CN101863919B - Preparation method of compound sodium ibandronate - Google Patents
Preparation method of compound sodium ibandronate Download PDFInfo
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- CN101863919B CN101863919B CN2010102168761A CN201010216876A CN101863919B CN 101863919 B CN101863919 B CN 101863919B CN 2010102168761 A CN2010102168761 A CN 2010102168761A CN 201010216876 A CN201010216876 A CN 201010216876A CN 101863919 B CN101863919 B CN 101863919B
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- phosphorus trichloride
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Abstract
The invention relates to a synthetic method of sodium ibandronate, which comprises the following steps: adding 3-(N-methyl-N-n-amyl amine)propanoic acid hydrochloride, orthophosphorous acid and phosphorus trichloride into a solvent, reacting to obtain ibandronic acid, and forming the salt of the ibandronic acid and sodium hydroxide to obtain the sodium ibandronate, and is characterized in that the added solvent is acetonitrile, the acetonitrile is used as the solvent, and a reaction product can be uniformly dispersed in the solvent, thereby the defect that other solvents enable the product to be in the shape of oil blocks to enable stirring to be more difficult is overcome, so that the process can be successfully used for large-scale production; the mol ratio of the 3-(N-methyl-N-n-amyl amine)propanoic acid hydrochloride to the phosphorus trichloride is 1:1.20 to 1.39, and the usage amount of the phosphorus trichloride is reduced, so that the refinement times can be reduced, thereby the refinement loss is reduced.
Description
Technical field
The invention belongs to medicine synthesising process, particularly a kind of synthesis technique of ibronate sodium.
Background technology
Bisphosphonates is one of focus of world's field of medicaments research recently, and application prospect is extremely wide.
Ibronate sodium be latest generation promptly the 3rd generation bisphosphonates, have efficient, low toxicity and advantage such as easy to use, have oral simultaneously and two kinds of formulations of vein.
Ibronate sodium can also prevent bone transfer and mammary cancer bone to shift the generation of back bone incident, and can prevent and treat osteoporosis except the treatment malignant metastatic tumor of bone.It is the widest diphosphonate medicine of present indication.
Ibronate sodium is used for the treatment of diseases such as hypercalcemia that malignant tumour causes, ostalgia, scleromalacia clinically.
Present national malignant tumor patient Estimate of Total Number is about 4,500,000 people, and the cancer patients of about 25%-85% (average 50%) becomes celestial and finds to have bone to shift, and ostalgia once appearred in patients wherein more than half.Pathological manifestations mostly is molten bone destruction, and blood calcium raises.Therefore, suppressing osteoclasia, alleviate ostalgia, is the important content that improves patient's life quality, and the hypercalcemia medicine has sizable market capacity.
The indication that ibronate sodium is new clinically is used for prevention and treatment osteoporosis.The sickness rate of the osteoporosis that various factors causes, particularly senile osteoporosis significantly increases.Therefore, the hypercalcemia that malignant tumour is caused and the prevention and the treatment of senile osteoporosis are that human society enters the serious challenge that 21 century faces.Along with the improvement and the medical skill of China people growth in the living standard, quality of life are upgraded day by day, national mean lifetime constantly prolongs, China is just entering an astogeny society, aging population trend is more and more obvious, and the elderly easily suffers from osteoporosis and diseases related, this disease is classified as one of three big diseases that threaten the elderly by WHO, be the important illness that the serious harm senior health and fitness is disabled.
Ibronate sodium also is used for postmenopausal women's osteoporosis, and this medicine is first and every month of the unique so far postmenopausal women's of being used for osteoporosis uses 1 time medicine that its market outlook are inestimable.
Ibronate sodium (Sodium Ibandronate), chemical name: [1-hydroxyl-3-(N-methyl-N-n-pentyl amido) propylidene] two phosphonic acids list sodium salt monohydrates, molecular formula:
C9H22NNaO7P2·H2O
Structural formula:
Disclose many synthesis routes of ibronate sodium both at home and abroad, what wherein be used to produce mainly is by 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate, and phosphorous acid, phosphorus trichloride add appropriate solvent and reacts, and obtain Ibandronic acid.Ibandronic acid and sodium hydroxide salify obtain ibronate sodium.Operational path is as follows:
International Patent Application WO 03/097055 discloses carries out the solvent that above-mentioned reaction is used, and has comprised fragrant benzene ring compound, as toluene, and dimethylbenzene, benzene, perhaps inertia silicone oil.
US 7214818B2 discloses and has carried out the solvent that above-mentioned reaction is used, and comprises phosphoric acid ester, carbonic ether, particularly diethyl carbonate.
We find by experiment: use above-mentioned solvent that the common shortcoming is arranged: resultant of reaction can not be dispersed in the solvent, resultant is the oil clot shape, adhere on the stirring rod, not only the influence reaction is proceeded, and make stirring more and more difficult, this situation will make technology be difficult to use in big production as not solving.
Simultaneously, we find: in the reaction, used phosphorus trichloride, excessive phosphorus trichloride and water effect generate hydrochloric acid, and then generate sodium-chlor with the sodium hydroxide reaction.The drug standard of ibronate sodium has strict requirement to muriate, and muriate detects concentration must not be greater than 0.030%.The process for refining of ibronate sodium, the most difficult is to remove muriate, because ibronate sodium, sodium-chlor are all soluble in water, and ibronate sodium is only soluble in water, be insoluble to other solvents, refining solvent must have water, has the part ibronate sodium soluble in water when refining, and treatment losses is very big, often to make with extra care 3-4 time each treatment losses about 10% repeatedly.
Summary of the invention
A kind of synthetic method of ibronate sodium may further comprise the steps: with 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate, phosphorous acid, phosphorus trichloride adds in the solvent, and reaction obtains Ibandronic acid, Ibandronic acid and sodium hydroxide salify obtain ibronate sodium, and the solvent of adding is an acetonitrile.
3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate: acetonitrile=1: 4-8 (w/w).
3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate, the mol ratio of phosphorus trichloride is: 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate: phosphorus trichloride=1: 1.20-1.39.
In adding the backflow device, add 3-(N-methyl-N-amylamine base) propionic salt hydrochlorate, phosphorous acid, acetonitrile, stir, slowly be warming up to 70 ℃, drip phosphorus trichloride, connect device for absorbing tail gas during dropping and absorb irritating HCl gas, after phosphorus trichloride dropwises there-necked flask slowly is warming up to 95--100 ℃, can be observed resultant of reaction and be dispersed in the solvent, do not have block to occur, temperature remains on 95-100 ℃, stirs.Be cooled to 60-65 ℃, pour beaker into, filter, get the Ibandronic acid crude product.
With the Ibandronic acid crude product, drip water, add NaOH, adjusting pH4.0-4.6 filters, and decompression is concentrated into raffinate with filtrate, adds ethanol, crystallization, ice bath stirs, and filters, and gets the ibronate sodium crude product.
We are surprised to find that, use acetonitrile to make solvent, resultant of reaction can be dispersed in the solvent, this has overcome above-mentioned solvent makes resultant be the oil clot shape, adhere on the stirring rod, the influence reaction is proceeded, make and stir more and more difficult shortcoming, make this technology can be used for big production smoothly, the key that solves the problems of the technologies described above may be the polarity and the fragrant benzene ring compound of acetonitrile, phosphoric acid ester, and carbonic ether has difference, and certain avidity is arranged with the resultant Ibandronic acid, avoided the situation of resultant caking.
We find, 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate: acetonitrile=1: 4-8 (w/w).Helping resultant is dispersed in the solvent.
We find that also it is refining that the consumption of phosphorus trichloride influences ibronate sodium.
Therefore, reduce the usage quantity of phosphorus trichloride, refining number of times is reduced, treatment losses reduces.
US 7214818B2 discloses 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate, phosphorous acid, the proportioning of phosphorus trichloride: 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate: phosphorus trichloride: the molar ratio range of phosphorous acid is 1: 3: 3 to 1: 1.4: 2.4, preferred 1: 1.6: 2.4 to 1: 1.4: 2.4.
We find: the consumption of phosphorus trichloride can also reduce, 3-(N-methyl N-n-pentyl amine) propionic salt hydrochlorate, the mol ratio of phosphorus trichloride is: 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate: phosphorus trichloride=1: 1.20-1.39, can guarantee to react and finish, and, ibronate sodium only need be made with extra care 2 times, and quality can reach drug standard.
Therefore, we have invented 3-(N-methyl N-n-pentyl amine) propionic salt hydrochlorate, and the mol ratio of phosphorus trichloride is: 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate: phosphorus trichloride=1: 1.20-1.39, can reduce the refining number of times of ibronate sodium, reduce treatment losses, improve product yield.
Specific embodiment
Embodiment 1
Material name consumption mole number mol ratio
3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate 100 grams 0.477 1
Phosphorus trichloride 79 grams 0.572 1.2
Phosphorous acid 121 grams 1.479 3.1
Acetonitrile 400 grams
The about 100mL of sodium hydroxide (50%)
Water 400mL
Technological process:
In adding the 1L there-necked flask of backflow device, add 3-(N-methyl-N-amylamine base) propionic salt hydrochlorate 100g, phosphorous acid 121g, acetonitrile 400 grams.Stir, slowly be warming up to 70 ℃, drip phosphorus trichloride 79 grams,, connect device for absorbing tail gas during dropping and absorb irritating HCl gas.After phosphorus trichloride dropwises there-necked flask slowly is warming up to 95-100 ℃,, can be observed resultant of reaction and be dispersed in the solvent, there is not block to occur, temperature remains on 95-100 ℃, stirs 12h.Be cooled to 60-65 ℃, pour beaker into, filter, get the Ibandronic acid crude product.
The Ibandronic acid crude product is added in the 1L there-necked flask, slowly drip water 400mL then, drip and finish, temperature rising reflux 3h is cooled to 20-25 ℃, the about 100mL of Dropwise 5 0%NaOH, regulate pH4.0-4.6, filter, decompression is concentrated into raffinate with filtrate, adds ethanol 200mL, crystallization, ice bath stirs 2h, filters, and gets ibronate sodium crude product 137 grams (pure).
Refining for the first time: ibronate sodium crude product 137 gram adding distil water 300mL, heat temperature raising to 50 ℃ dissolving removes by filter insolubles, slowly adds ethanol 150mL in the filtrate, stirs and separates out until a large amount of solids.Filter, get ibronate sodium (smart 1) 132 grams (pure).
Refining for the second time: ibronate sodium (smart 1) 132 gram adding distil water 300mL, heat temperature raising to 50 ℃ dissolving slowly adds ethanol 150mL, stirs and separates out until a large amount of solids.Filter, drying under reduced pressure gets ibronate sodium (smart 2) 120 grams (pure).
Total recovery: 70.1%
Record the infrared absorption spectrum data of ibronate sodium
IR (pressing potassium bromide troche cm
-1) 3680,3170,2962,2876,2384,1674,1653,1492,1427,1379,1290,1160,1069,1032,957,904,762,676,590,558,472,418
After testing, quality meets the national drug standards: WS1-(X-250)-2003Z.
Embodiment 2
Material name consumption mole number mol ratio
3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate 100 grams 0.477 1
Phosphorus trichloride 92 grams 0.662 1.39
Phosphorous acid 121 grams 1.479 3.1
Acetonitrile 800 grams
The about 100mL of sodium hydroxide (50%)
Water 400mL
Technological process:
In adding the 2L there-necked flask of backflow device, add 3-(N-methyl N-amylamine base) propionic salt hydrochlorate 100g, phosphorous acid 121g, acetonitrile 800 grams.Stir, slowly be warming up to 70 ℃, drip phosphorus trichloride 92 grams,, connect device for absorbing tail gas during dropping and absorb irritating HCl gas.After phosphorus trichloride dropwises there-necked flask slowly is warming up to 95-100 ℃,, can be observed resultant of reaction and be dispersed in the solvent, there is not block to occur, temperature remains on 95-100 ℃, stirs 12h.Be cooled to 60-65 ℃, pour beaker into, filter, get the Ibandronic acid crude product.
The Ibandronic acid crude product is added in the 1L there-necked flask, slowly drip water 400mL then, drip and finish, temperature rising reflux 3h is cooled to 20-25 ℃, the about 100mL of Dropwise 5 0%NaOH, regulate pH4.0-4.6, filter, decompression is concentrated into raffinate with filtrate, adds ethanol 200mL, crystallization, ice bath stirs 2h, filters, and gets ibronate sodium crude product 150 grams (pure).
Refining for the first time: ibronate sodium crude product 150 gram adding distil water 300mL, heat temperature raising to 50 ℃ dissolving removes by filter insolubles, slowly adds ethanol 150mL in the filtrate, stirs and separates out until a large amount of solids.Filter, get ibronate sodium (smart 1) 141 grams (pure).
Refining for the second time: ibronate sodium (smart 1) 141 gram adding distil water 300mL, heat temperature raising to 50 ℃ dissolving slowly adds ethanol 150mL, stirs and separates out until a large amount of solids.Filter, drying under reduced pressure gets ibronate sodium (smart 2) 130 grams (pure).
Total recovery: 75.9%
After testing, quality meets the national drug standards: WS1-(X-250)-2003Z.
Embodiment 3
Material name consumption mole number mol ratio
3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate 100 grams 0.477 1
Phosphorus trichloride 83 grams 0.596 1.25
Phosphorous acid 121 grams 1.479 3.1
Acetonitrile 600 grams
The about 100mL of sodium hydroxide (50%)
Water 400mL
Technological process:
In adding the 2L there-necked flask of backflow device, add 3-(N-methyl-N-amylamine base) propionic salt hydrochlorate 100g, phosphorous acid 121g, acetonitrile 600 grams.Stir, slowly be warming up to 70 ℃, drip phosphorus trichloride 83 grams,, connect device for absorbing tail gas during dropping and absorb irritating HCl gas.After phosphorus trichloride dropwises there-necked flask slowly is warming up to 95-100 ℃,, can be observed resultant of reaction and be dispersed in the solvent, there is not block to occur, temperature remains on 95-100 ℃, stirs 12h.Be cooled to 60-65 ℃, pour beaker into, filter, get the Ibandronic acid crude product.
The Ibandronic acid crude product is added in the 1L there-necked flask, slowly drip water 400mL then, drip and finish, temperature rising reflux 3h is cooled to 20-25 ℃, the about 100mL of Dropwise 5 0%NaOH, regulate pH4.0-4.6, filter, decompression is concentrated into raffinate with filtrate, adds ethanol 200mL, crystallization, ice bath stirs 2h, filters, and gets ibronate sodium crude product 152 grams (pure).
Refining for the first time: ibronate sodium crude product 155 gram adding distil water 300mL, heat temperature raising to 50 ℃ dissolving removes by filter insolubles, slowly adds ethanol 150mL in the filtrate, stirs and separates out until a large amount of solids.Filter, get ibronate sodium (smart 1) 142 grams (pure).
Refining for the second time: ibronate sodium (smart 1) 132 gram adding distil water 300mL, heat temperature raising to 50 ℃ dissolving slowly adds ethanol 150mL, stirs and separates out until a large amount of solids.Filter, drying under reduced pressure gets ibronate sodium (smart 2) 131 grams (pure).
Total recovery: 76.4%
After testing, quality meets the national drug standards: WS1-(X-250)-2003Z.
Claims (4)
1. the synthetic method of an ibronate sodium, may further comprise the steps: with 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate, phosphorous acid, phosphorus trichloride adds in the solvent, reaction, obtain Ibandronic acid, Ibandronic acid and sodium hydroxide salify obtain ibronate sodium, it is characterized in that: the solvent of adding is an acetonitrile.
2. the synthetic method of ibronate sodium according to claim 1 is characterized in that: 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate: acetonitrile=1: 4-8, w/w.
3. the synthetic method of ibronate sodium according to claim 2, it is characterized in that: described 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate, the mol ratio of phosphorus trichloride is: 3-(N-methyl-N-n-pentyl amine) propionic salt hydrochlorate: phosphorus trichloride=1: 1.20-1.39.
4. according to the synthetic method of each described ibronate sodium of claim 1-3, it is characterized in that: in the reflux device, add 3-(N-methyl-N-amylamine base) propionic salt hydrochlorate, phosphorous acid, acetonitrile, stir, slowly be warming up to 70 ℃, drip phosphorus trichloride, connect device for absorbing tail gas during dropping and absorb irritating HCl gas, after phosphorus trichloride dropwises there-necked flask slowly is warming up to 95-100 ℃, can be observed resultant of reaction is dispersed in the solvent, do not have block to occur, temperature remains on 95-100 ℃, stirs; Be cooled to 60-65 ℃, pour beaker into, filter, get the Ibandronic acid crude product, the Ibandronic acid crude product, drip water, add 50%NaOH, regulate pH4.0-4.6, filter, decompression is concentrated into raffinate with filtrate, add ethanol, crystallization, ice bath stirs, and filters, and gets the ibronate sodium crude product.
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| CN102093416B (en) * | 2011-03-17 | 2013-07-24 | 南京恒生制药有限公司 | Method for synthesizing sodium ibandronate |
| CN102898466B (en) * | 2011-07-29 | 2015-05-27 | 江苏奥赛康药业股份有限公司 | Preparation method of sodium ibandronate |
| EP2767543B1 (en) * | 2011-10-14 | 2017-08-30 | Aktsionernoe Obshcestvo "Proizvodstvenno-Kommercheskaya Assotsiatsiya AZT" | Salts of carbamoyl phosphonic acid esters which act as selective inhibitors of human immunodeficiency virus hiv-1 production |
| CN104628768A (en) * | 2015-03-06 | 2015-05-20 | 江苏正大清江制药有限公司 | Preparation method of sodium ibandronate |
| CN106397479A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | Preparation method of sodium ibandronate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101048165A (en) * | 2004-10-29 | 2007-10-03 | 霍夫曼-拉罗奇有限公司 | Process for the preparation of ibandronate |
| CN101279985A (en) * | 2008-06-02 | 2008-10-08 | 深圳市汉德森技术有限公司 | Synthetic method of ibandronate |
| CN101679465A (en) * | 2007-04-11 | 2010-03-24 | 霍夫曼-拉罗奇有限公司 | Ibandronate process |
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| EP1923394A1 (en) * | 2006-11-16 | 2008-05-21 | Sandoz A/S | Reagent and use thereof for the production of bisphosphonates |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101048165A (en) * | 2004-10-29 | 2007-10-03 | 霍夫曼-拉罗奇有限公司 | Process for the preparation of ibandronate |
| CN101679465A (en) * | 2007-04-11 | 2010-03-24 | 霍夫曼-拉罗奇有限公司 | Ibandronate process |
| CN101279985A (en) * | 2008-06-02 | 2008-10-08 | 深圳市汉德森技术有限公司 | Synthetic method of ibandronate |
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