CN102020676A - Method for preparing minodronate - Google Patents
Method for preparing minodronate Download PDFInfo
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- CN102020676A CN102020676A CN 201010574507 CN201010574507A CN102020676A CN 102020676 A CN102020676 A CN 102020676A CN 201010574507 CN201010574507 CN 201010574507 CN 201010574507 A CN201010574507 A CN 201010574507A CN 102020676 A CN102020676 A CN 102020676A
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- aminopyridine
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- ICSNLGPSRYBMBD-UHFFFAOYSA-N Nc1ncccc1 Chemical compound Nc1ncccc1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
- LNNMULCOMQAULG-UHFFFAOYSA-N CCOC(CC(C=O)Br)=O Chemical compound CCOC(CC(C=O)Br)=O LNNMULCOMQAULG-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a method for preparing minodronate, which comprises the following steps of: condensing a compound II and a compound III to form a compound IV, closing rings of the compound IV and 2-aminopyridine to obtain a compound V, hydrolyzing the compound V into a compound VI, and finally performing phosphonation to form a compound I. The method avoids using virulent chemical reagents such as sodium cyanide or bromine and the like, has mild and controllable reaction condition, short reaction step, high yield and low cost, and is suitable for industrialized production.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of preparation method of minot phosphoric acid.
Background technology
Minodronic acid (Minodronate), chemistry 1-hydroxyl by name-2-[(imidazo [1,2-a] pyridin-3-yl] ethylidene-1, the 1-di 2 ethylhexyl phosphonic acid, it is new type heterocycle bis-phosphonic acids compounds by the exploitation of Japanese Yamanouchi company, be used for the treatment of the hypercalcemia that is caused by osteoporosis and malignant tumour, its inhibition bone resorption activity is respectively ineadronic acid disodium, alendronate sodium and Pamidronate Disodium 2 times, 10 times and 100 times.This product is having remarkable benefit aspect the spinal fracture incidence, simultaneously very big minimizing is being arranged aspect the stomach side effect, has been defined as the novel drugs of effective osteoporosis now, the prevention fracture.The development of this medicine undoubtedly will for the clinical disease patient provide a kind of safer, effectively, medicine easily, will produce good social benefit and economic benefit after the listing.
The preparation method of minodronic acid respectively EP0354806 (open day: report is arranged, its chemistry 1-hydroxyl by name-2-[(imidazo [1,2-a] pyridin-3-yl 1990-02-14)] ethylidene-1, the 1-di 2 ethylhexyl phosphonic acid, structural formula is as follows:
EP0354806 (open day: 1990-02-14) disclosed preparation method:
(open day: 1990-02-14) disclosed preparation method did not provide raw material sources to EP0354806, and yield is lower.
Chinese Journal of Pharmaceuticals 35 (4), 2004,193-194 and document J.Med.Chem., 1969,12 (1): the disclosed preparation method of 122-126 is as follows:
With imidazo [1,2-a] pyridine is starting raw material, with paraformaldehyde and dimethylamine hydrochloride react 3-[(N, the N dimethylamine base) methyl] imidazo [1,2-a] pyridine, form quaternary ammonium salt with haloalkane reaction, after cyano group replaces directly in hydrolysis under alkaline condition, again with phosphorus trichloride and phosphorous acid appropriate solvent react target compound.This synthetic method has been used the highly toxic product sodium cyanide, operational hazards, and reactions steps is longer, and complex operation is not suitable for suitability for industrialized production.
CN101531681 (open day: 2009-09-16) disclosed preparation method:
CN101531681 (open day: 2009-09-16) among the disclosed preparation method, during preparation 4-aldehyde radical ethyl butyrate, require anhydrous and oxygen-free, and temperature of reaction is difficult to realize at-80 ℃.During preparation 3-bromine 4-aldehyde radical ethyl butyrate, agents useful for same relates to liquid bromine and tetracol phenixin, and toxicity is bigger, is not suitable for the scale operation of medicine industry.
Consider social benefit and economic benefit and reaction yield, industrialized condition and environmental protection policy that minot phosphoric acid is good, relate to a kind of can be safely and easily the effective ways of the synthetic compound I of control be necessary.
Summary of the invention
The objective of the invention is the shortcoming that is difficult to accomplish scale production at existing method; on bases, provide a kind of and can effectively avoid using hypertoxic chemical reagent, reaction conditions gentleness, controllability is strong, reactions steps is short, yield is higher, cost is lower, be fit to the method for preparing minodronic acid of suitability for industrialized production by a large amount of experiments.
Purpose of the present invention can reach by following measure:
A kind of preparation formula (I) compound 1-hydroxyl-2-[(imidazo [1,2-a] pyridin-3-yl] ethylidene-1, the method of 1-di 2 ethylhexyl phosphonic acid, it is characterized in that earlier compound ii and compound III being condensed into the compound IV, with compound IV and 2-aminopyridine closed loop, obtain the compound V again, the compound V is hydrolyzed into the compound VI, phosphoric acid changes into chemical compounds I more at last, and its reaction scheme is as follows:
In compound ii and the reaction of compound III, reaction solvent is selected one or more mixed solvents in the non-proton type solvents such as sherwood oil, normal hexane, hexanaphthene, ether, tetrahydrofuran (THF) for use, one or both mixed solvents in wherein preferred normal hexane or the hexanaphthene.It is catalyzer that catalysts is selected one or more mixed bases in the mineral alkalis such as yellow soda ash, sodium bicarbonate, salt of wormwood saleratus for use, one or both mixed bases in wherein preferred yellow soda ash or the salt of wormwood.The consumption of catalysts is 6～8 times of compound ii quality.The temperature of reaction of compound ii and compound III is 20～30 ℃.The weightmeasurement ratio of compound ii and compound III (g/mL) is 6: 20～30.
In compound IV and the ring-closure reaction of 2-aminopyridine, it is reaction solvent that reaction solvent is selected methanol-water, alcohol-water or acetonitrile-water isopolarity solvent system for use, and wherein preferred acetonitrile-water is a reaction solvent.The volume ratio of organic solvent and water is 10: 0.5～3 in the reaction solvent.Catalysts selects for use in the strong acid such as hydrochloric acid, sulfuric acid and tosic acid one or more for catalyzer.Wherein preferred tosic acid is a catalyzer.The mass ratio of catalysts and compound IV is 1: 18～22, be preferably 1: 19～and 21.The compound IV is 2～4 times of quality of 2-aminopyridine, is preferably 2.5～3.5 times.The ring-closure reaction temperature of compound IV and 2-aminopyridine is 70～100 ℃.
Compound V hydrolysis reaction carries out under alkaline condition, and one or both mixed bases that described alkali is selected from the inorganic strong alkalis such as selecting potassium hydroxide and sodium hydroxide for use are reactant.Compound V hydrolysising reacting temperature is 70～100 ℃.Can select methyl alcohol, ethanol, acetonitrile and water isopolarity solvent recrystallization compound V for use after this step reaction, wherein preferably water is a solvent recrystallization compound V.
In the compound VI phosphorylation reaction, reaction solvent is selected from one or more in the high boiling solvents such as toluene, dimethylbenzene, chlorobenzene and bromobenzene; One or both mixed solvents in preferred chlorobenzene or the toluene are reaction solvent.Phosphorylation reaction reagent is selected from one or both in phosphorous acid, the phosphorus trichloride.The mass ratio of compound VI and phosphorylation reaction reagent is 3: 7～14, be preferably 3: 8～and 12.The phosphorylation reaction temperature is 70～100 ℃.
The detailed synthetic route of an instruction of the present invention is shown below:
The present invention has avoided hypertoxic chemical reagent such as use sodium cyanide or bromine, and the reaction conditions gentleness is controlled, and reactions steps is shorter, and yield is higher, and cost is lower, is fit to suitability for industrialized production.
Embodiment
By the specific embodiments of following examples form, foregoing of the present invention further is elaborated, to those skilled in the art, this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.
Embodiment 1
1, (E)-4, the preparation of 4-dimethoxy-2-butylene acetoacetic ester
Add 120g 2 in four-hole bottle, 2-methoxyl group acetaldehyde and 4L hexanaphthene stir adding 900g Anhydrous potassium carbonate down, stir 1h.Dropwise 5 00mL phosphine acyl acetic acid three ethyl, reaction 6h.Reaction finishes, and adds 1.5L water in reaction solution, separatory, and organic phase is washed with saturated common salt, and anhydrous sodium sulfate drying removes solvent under reduced pressure, gets colourless oil liquid, with the oily liquids underpressure distillation, gets colorless oil 150g, yield 71%.
2, the preparation of 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate
Under the nitrogen protection, add 200g (E)-4 in there-necked flask, 4-dimethoxy-2-butylene acetoacetic ester, 1000mL acetonitrile and 100mL water add the 10g tosic acid again, stir.Add 70g 2-aminopyridine, reflux, reaction 1h.After reaction finished, suction filtration got black filtrate, removes solvent under reduced pressure, gets the dark oil thing, directly cast the step reaction.
3, the preparation of 2-(imidazo [1,2-a] pyridin-3-yl) acetate
To go up step reaction gained oily matter 1500mL dissolve with ethanol, join in the 3L there-necked flask, add the water-soluble 120g sodium hydroxide of 600mL, reaction 2h down in 80 ℃.Naturally cooling after reaction finishes, extremely neutral with glacial acetic acid conditioned reaction liquid, adding gac stirring and refluxing, suction filtration, solid is washed with ethanol, filtrate concentrates, cooling, and suction filtration, filter cake is washed respectively, ethanol is washed, and solid water recrystallization gets brown solid 104g, yield 85%.
4,1-hydroxyl-2-[(imidazo [1,2-a] pyridin-3-yl] ethylidene-1,1-di 2 ethylhexyl phosphonic acid (I) is the preparation of minot phosphoric acid
In four-hole bottle, add 60g 2-(imidazo [1,2-a] pyridin-3-yl) acetate, the 1L chlorobenzene, 80 ℃ add 60g phosphorous acid down, stir 1h, drip the 140g phosphorus trichloride, back flow reaction 5h.Reaction finishes, cooling, and the benzene of falling the dechlorination adds the 1L concentrated hydrochloric acid, back flow reaction 2h.Cooling, suction filtration, filtrate decompression is concentrated, gets faint yellow oily thing, and the cooling back adds 1L methyl alcohol, separates out white solid, and suction filtration, solid get minot phosphoric acid 50g, yield 45% in 45 ℃ of vacuum-dryings.
Embodiment 2
1, (E)-4, the preparation of 4-dimethoxy-2-butylene acetoacetic ester
Add 180g2 in round-bottomed flask, 2-dimethoxy acetaldehyde, 1300g Anhydrous potassium carbonate and 5800mL hexanaphthene stir, and drip the 670mL phosphine acyl acetic acid three ethyl, drip and finish afterreaction 6h.React the end back and add 2200mL, the saturated common salt water washing of separatory, organic layer, anhydrous sodium sulfate drying, the elimination siccative, filtrate decompression concentrates, and gets colourless oil liquid, and oily liquids in underpressure distillation, is got product 210g, yield 70%.
2, the preparation of 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate
Under the nitrogen protection, add 196g (E)-4 in there-necked flask, 4-dimethoxy-2-butylene acetoacetic ester, 1000mL acetonitrile and 80mL water stir, and add the 10g tosic acid, add the 65g2-aminopyridine again, heating, back flow reaction 4h.After reaction finished, suction filtration got brownish black filtrate, removes solvent under reduced pressure, gets the dark oil thing.
3, the preparation of 2-(imidazo [1,2-a] pyridin-3-yl) acetate
Step reaction gained oily matter be will go up with adding the 1500mL dissolve with ethanol, 600mL water and 120g sodium hydroxide added again, heating reflux reaction 2h.After reaction finished, cooling with glacial acetic acid regulator solution PH=6-7, added gac, reflux, suction filtration while hot, filtrate concentrates, cooling, suction filtration, solid is water and washing with alcohol respectively, solid water recrystallization, vacuum-drying, product 105g, yield 86%.
4,1-hydroxyl-2-[(imidazo [1,2-a] pyridin-3-yl] ethylidene-1,1-di 2 ethylhexyl phosphonic acid (I) is that the preparation of minot phosphoric acid adds 90g2-(imidazo [1 in four-hole bottle, 2-a] pyridin-3-yl) acetate and 2000mL chlorobenzene, 80 ℃ add 90g phosphorous acid down, stir 1h, drip the 210g phosphorus trichloride, drip and finish back back flow reaction 5h.After reaction finished, dechlorination benzene was toppled in cooling, added the 2L concentrated hydrochloric acid, back flow reaction 2h.After the reaction end, cooling, suction filtration, filtrate decompression is steamed and is desolventized, and gets faint yellow oily thing, adds 750mL methyl alcohol, separates out white solid, and suction filtration, solid get crude product 80g, yield 46% in 45 ℃ of vacuum-dryings.
Claims (9)
1. a preparation formula (I) compound 1-hydroxyl-2-[(imidazo [1,2-a] pyridin-3-yl] ethylidene-1, the method of 1-di 2 ethylhexyl phosphonic acid, it is characterized in that earlier compound ii and compound III being condensed into the compound IV, with compound IV and 2-aminopyridine closed loop, obtain the compound V again, the compound V is hydrolyzed into the compound VI, phosphoric acid changes into chemical compounds I more at last, and its reaction scheme is as follows:
2. method according to claim 1 is characterized in that reaction solvent is selected from one or more in sherwood oil, normal hexane, hexanaphthene, ether, the tetrahydrofuran (THF) in the reaction of compound ii and compound III; Catalysts is selected from one or more in yellow soda ash, sodium bicarbonate, salt of wormwood, the saleratus.
3. method according to claim 1, the temperature of reaction that it is characterized in that compound ii and compound III is 20～30 ℃.
4. method according to claim 1 is characterized in that in compound IV and the ring-closure reaction of 2-aminopyridine that reaction solvent is methanol-water, alcohol-water or acetonitrile-water mixing polar solvent; Catalysts is selected from one or more in hydrochloric acid, sulfuric acid and the tosic acid.
5. method according to claim 1, the ring-closure reaction temperature that it is characterized in that compound IV and 2-aminopyridine is 70～100 ℃.
6. method according to claim 1 is characterized in that compound V hydrolysis reaction carries out under alkaline condition, described alkali is selected from one or both in potassium hydroxide and the sodium hydroxide.
7. method according to claim 1 is characterized in that compound V hydrolysising reacting temperature is 70～100 ℃.
8. method according to claim 1 is characterized in that reaction solvent is selected from one or more in toluene, dimethylbenzene, chlorobenzene and the bromobenzene in the compound VI phosphorylation reaction.
9. method according to claim 1 is characterized in that compound VI phosphorylation reaction reagent is selected from one or both in phosphorous acid, the phosphorus trichloride; The phosphorylation reaction temperature is 70～100 ℃.
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102268042A (en) * | 2011-06-01 | 2011-12-07 | 合肥医工医药有限公司 | Minodronate crystalform II and preparation method thereof |
| CN102344463A (en) * | 2011-10-17 | 2012-02-08 | 南京艾德凯腾生物医药有限责任公司 | Method for preparing 1-hydroxy-2-(imidazo [1, 2-a] pyridine-3-radical) ethylidene-1, 1-bisphosphonic acid compound |
| CN102875602A (en) * | 2012-10-25 | 2013-01-16 | 江苏神龙药业有限公司 | Preparation method of Minodronic acid hydrate |
| CN102887896A (en) * | 2012-10-26 | 2013-01-23 | 南京工业大学 | Preparation method of 2-(imidazo-[1,2-a]pyridyl-3-yl)acetonitrile |
| CN102887897A (en) * | 2012-10-26 | 2013-01-23 | 南京工业大学 | Preparation method of methyl 2-(imidazo-[1,2-a]pyridyl-3-yl)acetate |
| CN103183709A (en) * | 2011-12-30 | 2013-07-03 | 天津药物研究院 | Minodronic acid new crystal form, preparation method and application |
| CN104292267A (en) * | 2014-09-11 | 2015-01-21 | 北京诺泓医药科技有限公司 | Preparation method of 1-hydroxyl-2-(imidazo[1,2-A]pyridine-3-yl)ethane-1,1-bisphosphonic acid |
| CN104725422A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Minodronic acid preparation method |
| CN105111238A (en) * | 2015-07-01 | 2015-12-02 | 中山海泓药业有限公司 | Method for producing minodronic acid monohydrate by using water as solvent |
| WO2016024287A1 (en) * | 2014-08-14 | 2016-02-18 | Ind-Swift Laboratories Limited | An improved process for preparing pure minodronic acid and intermediates thereof |
| CN109608492A (en) * | 2018-12-19 | 2019-04-12 | 深圳市第二人民医院 | A kind of bisphosphonate compound and preparation method thereof for osteoporosis |
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| WO2008035131A1 (en) * | 2006-09-19 | 2008-03-27 | Orchid Chemicals And Pharmaceuticals Limited | An improved process for the preparation of bisphosphonic acid |
| CN101531681A (en) * | 2008-03-10 | 2009-09-16 | 北京德众万全医药科技有限公司 | High-purity minodronic acid and preparation method thereof |
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2010
- 2010-12-03 CN CN 201010574507 patent/CN102020676B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008035131A1 (en) * | 2006-09-19 | 2008-03-27 | Orchid Chemicals And Pharmaceuticals Limited | An improved process for the preparation of bisphosphonic acid |
| CN101531681A (en) * | 2008-03-10 | 2009-09-16 | 北京德众万全医药科技有限公司 | High-purity minodronic acid and preparation method thereof |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102268042A (en) * | 2011-06-01 | 2011-12-07 | 合肥医工医药有限公司 | Minodronate crystalform II and preparation method thereof |
| CN102268042B (en) * | 2011-06-01 | 2014-06-25 | 广东宏远集团药业有限公司 | Minodronate crystalform II and preparation method thereof |
| CN102344463A (en) * | 2011-10-17 | 2012-02-08 | 南京艾德凯腾生物医药有限责任公司 | Method for preparing 1-hydroxy-2-(imidazo [1, 2-a] pyridine-3-radical) ethylidene-1, 1-bisphosphonic acid compound |
| CN103183709B (en) * | 2011-12-30 | 2015-11-18 | 天津药物研究院 | A kind of minodronic acid new crystal and its production and use |
| CN103183709A (en) * | 2011-12-30 | 2013-07-03 | 天津药物研究院 | Minodronic acid new crystal form, preparation method and application |
| CN102875602B (en) * | 2012-10-25 | 2015-05-20 | 江苏神龙药业有限公司 | Preparation method of Minodronic acid hydrate |
| CN102875602A (en) * | 2012-10-25 | 2013-01-16 | 江苏神龙药业有限公司 | Preparation method of Minodronic acid hydrate |
| CN102887897A (en) * | 2012-10-26 | 2013-01-23 | 南京工业大学 | Preparation method of methyl 2-(imidazo-[1,2-a]pyridyl-3-yl)acetate |
| CN102887896A (en) * | 2012-10-26 | 2013-01-23 | 南京工业大学 | Preparation method of 2-(imidazo-[1,2-a]pyridyl-3-yl)acetonitrile |
| CN102887896B (en) * | 2012-10-26 | 2015-11-18 | 南京工业大学 | A kind of 2-(imidazo [1,2-a] pyridin-3-yl) preparation method of acetonitrile |
| CN104725422A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Minodronic acid preparation method |
| CN104725422B (en) * | 2013-12-18 | 2018-07-31 | 山东新时代药业有限公司 | A kind of preparation method of minodronic acid |
| WO2016024287A1 (en) * | 2014-08-14 | 2016-02-18 | Ind-Swift Laboratories Limited | An improved process for preparing pure minodronic acid and intermediates thereof |
| CN104292267A (en) * | 2014-09-11 | 2015-01-21 | 北京诺泓医药科技有限公司 | Preparation method of 1-hydroxyl-2-(imidazo[1,2-A]pyridine-3-yl)ethane-1,1-bisphosphonic acid |
| CN105111238A (en) * | 2015-07-01 | 2015-12-02 | 中山海泓药业有限公司 | Method for producing minodronic acid monohydrate by using water as solvent |
| CN109608492A (en) * | 2018-12-19 | 2019-04-12 | 深圳市第二人民医院 | A kind of bisphosphonate compound and preparation method thereof for osteoporosis |
| CN109608492B (en) * | 2018-12-19 | 2021-02-09 | 深圳市第二人民医院 | Diphosphonic acid compound for osteoporosis and preparation method thereof |
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Effective date of registration: 20151208 Address after: 210046, Nanjing, Jiangsu province Qixia Road, No. 9, building C3 on the first floor Patentee after: Jiangsu Li Hua Bioisystech Co., Ltd Address before: Huawei Technology Building No. 8 road in Yuhuatai District of Nanjing City, 210012 flora in Jiangsu Province Patentee before: Nanjing Huawe Medical Science & Technology Development Co., Ltd. |