Alendronate sodium trihydrate synthesis
- Product Name:Alendronate sodium trihydrate
- CAS Number:121268-17-5
- Molecular formula:C4H13NO7P2.3H2O.Na
- Molecular Weight:326.13
56-12-2
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121268-17-5
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Yield:121268-17-5 82%
Reaction Conditions:
with phosphorous acid;phosphorus trichloride in methanesulfonic acid at 65;
Steps:
3.1 Step 1:
Synthesis of 4-amino-1-hydroxybutylidene)bisphosphonic acid (alendronate)
Step 1:
Synthesis of 4-amino-1-hydroxybutylidene)bisphosphonic acid (alendronate)
4-Aminobutyric acid (20 g, 0.19 mol) and one equivalent of phosphorous acid H3PO3 (16 g, 0.19) were put in a 250-mL four-necked flask equipped with a mechanical stirrer, a thermometer, and a dropping funnel.
They were dissolved in a minimum of methanesulfonic acid and then the reaction mixture was heated to 65° C.
Maintaining the temperature at 65° C., two equivalents of phosphorus trichloride PCl3 (35 mL, 0.40 mol) were added dropwise in 20 minutes.
The reaction mixture was then stirred at 65° C. overnight.
Next, the reaction mixture was quenched, using iced distilled water, and then the mixture obtained was transferred to a 500-mL three-necked flask.
The mixture was refluxed for 5 hours.
The reaction mixture was brought back to room temperature using an ice bath.
Using an aqueous solution of NaOH at 50% (by weight), the pH was adjusted to 4.3 to promote precipitation of the bisphosphonic acid.
The precipitate was filtered and dried under vacuum.
Purification of the alendronate consists of performing several washings with anhydrous methanol until the methanesulfonic acid has been removed.
The precipitate was then dried overnight in a heated desiccator (at 40° C.)
Yield: 82%
IR (cm-1): 1524, 1473, 1168, 1073, 913 cm-1
1H NMR (500 MHz, D2O): 2.93 (m, 2H), 1.88 (m, 4H)
31P NMR {1H} (80.9 MHz, H3PO4/D2O): 18.5 (s).
References:
Gref, Ruxandra;Agostoni, Valentina;Daoud-Mahammed, Samia;Rodriguez-Ruiz, Violeta;Malanga, Milo;Jicsinszky, Laszlo;Horcajada-Cortes, Patricia;Serre, Christian US2015/150981, 2015, A1 Location in patent:Paragraph 0447; 0448; 0449; 0450; 0451; 0452; 0453
66376-36-1
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121268-17-5
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1310-73-2
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121268-17-5
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616-45-5
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121268-17-5
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