CN102344448A - Preparation method of antiosteoporosis drug minodronate key intermediate - Google Patents
Preparation method of antiosteoporosis drug minodronate key intermediate Download PDFInfo
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- CN102344448A CN102344448A CN2011102080844A CN201110208084A CN102344448A CN 102344448 A CN102344448 A CN 102344448A CN 2011102080844 A CN2011102080844 A CN 2011102080844A CN 201110208084 A CN201110208084 A CN 201110208084A CN 102344448 A CN102344448 A CN 102344448A
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Abstract
The invention belongs to a preparation method of an antiosteoporosis drug minodronate key intermediate. In the method, alpha-ketoglutaric acid is used as a starting material to prepare a target product through five steps of esterification, bromination, cyclization, hydrolysis and decarboxylation. The method is characterized in that (1) the alpha-ketoglutaric acid is esterified with alkanol under certain temperature and catalysis conditions; (2) alpha-ketoglutaric acid ester and a bromination agent are brominated in a certain solvent; (3) 3-bromination-2-ketoglutaric acid ester and 2-aminopyridine are cyclized in a certain solvent; (4) a cyclization product is hydrolyzed in a certain solvent under an alkaline condition; and (5) hydrolysate is decarboxylated under the effect of a catalyst at a certain temperature in a solvent to generate the minodronate key intermediate 2-(imidazo [1, 2-a] pyridine-3-base) acetic acid. The preparation method disclosed by the invention has the advantages that the defects of a preparation process reported in a literature are overcome, a novel method for synthesizing the key intermediate is found, and compared with the prior art, the method of the invention has simple post-processing and is more suitable for industrial production.
Description
Technical field
The invention belongs to the preparation method of osteosporosis resistant medicament minodronic acid key intermediate.
Background technology
Osteoporosis (osteoporosis) is a kind of performance of body naturally-aged, weathering process; It is systemic skeletal diseases; Impaired with the osseous tissue microstructure; Bone ore deposit composition and ground substance of bone etc. constantly reduce; The sclerotin attenuation; The bone amount reduces, and bone fragility increases and the disease of a kind of general dysostosis that the risk of fractures degree raises is characteristic.The elderly adds that outdoors and Exposure to Sunlight are limited because calcium is taken in, absorb and reduce, and makes the synthetic deficiency of vitamins D, influences the absorption of calcium, makes that bone is calcareous to be excluded easily.
The whole world has 200,000,000 people to suffer from osteoporosis approximately at present, and its sickness rate has leapt to common disease, frequently-occurring disease the 7th, and ill ratio accounts for over half among China the elderly.Especially the osteoporotic sickness rate of postclimacteric women is higher, and China women's more than 60 years old osteoporosis sickness rate is up to 70%.Multiple fracture by it causes is in rising trend this year, causes patient's deformity, independent living ability to reduce or forfeiture, has become harm senior health and fitness's a big problem.
Minodronic acid (minnodronic acid; YM-529; Ono-5920; YH-529), chemistry 1-hydroxyl-2-[(imidazo [1,2-a] pyridin-3-yl) by name] ethylidene-1; The two phosphonic acids of 1-; With the monohydrate is medicinal forms, is that its structural formula is as follows by Yamanouchi company synthetic third generation azepine aromatic double phosphate derivative:
A multicenter that after 352 are diagnosed as the menopause of osteoporosis, carries out among the Japanese women, at random, placebo-controlled trial verified these article (0.5,1 and 15mgd
-1Lasting 36 weeks) validity and security; All experimenters use calcium lactate tonic (0.8g) simultaneously therebetween; The result shows: compare with placebo; After 36 weeks, the bone mineral density (BMD) of each dose groups experimenter the 2nd～4 lumbar vertebra of these article significantly increases (105.65%, 106.42% and 105.93%vs100.72%); Urine Deoxypyridinoline/creatinine and I Collagen Type VI crosslinked N-terminal peptide/creatinine ratio and the serum bone specificity alkaline phosphatase enzyme level 12 weeks after of these article treatment group experimenter after 4 weeks all significantly reduces (pharmacy progress, 2009,33 (11): 526-527).
At present, existing multiple open method is used for the preparation of minodronic acid, and part relates to the synthesis method of key intermediate 2-(imidazo [1,2-a] pyridin-3-yl) acetate, but all there is certain problem in synthesis technique.
US5464843 discloses the synthesis method of a kind of 2-carboxyl imidazo [1,2-a] pyridine-3-acetate: 2-oxopentanedioic acid methyl esters elder generation's bromo and 2-aminopyridine are reacted, hydrolysis makes target compound again.The synthetic route See Figure:
Bromo-reaction impurity is more in this route, and separation needs high vacuum condition.Adopt column chromatography for separation after the cyclization, and yield is not described.The acidic hydrolysis time long (14h), yield low (51%).The more important thing is that this patent is not further reported the method for decarboxylation Synthetic 2-(imidazo [1,2-a] pyridin-3-yl) acetate.
Summary of the invention:
Based on the technological deficiency of above-mentioned operational path, the purpose of this invention is to provide a kind of technology of new preparation minodronic acid key intermediate 2-(imidazo [1,2-a] pyridin-3-yl) acetate, to overcome the problem that prior art exists.
For solving the problems of the technologies described above, the present invention has done further improvement to it, comprises new decarboxylation method used.In the process of synthetic bromide for ester; We adopt the method for liquid bromine and cupric bromide bromo respectively, and the bromo ester of gained further carries out cyclization with the 2-aminopyridine, and we surprisingly find; The ester of cupric bromide bromo gained is owing to the cupric ion of residual minim, and cupric ion is the catalyzed cyclization process well.In hydrolysing step, acid hydrolysis is very slow, and energy consumption is high.Directly under strong alkaline condition, heating reflux reaction, impurity is more, can't separate out solid effectively.We find that under weak basic condition, hydrolysis is complete smoothly for the backflow certain hour in certain solvent.In decarboxylation step, 2-carboxyl imidazo [1,2-a] pyridine-3-acetate is under the catalysis of copper powder, and in certain temperature and solvent, the carboxyl that can slough 2 well obtains 2-(imidazo [1,2-a] pyridin-3-yl) acetate.
On a large amount of experiment basis, the present invention provides a kind of method of new preparation 2-(imidazo [1,2-a] pyridin-3-yl) acetate, and this method may further comprise the steps:
(1) esterification
α-Yang Daiwuersuan is under lower temperature condition, at C
1～C
5Alkyl alcohol in charge into hydrogen chloride gas and react, perhaps prior to C
1～C
5Alkyl alcohol in charge into hydrogen chloride gas to saturated, add α-Yang Daiwuersuan again, prepare the C of α-Yang Daiwuersuan
1～C
5Alkyl ester.Described temperature of reaction is 0～50 ℃, preferred 0～10 ℃; Reaction times is 2～4h, preferred 3h; The hydrogen chloride gas scale of construction that charges into is advisable with saturated.
(2) halo
The C of α-Yang Daiwuersuan
1～C
5Alkyl ester in certain solvent with brominated reagent react the C of 3-bromo-2-oxopentanedioic acid
1～C
5Alkyl ester.Described solvent is ethyl acetate, chloroform, methylene dichloride, a kind of or two kinds of mixed solutions in the tetracol phenixin, the mixed solution of ethyl acetate and chloroform; Described brominated reagent can be liquid bromine or cupric bromide, preferred cupric bromide; Described temperature of reaction is 0～100 ℃, preferred 60～70 ℃; Reaction times is 1～30h, preferred 15～20h; The C of α-Yang Daiwuersuan
1～C
5The mol ratio of alkyl ester and cupric bromide is 1: 5, preferred 1: 3.
(3) cyclization
The above-mentioned 3-bromo-2-oxopentanedioic acid C that makes
1～C
5Alkyl ester and 2-aminopyridine heating reflux reaction certain hour in certain solvent, regulate certain pH, make cyclocomplex.Described solvent can be dehydrated alcohol, Virahol, methyl alcohol, acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, 95% ethanol, preferred 95% ethanol or acetonitrile; Reaction times is 1～5h, preferred 1～2h; PH can be 6～10, preferred 7～8; 3-bromo-2-oxopentanedioic acid C
1～C
5Alkyl ester and the mol ratio of 2-aminopyridine be 1～1.5: 1, preferred 1.1～1.2: 1; Described temperature of reaction is 0～100 ℃, preferred 75～85 ℃;
(4) hydrolysis
Above-mentioned cyclocomplex is in the mixture of certain organic solvent and water, and alkaline condition is the reaction certain hour down, regulates certain pH, is prepared into 2-carboxyl-3-imidazo [1,2-a] pyridylacetic acid(HPAC).Described organic solvent can be dehydrated alcohol, Virahol, methyl alcohol, tetrahydrofuran (THF), 1, and the 4-dioxane is preferred 1, the 4-dioxane, and the ratio of itself and water is 1～5: 1, preferred 3: 1; Reaction times is 1～10h, preferred 5～7h; The alkali of this reaction can be mineral alkali, like sodium hydroxide, potassium hydroxide, salt of wormwood, yellow soda ash, lithium hydroxide, and preferred lithium hydroxide; The ratio of hydrolyzate and alkali is 1～5: 1, preferred 2.5～3: 1; PH can be 4～7, preferred 5～6; Described temperature of reaction is 0～150 ℃, preferred 90～110 ℃;
(5) decarboxylation
2-carboxyl-3-imidazo [1,2-a] pyridylacetic acid(HPAC) is prepared into 2-(imidazo [1,2-a] pyridin-3-yl) acetate under the catalysis of copper powder, in suitable solvent, react certain hour under the certain temperature.Described solvent can be terepthaloyl moietie, quinoline, preferred terepthaloyl moietie; Reaction times is 1～10h, preferred 8～10h; Described temperature of reaction is 100～200 ℃, preferred 190～220 ℃; The purified solvent can be methyl alcohol, ethanol, tetrahydrofuran (THF), 1, the mixed solution of single solvents such as 4-dioxane or they and water, the mixed solution of preferred alcohol and water.
Detailed preparation were established:
Wherein, wherein R is C
1～C
5Alkyl
The present invention has following advantage with respect to prior art:
(1) the invention provides the synthesis method of minodronic acid key intermediate 2-(imidazo [1,2-a] pyridin-3-yl) acetate, this method is simple and easy to operate, and yield is high, is suitable for suitability for industrialized production.
(2) the many problems of hydrolysis impurity under strongly-acid or strong alkaline condition have been solved.
(3) grope through experiment, find the technology of new purifying 2-(imidazo [1,2-a] pyridin-3-yl) acetate.
(4) after the present invention handles through above-mentioned method, target product list content＜0.1% of mixing, purity＞99.9%.
Embodiment
Describe the present invention in detail below in conjunction with specific embodiment, purpose is to make advantage of the present invention fuller and more accurate, and unrestricted the present invention.
Embodiment 1
(a) preparation of α-Yang Daiwuersuan dimethyl ester
In the 250ml three-necked bottle, add anhydrous methanol (100ml), pentanedioic acid (14.6g; 0.1mol), be cooled to 0 ℃, charge into hydrogen chloride gas until saturated; Temperature control continues to stir 20h in 0～10 ℃; Add frozen water (100ml), chloroformic solution (100ml), separatory; Organic phase is washed with saturated sodium bicarbonate; Be washed with water to neutrality again, anhydrous magnesium sulfate drying directly is used for next step.
(b) preparation of 3-bromo-2-oxopentanedioic acid methyl esters
(63.5g, 0.28mol), ethyl acetate (300ml) joins in the 1L there-necked flask, stirs into suspension-s, goes on foot the chloroformic solution (100ml) of liquid in the dropping, finishes temperature rising reflux reaction 18h with cupric bromide.Be cooled to room temperature, suction filtration reclaims solvent, gets blackish green liquid (22.7g, two step yields are 89.7%).
(c) preparation of 2-methoxycarbonyl-3-imidazo [1,2-a] pyridylacetic acid(HPAC) methyl esters
In the 250ml there-necked flask, add the 2-aminopyridine (7.1g 74.8mmol), 95% ethanol (80ml), stirs into homogeneous phase, add again 3-bromo-2-oxopentanedioic acid methyl esters (22.7g, 89.7mmol), heating reflux reaction 1h.Reclaim solvent, debris adds distilled water (30ml), and ethyl acetate (20ml) extraction discards organic phase, and water is regulated pH to 7～8 with saturated sodium bicarbonate solution, separates out yellow solid, and the acetone-water recrystallization gets off-white color solid (13.5g, yield 73%).
(d) preparation of 2-carboxyl-3-imidazo [1,2-a] pyridylacetic acid(HPAC)
In the 50ml there-necked flask, add 2-methoxycarbonyl-3-imidazo [1; 2-a] and the pyridylacetic acid(HPAC) methyl esters (3.7g, 14.9mmol), 1,4-dioxane (30ml); Distilled water (10ml); Lithium hydroxide (0.9g, 37.5mmol), heating reflux reaction 5h; Reclaim solvent; 10% acetate is regulated pH to 5～6, separates out yellow solid (2.8g, yield 86%).
(e) preparation of 2-(imidazo [1,2-a] pyridin-3-yl) acetate
With 2-carboxyl-3-imidazo [1,2-a] pyridylacetic acid(HPAC) (2.8g, 12.7mmol), terepthaloyl moietie (20ml); (1.6g 0.025mol) joins in the 50ml there-necked flask copper powder, is heated to 190 ℃ of reaction 6h; Reaction is finished, and is cooled to room temperature, adds distilled water (10ml); Suction filtration, filtrating is with propyl carbinol (10ml*3) extraction, and saturated aqueous common salt (20ml) washs; Revolve and desolventize, add acetone, separate out little yellow solid; Water-ethyl alcohol recrystallization gets white solid (1.7g, yield 75%).
Embodiment 2.
(a) preparation of α-Yang Daiwuersuan diethyl ester
Dehydrated alcohol in the 500ml three-necked bottle (280ml); Be cooled to 0 ℃; Charge into hydrogen chloride gas until saturated, gradation add pentanedioic acid (29.2g, 0.2mol), temperature control continues to stir 3h in 0～10 ℃; Add frozen water (200ml); Chloroformic solution (200ml) separatory, organic phase is washed with saturated sodium bicarbonate, and water washing is to neutral again; Anhydrous magnesium sulfate drying directly is used for next step.
(b) preparation of 3-bromo-2-oxopentanedioic acid ethyl ester
(128.7g, 0.576mol), ethyl acetate (600ml) joins in the 1L there-necked flask, stirs into suspension-s, goes on foot the chloroformic solution (200ml) of liquid in the dropping, finishes temperature rising reflux reaction 18h with cupric bromide.Be cooled to room temperature, suction filtration reclaims solvent, gets blackish green liquid (49g, 87.2%).
(c) preparation of 2-ethoxycarbonyl-3-imidazo [1,2-a] pyridylacetic acid(HPAC) ethyl ester
In the 250ml there-necked flask, add the 2-aminopyridine (13.7g 145.3mol), 95% ethanol (100ml), stirs into homogeneous phase, add again 3-bromo-2-oxopentanedioic acid ethyl ester (49g, 174.4mmol), heating reflux reaction 2h.Reclaim solvent, debris adds distilled water (100ml), and ethyl acetate (60ml) extraction discards organic phase, and water is regulated pH to 7～8 with saturated sodium bicarbonate solution, separates out yellow solid, and Virahol-water recrystallization gets off-white color solid (30.9g, yield 77%).
(d) preparation of 2-carboxyl-3-imidazo [1,2-a] pyridylacetic acid(HPAC)
In the 250ml there-necked flask, add 2-ethoxycarbonyl-3-imidazo [1; 2-a] and the pyridylacetic acid(HPAC) ethyl ester (21.3g, 77mmol), 1,4-dioxane (100ml); Distilled water (30ml); Lithium hydroxide (5.5g, 231mmol), heating reflux reaction 7h; Reclaim solvent; 10% acetate is regulated pH to 5～6, separates out yellow solid (14.1g, yield 83%).
(e) preparation of 2-(imidazo [1,2-a] pyridin-3-yl) acetate
With 2-carboxyl-3-imidazo [1; 2-a] pyridylacetic acid(HPAC) (14.1g; 63.9mmol), terepthaloyl moietie (140ml); (8.1g 0.127mol) joins in the 250ml there-necked flask copper powder, is heated to 190 ℃ of stirring reaction 6h; Reaction is finished; Be cooled to room temperature, add distilled water (50ml), suction filtration; Filtrating extracts with propyl carbinol (30ml*3); The 0.2%EDTA-2Na solution washing, saturated common salt washs, and revolves to desolventize; Add Virahol; Separate out little yellow solid, water-ethyl alcohol recrystallization gets white solid (8.2g, yield 72.6%).
Claims (8)
1. the preparation method of an osteosporosis resistant medicament minodronic acid key intermediate is characterized in that:
(1) α-Yang Daiwuersuan is under certain temperature and catalytic condition and alkyl alcohol generation esterification;
(2) bromo takes place in α-Yang Daiwuersuanzhi and bromo agent in certain solvent;
(3) cyclization takes place in 3-bromo-2-oxopentanedioic acid ester and 2-aminopyridine in certain solvent;
(4) cyclocomplex in certain solvent, alkaline condition issues unboiled water and separates;
(5) decarboxylation takes place and generates minodronic acid key intermediate 2-(imidazo [1,2-a] pyridin-3-yl) acetate under catalyst action in hydrolyzate in certain temperature and solvent.
2. the preparation method of osteosporosis resistant medicament minodronic acid key intermediate according to claim 1 is characterized in that: the used alcohol of esterification is C
1～C
5Alkyl alcohol; Temperature of reaction is 0～30 ℃, preferred 0～10 ℃; Used catalyzer is a hydrogen chloride gas.
3. the preparation method of osteosporosis resistant medicament minodronic acid key intermediate according to claim 1 is characterized in that: the selected bromo agent of bromo is a cupric bromide; The mixed solution of described solvent ethyl acetate of bromo and chloroform.
4. the preparation method of osteosporosis resistant medicament minodronic acid key intermediate according to claim 1 is characterized in that: generating the used catalyzer of cyclocomplex is bivalent cupric ion, preferred 95% ethanol of described solvent or acetonitrile.
5. the preparation method of osteosporosis resistant medicament minodronic acid key intermediate according to claim 1 is characterized in that: the mol ratio of 3-bromo-2-oxopentanedioic acid ester and 2-aminopyridine is 1～1.5: 1, preferred 1.1～1.2: 1.
6. the preparation method of osteosporosis resistant medicament minodronic acid key intermediate according to claim 1 is characterized in that: the described alkali of hydrolysis is sodium hydroxide, potassium hydroxide, lithium hydroxide, preferred lithium hydroxide.
7. the preparation method of osteosporosis resistant medicament minodronic acid key intermediate according to claim 1; It is characterized in that: the temperature of decarboxylic reaction is 190～220 ℃; Described catalyzer is a copper powder, and described solvent can be terepthaloyl moietie or quinoline, preferred terepthaloyl moietie.
8. the preparation method of osteosporosis resistant medicament minodronic acid key intermediate according to claim 1; It is characterized in that: 2-(imidazo [1; 2-a] pyridin-3-yl) the purified solvent of acetate can be methyl alcohol, ethanol, tetrahydrofuran (THF), 1; The mixed solution of single solvents such as 4-dioxane, Glacial acetic acid or they and water, the mixed solution of preferred alcohol and water.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102738060A (en) * | 2012-07-02 | 2012-10-17 | 中国科学院上海微系统与信息技术研究所 | Preparation method of gate oxide integrity (GOI) wafer structure |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5464843A (en) * | 1992-06-23 | 1995-11-07 | G.D. Searle & Co. | Imidazo[1,2-a]pyridinyldiacid compounds for cognitive enhancement and for treatment of cognitive disorders and neutrotoxic injury |
-
2011
- 2011-07-14 CN CN2011102080844A patent/CN102344448A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5464843A (en) * | 1992-06-23 | 1995-11-07 | G.D. Searle & Co. | Imidazo[1,2-a]pyridinyldiacid compounds for cognitive enhancement and for treatment of cognitive disorders and neutrotoxic injury |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102738060A (en) * | 2012-07-02 | 2012-10-17 | 中国科学院上海微系统与信息技术研究所 | Preparation method of gate oxide integrity (GOI) wafer structure |
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Application publication date: 20120208 |