CN104558028A - Preparation method for alendronate sodium - Google Patents
Preparation method for alendronate sodium Download PDFInfo
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- CN104558028A CN104558028A CN201410821858.4A CN201410821858A CN104558028A CN 104558028 A CN104558028 A CN 104558028A CN 201410821858 A CN201410821858 A CN 201410821858A CN 104558028 A CN104558028 A CN 104558028A
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- alendronate sodium
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Abstract
The invention discloses a preparation method for alendronate sodium, and belongs to the technical field of medicine synthesis. The key points of the technical scheme provided by the invention are as follows: the preparation method for the alendronate sodium comprises the following steps: sequentially adding 4-aminobutyric acid, phosphorous acid and ionic liquid in a reaction kettle, adding phosphorus trichloride when heating to 60-65 DEG C, controlling the temperature to be 55-65 DEG C for reacting, and refining to obtain white crystalline powder alendronate sodium trihydrates. According to the preparation for the alendronate sodium, a new medicine alendronate sodium is synthesized by taking the ionic liquid as a reaction medium; compared with the prior art, the preparation method for the alendronate sodium has the advantages that the reaction conditions are mild, operations are simple, products are easy to separate and purify, the yield and the purity are high, the residual quantity of related substances and organic solvents is small and the medical standards are met, the environment friendliness is achieved, and the ionic liquid can be utilized as the reaction medium and also has a catalytic effect.
Description
Technical field
The invention belongs to medical synthesis technical field, be specifically related to a kind of preparation method of alendronate sodium.
Background technology
Alendronate sodium (Alendronate sodium 1) chemistry ALENDRONATE one sodium salt trihydrate by name, is developed by Italian Gentili company, first goes on the market in June, 1993 in Italy.U.S. FDA approved its be the medicine of osteoporosis, it has and powerful suppresses bone resorption, reduces bone conversion, prevents bone loss, increases bone amount, reduces the effects such as incidence of fracture, and its therapeutic dose does not cause mineralising obstacle.In addition, alendronate sodium has Prevention and Curation effect to post-menopausal osteoporosis and primary osteoporosis.Current biphosphonates is still in the starting stage of clinical application in China, but achieves the progress of advancing by leaps and bounds in recent years, and market application foreground is wide.The synthesising method reacting condition of bibliographical information is harsher, and uses the larger methyl alcohol of toxicity, chloroform and chlorobenzene, and Determination of Residual Organic Solvents easily exceeds standard, and productive rate is low, and product purity is low, and contaminate environment does not meet medicinal standard, is unfavorable for suitability for industrialized production.
Summary of the invention
The technical problem that the present invention solves there is provided a kind of raw materials technology and is easy to get, and easy and simple to handle, yield is high, and product purity is high, environmental friendliness and meet the preparation method of the alendronate sodium of pharmaceutical production requirement.
For solving the problems of the technologies described above, the present invention adopts following technical scheme: a kind of preparation method of alendronate sodium, it is characterized in that comprising the following steps:
(1) by 4-Aminobutanoicacid, phosphorous acid and ionic liquid join in reactor successively, phosphorus trichloride is added when being heated to 60-65 DEG C, temperature control 55-65 DEG C of reaction, cool after reaction terminates, add dried up in 20 DEG C time, to add in deionized water process temperature control lower than 30 DEG C, then filtering insolubles, filtrate reflux, be cooled with an ice bath after backflow, pH is regulated to be 4.3 with the sodium hydroxide solution that mass concentration is 50% again, separate out solid, suction filtration after stirring, crude product alendronate sodium is obtained with the ethanol purge that volume fraction is 95% again after filter cake washed with de-ionized water twice,
(2) in crude product alendronate sodium, add deionized water, wherein add 1L deionized water, reflux in every 15g crude product alendronate sodium, heat filter, filtrate leaving standstill is separated out, suction filtration, filter cake deionized water wash, then drying obtains white crystalline powder clinic effect of alendronate sodium trihydrate.
Further preferably, described ionic liquid is 1-normal-butyl-3-methyl imidazolium tetrafluoroborate ([bmim] BF4), N-ethylpyridine a tetrafluoro borate ([EPy] BF4), 1-normal-butyl-3-Methylimidazole hexafluorophosphate ([bmim] PF6), 1-hydroxyethyl-2,3-methylimidazole villaumite (LOH), 1-nitrile propyl group-3-Methylimidazole villaumite (LCN) or 1-propyloic-3-Methylimidazole villaumite (LOOH).
The present invention is that reaction medium has synthesized new drug alendronate sodium with ionic liquid, compared with prior art, the method has reaction conditions gentleness, simple to operate, and product is easy to separation and purification, productive rate is high, purity is high, and related substance and Determination of Residual Organic Solvents are very little, meet medicinal standard, environmentally friendly, ionic liquid not only can be made reaction medium but also plays the advantages such as katalysis.And reaction terminate after, ionic liquid can reclaim and effectively repeatedly reuse.This synthetic method is that pharmaceutical synthesis provides a green and effectively synthesizes new way.Simultaneously, what ionic liquid had can reclaim and reusable special performance (revolves steaming with the ionic liquid crossed during recovery, at 110 DEG C of i.e. reusable edibles that dry to constant weight), not only solve because discharging the problem of environmental pollution brought, but also avoiding the wasting of resources that the disposable consumption of reaction medium in chemical reaction causes, these advantages all make this green reaction medium of ionic liquid have a good application prospect in pharmaceutical synthesis.
Accompanying drawing explanation
Fig. 1 is reaction product alendronate sodium yield variation with temperature curve in the embodiment of the present invention 1, Fig. 2 is reaction product alendronate sodium yield curve over time in the embodiment of the present invention 1, and Fig. 3 is that ionic liquid of the present invention reuses the influence curve of number of times to alendronate sodium yield.
Embodiment
Be described in further details foregoing of the present invention by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Synthetic route of the present invention is:
1, by 4-Aminobutanoicacid 25.8g(0.25mol), phosphorous acid 30.3g(0.37mol) and 1-normal-butyl-3-methyl imidazolium tetrafluoroborate [bmin] BF
4(25mL) add in the three-necked bottle with reflux condensing tube successively, when being heated to 60-65 DEG C, drip phosphorus trichloride 67.9g(0.5mol), within 20 minutes, drip off.Dropwise rear control temperature at about 60 DEG C (the highest be no more than 65 DEG C) reaction 15h.After reaction terminates, cool, in 20 DEG C time, add 250mL go dried up, in adition process, temperature control is lower than 30 DEG C.Suction filtration, filtering insolubles, filtrate reflux 6h.After backflow, with cryosel bath cooling, regulate pH to be 4.3 with the sodium hydroxide solution that mass concentration is 50%, separate out solid.Stir 2h again, suction filtration, filter cake deionized water is washed after twice and is washed once with the ethanol that volume fraction is 95% again, obtains crude product alendronate sodium.
2, alendronate sodium is refined: by crude product alendronate sodium quality (g): deionized water volume (L)=1.5:1, adds deionized water in crude product, reflux 15 minutes, and heat filter, filtrate leaving standstill separates out (also can slowly stir).Suction filtration, filter cake deionized water wash, first forced air drying, then vacuum-drying at 40 DEG C, obtain white crystalline powder clinic effect of alendronate sodium trihydrate 75.02g, productive rate: 92.3%, content: 99.7%(HPLC area normalization method).mp239℃。IR:1233cm
-1for the stretching vibration peak of P=O, 547cm
-1, 473cm
-1for the skeletal vibration of phosphate group, 1062cm
-1for the stretching vibration peak of P-O, 3487cm
-1for the stretching vibration peak of N-H, 1646cm
-1for the flexural vibration peak of N-H, 3237cm
-1for the stretching vibration peak of O-H, 2964cm
-1for the antisymmetric stretching vibration of C-H, 2802cm
-1for the symmetrical stretching vibration of C-H, 1441cm
-1for the symmetric curvature of C-H is vibrated.
1HNMR (400MHz,D
2O),δ:3.01(2H,t), 1.97(4H,m)。
Embodiment 2
Temperature of reaction is on the impact of alendronate sodium yield
Fix other condition constant, change temperature of reaction, specifically investigate temperature of reaction that 4-Aminobutanoicacid and phosphorous acid and phosphorus trichloride react to the impact of alendronate sodium yield.The results are shown in Figure 1, test-results shows, along with temperature raises, productive rate increases gradually, but when reflux temperature is higher, yield is on a declining curve.When temperature is too high, reaction reagent volatilization and leakage losses must increase, and productive rate reduces.When reflux temperature is lower, speed of reaction is slow, reacts insufficient, so yield is low.Test shows at 50 DEG C, reaction needed 3 days, and at about 60 DEG C, reaction is spent the night and just can be completed, and has very high yield.Therefore, optimal reaction temperature is about 60 DEG C.
Embodiment 3
Reaction times is on the impact of alendronate sodium yield
When synthesizing alendronate sodium in ionic liquid, it is constant to fix other condition, only changes the reaction times, has specifically investigated the impact of reaction times on alendronate sodium yield.The results are shown in Figure 2, test-results shows, when the reaction times is shorter, not exclusively, yield is lower in hydrolysis, and when the reaction times is longer, yield improves little, and by product increases, and product purity reduces.Reaction Best Times should control at about 6h, and reaction yield is higher, the high and less expensive of product purity.
Embodiment 4
Ionic liquid reuses the impact of number of times on alendronate sodium yield
Can reaction medium used reclaim and reuse is the important content that " Green Chemistry " is paid close attention to, and the present embodiment specifically examines ionic liquid and reuses situation for the synthesis of alendronate sodium.The results are shown in Figure 3, as seen from Figure 3, ionic liquid is after 5 times use, and product yield just starts to reduce, and this illustrates that ionic liquid is recyclable and effectively reuse, and repeat performance well, and it is a kind of green and environment-friendly solvent that can be recycled.
Embodiment 5
Different ionic liquid is on the impact of alendronate sodium yield
Ionic liquid 1-normal-butyl-3-methyl imidazolium tetrafluoroborate ([bmim] BF has been investigated respectively under the same terms
4), N-ethylpyridine a tetrafluoro borate ([EPy] BF
4), 1-normal-butyl-3-Methylimidazole hexafluorophosphate ([bmim] PF
6), 1-hydroxyethyl-2,3-methylimidazole villaumite (LOH), 1-nitrile propyl group-3-Methylimidazole villaumite (LCN) or 1-propyloic-3-Methylimidazole villaumite (LOOH) be on the impact of alendronate sodium yield.The results are shown in Table 1, test-results shows that the yield impact of different ionic liquid on synthesis is little.
Table 1 different ionic liquid is on the impact of reaction yield
| Ionic liquid | Yield/% |
| [bmim]BF 4 | 92.3 |
| [EPy]BF 4 | 92.5 |
| [bmim]PF 6 | 92.1 |
| LOH | 93.63 |
| LCN | 93.87 |
| LOOH | 93.13 |
More than experiment shows, be that reaction medium has synthesized new drug alendronate sodium with ionic liquid, compared with prior art, the method has reaction conditions gentleness, simple to operate, product is easy to separation and purification, and productive rate is high, and purity is high, related substance and Determination of Residual Organic Solvents are very little, meet medicinal standard, environmentally friendly, ionic liquid not only can be made reaction medium but also plays the advantages such as katalysis.And reaction terminate after, ionic liquid can reclaim and effectively repeatedly reuse.This synthetic method is that pharmaceutical synthesis provides a green and effectively synthesizes new way.Simultaneously, what ionic liquid had can reclaim and reusable special performance (revolves steaming with the ionic liquid crossed during recovery, at 110 DEG C of i.e. reusable edibles that dry to constant weight), not only solve because discharging the problem of environmental pollution brought, but also avoiding the wasting of resources that the disposable consumption of reaction medium in chemical reaction causes, these advantages all make this green reaction medium of ionic liquid have a good application prospect in pharmaceutical synthesis.
Above embodiment is only and technological thought of the present invention is described, can not limit protection scope of the present invention with this, and every technological thought proposed according to the present invention, any change that technical scheme basis is done, all falls within scope.
Claims (2)
1. a preparation method for alendronate sodium, is characterized in that comprising the following steps:
(1) by 4-Aminobutanoicacid, phosphorous acid and ionic liquid join in reactor successively, phosphorus trichloride is added when being heated to 60-65 DEG C, temperature control 55-65 DEG C of reaction, cool after reaction terminates, add dried up in 20 DEG C time, to add in deionized water process temperature control lower than 30 DEG C, then filtering insolubles, filtrate reflux, be cooled with an ice bath after backflow, pH is regulated to be 4.3 with the sodium hydroxide solution that mass concentration is 50% again, separate out solid, suction filtration after stirring, crude product alendronate sodium is obtained with the ethanol purge that volume fraction is 95% again after filter cake washed with de-ionized water twice,
(2) in crude product alendronate sodium, add deionized water, wherein add 1L deionized water, reflux in every 15g crude product alendronate sodium, heat filter, filtrate leaving standstill is separated out, suction filtration, filter cake deionized water wash, then drying obtains white crystalline powder clinic effect of alendronate sodium trihydrate.
2. the preparation method of alendronate sodium according to claim 1, it is characterized in that: described ionic liquid is 1-normal-butyl-3-methyl imidazolium tetrafluoroborate, N-ethylpyridine a tetrafluoro borate, 1-normal-butyl-3-Methylimidazole hexafluorophosphate, 1-hydroxyethyl-2,3-methylimidazole villaumite, 1-nitrile propyl group-3-Methylimidazole villaumite or 1-propyloic-3-Methylimidazole villaumite.
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Non-Patent Citations (1)
| Title |
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| 郝二军 等: "阿仑膦酸钠合成工艺的改进", 《华西药学杂志》 * |
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Application publication date: 20150429 |