CN105153232A (en) * 2015-10-17 2015-12-16 青岛辰达生物科技有限公司 Preparation method of minodronic acid for treating osteoporosis
WO2016198117A1 (en) * 2015-06-12 2016-12-15 Polycrystalline S.R.L. New crystal forms of minodronic acid
CN109456363A (en) * 2018-11-01 2019-03-12 南京海纳医药科技股份有限公司 A kind of preparation method of minodronic acid process impurity
CN109503542A (en) * 2019-01-04 2019-03-22 浙江宏元药业股份有限公司 A kind of Atorvastatin calcium intermediate and its preparation method and application

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Publication number Priority date Publication date Assignee Title
WO2016198117A1 (en) * 2015-06-12 2016-12-15 Polycrystalline S.R.L. New crystal forms of minodronic acid
JP2018519360A (en) * 2015-06-12 2018-07-19 ポリクリスタリン・ソチエタ・ア・レスポンサビリタ・リミタータPolyCrystalLine S.r.l. A new crystal form of minodronic acid
CN104945436A (en) * 2015-07-09 2015-09-30 山东罗欣药业集团股份有限公司 Minodronic acid preparing method
CN105153232A (en) * 2015-10-17 2015-12-16 青岛辰达生物科技有限公司 Preparation method of minodronic acid for treating osteoporosis
CN109456363A (en) * 2018-11-01 2019-03-12 南京海纳医药科技股份有限公司 A kind of preparation method of minodronic acid process impurity
CN109503542A (en) * 2019-01-04 2019-03-22 浙江宏元药业股份有限公司 A kind of Atorvastatin calcium intermediate and its preparation method and application

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