CN1325506C - Allan phosphonic acid as bone re-absorption inhibitor and its physiologically acceptable salt and their prepn - Google Patents
Allan phosphonic acid as bone re-absorption inhibitor and its physiologically acceptable salt and their prepn Download PDFInfo
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- CN1325506C CN1325506C CNB031169538A CN03116953A CN1325506C CN 1325506 C CN1325506 C CN 1325506C CN B031169538 A CNB031169538 A CN B031169538A CN 03116953 A CN03116953 A CN 03116953A CN 1325506 C CN1325506 C CN 1325506C
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- alendronic acid
- allan
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Abstract
The present invention discloses an improved preparing method for Allan phosphonic acid as a bone reabsorption inhibitor and physiologically acceptable salt. In the method, alpha-pyrrolidone used as initial raw materials reacts with a phosphorous compound in the existence of methane sulfonic acid, and the pH value of reactants is adjusted by alkali so as to obtain single potassium salt or sodium salt of Allan phosphonic acid or Allan phosphonic acid. The method is applicable to industrial production and greatly reduces cost.
Description
Technical field
The present invention relates to a kind of preparation method's of compound improvement, more specifically the preparation method of phalanges cell reabsorption inhibitor Alendronic acid and sodium salt thereof.
Background technology
Osteoporosis (osteoporosis) is a kind of common bone metabolic disease.Osteoporosis has leapt to the 7th in world's common frdquently encountered disease at present according to statistics, existing patient's number surpasses 200,000,000 people, at China 50-60 year sickness rate is 21%, 60-70 year, sickness rate was 58%, and the women after climacteric is because ovarian function is degenerated, estrogen secretion reduces, the unit volume osseous tissue reduces to be accelerated, so the sickness rate of osteoporosis and fracture complication is higher, and M-F is about 1: 8.Along with the quickening of world population aging, osteoporosis treatment has become the key areas that various countries the world of medicine extremely pays close attention to.Since the eighties, people have researched and developed the bone resorption inhibitor bisphosphonates, be successfully used to the treatment of osteoporosis, clinical research confirmation this compounds suppressing heavily absorbing, increase the bone amount, reducing and have significant curative effect and higher security aspect the incidence of fracturing of osteoclast, more and more receive the concern of Pharmaceutical Chemist.And sodium alendronate becomes first is used for treating osteoporosis by drugs approved by FDA bisphosphonate class of drugs as s-generation diphosphonate compounds.
Document is more about the synthetic method of this compound, but all methods all are to be that starting raw material makes with the γ-An Jidingsuan.Patent GB2118042 has reported that Alendronic acid is made with anhydrous sodium phosphoric acid and phosphorus trichloride reaction in chlorobenzene by γ-An Jidingsuan, and chemical equation is as follows:
But along with the carrying out of reaction, reactant can precipitate caking, can't stir, industrial and be not suitable for.The Kieczykowski report is a solvent with the methylsulfonic acid, with the γ-An Jidingsuan is raw material, anhydrous sodium phosphoric acid and phosphorus trichloride are that reaction reagent has made Alendronic acid and sodium salt thereof, this kind method has overcome the shortcoming that this type of reaction can't homogeneous phase be reacted, but this method still exists long reaction time shortcomings such as (16-20 hours), the also useful methylsulfonic acid acid anhydride of patent, the polyoxyethylene glycol report as solvent is arranged subsequently, but all be to be raw material with the γ-An Jidingsuan.
Summary of the invention
The object of the invention be to overcome prior art not enough and provide a kind of with than the more cheap raw material alpha-pyrrolidone of γ-An Jidingsuan as starting raw material, be the method that reaction reagent makes Alendronic acid and sodium salt thereof with the phosphorus compound.
Chemical equation:
The present invention implements through the following steps:
By alpha-pyrrolidone as starting raw material, in the presence of methylsulfonic acid or moisture methylsulfonic acid, reflux a few hours earlier, usually reaction is 6-8 hour, be cooled to 65-80 ℃, drip phosphorus trichloride (or dripping phosphorus oxychloride or phosphorus pentachloride) while stirring, after finishing, continue under this temperature stoichiometric number hour again, reaction is finished, stop to stir, treat that cold reactant regulates pH with alkali lye and control alkali with monovalence or diatomic hydrogen oxide compound, better oxyhydroxide is potassium hydroxide, sodium hydroxide, precipitation is separated out in placement, and products obtained therefrom is Alendronic acid or Alendronic acid list sodium salt.When being 4-5 with alkali lye conditioned reaction liquid pH, filter the precipitation of separating out, the water recrystallization then gets Alendronic acid list sodium salt again; When being 1.5-2.0, separate out precipitation, filter, then get Alendronic acid with alkali lye conditioned reaction liquid pH.
Beneficial effect:
1, the alpha-pyrrolidone of the present invention's employing has replaced γ-An Jidingsuan as starting raw material, greatly reduces cost.
2, the reaction solvent of the present invention's employing is methylsulfonic acid or aqueous methylsulfonic acid (water ratio 1-20%), is applicable to industrial production.
3, the reaction times shortens, and has reduced cost.
4, the present invention is fit to industrial mass production.
Specific implementation method
The invention will be further described below in conjunction with embodiment, but do not limit the present invention.
Embodiment
In the four-hole reaction flask, add alpha-pyrrolidone 8.6g (0.101mol), water 10.4ml (0.578mol), methylsulfonic acid 40ml, heat up and be heated to 110 ℃, back flow reaction 7h, be cooled to 75 ℃, drip phosphorus trichloride 30ml (0.345mol), continue under this temperature, to react 8h, cooling is regulated pH to 4.3 with 40%NaOH, separates out precipitation, filter, with 45ml water recrystallization, get Alendronic acid list sodium salt 26.6g, yield 81.0%, mp258-261 ℃, ultimate analysis: C
4H
12NNaO
7P
2.3H
2O theoretical value (%), C14.77, H5.54, N4.31, measured value C14.88, H5.58, N4.41,
1HNMR (D
2O/NaOD): δ 1.94-2.02 (m, 4H), 3.06 (t, 2H),
31PNMR 18.4
As with pH regulator to 1.8, then separate out and be precipitated as Alendronic acid 19.48, yield 71.9%.
Ultimate analysis: C
4H
13NO
7P
2.H
2O theoretical value (%) C17.97, H5.62, N5.24, measured value C18.04, H5.56, N5.30.
Claims (6)
1, a kind of preparation method who prepares Alendronic acid and physiologically acceptable salt thereof by alpha-pyrrolidone as starting raw material, it is characterized in that with alpha-pyrrolidone as starting raw material, existence at methylsulfonic acid or moisture methylsulfonic acid is flowed a few hours next time, be cooled to 65-80 ℃, drip phosphorus compound again, behind the stoichiometric number hour, treat that colod-application alkali regulates PH, Alendronic acid and physiologically acceptable salt thereof are separated out in control.
2, the preparation method of Alendronic acid according to claim 1 and physiologically acceptable salt thereof, it is characterized in that alpha-pyrrolidone earlier with methylsulfonic acid or moisture methylsulfonic acid in stoichiometric number hour.
3, the preparation method of Alendronic acid according to claim 2 and physiologically acceptable salt thereof is characterized in that temperature of reaction is backflow, reaction times 6-8 hour.
4, the preparation method of Alendronic acid according to claim 1 and physiologically acceptable salt thereof is characterized in that phosphorus compound is phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride.
5, the preparation method of Alendronic acid according to claim 1 and physiologically acceptable salt thereof is characterized in that regulating pH with monovalence or diatomic hydrogen oxide compound.
6, the preparation method of Alendronic acid according to claim 5 and physiologically acceptable salt thereof is characterized in that monovalence oxyhydroxide is selected from potassium hydroxide or sodium hydroxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031169538A CN1325506C (en) | 2003-05-15 | 2003-05-15 | Allan phosphonic acid as bone re-absorption inhibitor and its physiologically acceptable salt and their prepn |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031169538A CN1325506C (en) | 2003-05-15 | 2003-05-15 | Allan phosphonic acid as bone re-absorption inhibitor and its physiologically acceptable salt and their prepn |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1548442A CN1548442A (en) | 2004-11-24 |
| CN1325506C true CN1325506C (en) | 2007-07-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031169538A Expired - Fee Related CN1325506C (en) | 2003-05-15 | 2003-05-15 | Allan phosphonic acid as bone re-absorption inhibitor and its physiologically acceptable salt and their prepn |
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| CN (1) | CN1325506C (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8853266B2 (en) * | 2001-12-06 | 2014-10-07 | University Of Tennessee Research Foundation | Selective androgen receptor modulators for treating diabetes |
| ES2323728T3 (en) | 2005-12-27 | 2009-07-23 | Ipca Laboratories Limited | IMPROVED PROCESS FOR THE MANUFACTURE OF 4-AMINO-HYDROXIBUTYLENE-1,1-BISPHOSPHONIC AND ITS SALTS. |
| US10314807B2 (en) | 2012-07-13 | 2019-06-11 | Gtx, Inc. | Method of treating HER2-positive breast cancers with selective androgen receptor modulators (SARMS) |
| LT2872482T (en) | 2012-07-13 | 2020-12-28 | Oncternal Therapeutics, Inc. | A method of treating breast cancers with selective androgen receptor modulator (sarm) |
| US10258596B2 (en) | 2012-07-13 | 2019-04-16 | Gtx, Inc. | Method of treating HER2-positive breast cancers with selective androgen receptor modulators (SARMS) |
| US9969683B2 (en) | 2012-07-13 | 2018-05-15 | Gtx, Inc. | Method of treating estrogen receptor (ER)-positive breast cancers with selective androgen receptor modulator (SARMS) |
| US9744149B2 (en) | 2012-07-13 | 2017-08-29 | Gtx, Inc. | Method of treating androgen receptor (AR)-positive breast cancers with selective androgen receptor modulator (SARMs) |
| US10987334B2 (en) | 2012-07-13 | 2021-04-27 | University Of Tennessee Research Foundation | Method of treating ER mutant expressing breast cancers with selective androgen receptor modulators (SARMs) |
| US9622992B2 (en) | 2012-07-13 | 2017-04-18 | Gtx, Inc. | Method of treating androgen receptor (AR)-positive breast cancers with selective androgen receptor modulator (SARMs) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4407761A (en) * | 1980-04-28 | 1983-10-04 | Henkel Kommanditgesellschaft Auf Aktien | Process for the production of ω-amino-1-hydroxyalkylidene-1,1-bisphosphonic acid |
| US4621077A (en) * | 1982-04-15 | 1986-11-04 | Istituto Gentili S.P.A. | Pharmacologically active biphosphonates, process for the preparation thereof and pharmaceutical compositions therefrom |
| US4705651A (en) * | 1984-10-29 | 1987-11-10 | Istituto Gentili S.P.A. | Process for the preparation of diphosphonic acids |
-
2003
- 2003-05-15 CN CNB031169538A patent/CN1325506C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4407761A (en) * | 1980-04-28 | 1983-10-04 | Henkel Kommanditgesellschaft Auf Aktien | Process for the production of ω-amino-1-hydroxyalkylidene-1,1-bisphosphonic acid |
| US4621077A (en) * | 1982-04-15 | 1986-11-04 | Istituto Gentili S.P.A. | Pharmacologically active biphosphonates, process for the preparation thereof and pharmaceutical compositions therefrom |
| US4705651A (en) * | 1984-10-29 | 1987-11-10 | Istituto Gentili S.P.A. | Process for the preparation of diphosphonic acids |
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| CN1548442A (en) | 2004-11-24 |
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