121268-17-5

Basic information

• Product Name: Alendronate sodium
• Synonyms: G-704650;ALENDRONATE SODIUM SALT;ALENDRONATE, SODIUM SALT TRIHYDRATE;ALENDRONATE SODIUM TRIHYDRATE;ALENDRONNATE SODIUM TRIHYDRATE;ALENDRONIC ACID, MONOSODIUM SALT, TRIHYDRATE;ADRONAT;4-AMINO-1-HYDROXYBUTYLIDINE-1,1-BISPHOSPHONATE SODIUM SALT TRIHYDRATE
• CAS NO: 121268-17-5
• Molecular Formula: C₄H₁₂NO₇P₂*Na
• Molecular Weight: 325.12
• EINECS: 1806241-263-5
• Product Categories: Miscellaneous Biochemicals;All Inhibitors;Osteoporosis;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Miscellaneous Compounds;Phosphorylating and Phosphitylating Agents;REQUIP
• Mol File: 121268-17-5.mol

Chemical Properties

• Melting Point: 245°C
• Boiling Point: 616.7 °C at 760 mmHg
• Flash Point: 326.7 °C
• Appearance: white/solid
• Density: 1.857 g/cm³
• Storage Temp.: −20°C
• Solubility: water, double-distilled: 10 mg/mL
• Water Solubility: Soluble in water at 10mg/ml
• Stability: Store in freezer
• Merck: 14,229
• CAS DataBase Reference: Alendronate sodium(CAS DataBase Reference)
• NIST Chemistry Reference: Alendronate sodium(121268-17-5)
• EPA Substance Registry System: Alendronate sodium(121268-17-5)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 22-36/37/38
• Safety Statements: 26-36-60
• WGK Germany: 3
• RTECS: SZ6523500
• Hazardous Substances Data: 121268-17-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Alendronate sodium is used as a bone resorption inhibitor for the treatment of osteoporosis and Paget's disease. It inhibits bone resorption and increases bone density, helping to prevent fractures and improve overall bone health.
Alendronate sodium is used as a farnesyl diphosphate synthase inhibitor and CD45 protein tyrosine phosphatase inhibitor for the treatment of osteolysis. It acts as a robust inhibitor of bone resorption and induces apoptosis in affected cells.
Alendronate sodium is used as a dopamine receptor agonist for the treatment of Parkinson's disease. It helps alleviate symptoms and improve the quality of life for patients suffering from this neurodegenerative disorder.
Alendronate sodium is used as an inhibitor of CD45RC and MMP, interfering with the mevalonate pathway and inhibiting the migration and invasion of PC-3 cells (sc-2220), which can be beneficial in cancer treatment.

Originator

Adronat ,Neopharmed ,Italy

Manufacturing Process

4-Amino-1-hydroxybutylidene-1,1-diphosphonic acid (ABDT). Orthosphophorous acid (102.7 g; 1.25 moles) is introduced into a 2 liter-flask with condenser, stirrer and dropping funnel, placed on a thermostatized bath; the air is then removed with a nitrogen stream which is continued during all the reaction. The acid is melted by heating the bath to 95°C. When melting is complete, 4-aminobutyric acid (103.3; 1 mole) is added under stirring which is continued till obtaining a doughy fluid. Phosphorous trihalide (176 ml; 2 moles) is added dropwise causing the mixture to boil and evolution of gaseous hydrochloric acid which is damped by means of a suitable trap. The addition rate is adjusted so as to keep a constant reflux for about 60 minutes. When the addition is nearly over, the mixture swells, slowly hardening. Stirring is continued as long as possible, whereafter the mixture is heated for further 3 hours. Without cooling, but removing the bath, water (300 ml) is added, first slowly and then quickly. Heating and stirring are started again. Decolorizing charcoal is added and the mixture is boiled for about 5 minutes, then hotfiltered on paper and the filtrate is refluxed for 6 hours. After cooling is slowly poured in stirred methanol (1500 ml) causing thereby the separation of a white solid which collected and dried (161 g; 64.6%). The structure of ABDT is confirmed by IR spectrum, proton magnetic and nuclear magnetic resonance spectrum and elemental analysis. The sodium salt of this acid may be prepared by adding of equivalent of sodium hydroxide.

Therapeutic Function

Antiosteoporotic

Biochem/physiol Actions

Alendronate sodium trihydrate is a bone resorption inhibitor; farnesyl diphosphate synthase inhibitor (IC50 = 460 nM); CD45 protein tyrosine phosphatase inhibitor.

InChI:InChI=1/C4H13NO7P2.4Na/c5-3-1-2-4(6,13(7,8)9)14(10,11)12;;;;/h6H,1-3,5H2,(H2,7,8,9)(H2,10,11,12);;;;/q;4*+1/p-4

Synthetic route

4-amino-n-butyric acid (56-12-2) → sodium alendronate (121268-17-5)

Conditions	Yield
Stage #1: 4-amino-n-butyric acid With phosphonic Acid; methanesulfonic acid; phosphorus trichloride at 65℃; Stage #2: With water Reflux; Stage #3: With sodium hydroxide In water	91%
With phosphorous acid; phosphorus trichloride In methanesulfonic acid at 65℃;	82%
Stage #1: 4-amino-n-butyric acid With 1-butyl-3-methylimidazolium Tetrafluoroborate; phosphorous acid; phosphorus trichloride In sulfolane at 75℃; for 3h; Stage #2: With water In sulfolane at 105℃; for 3h; Stage #3: With sodium hydroxide In sulfolane at 0 - 25℃; for 14h; pH=4.6; Reagent/catalyst;	80%

tetraethyl 2-N-phthalimide-1-hydroxybutylidene-1,1-bisphosphonate (183959-44-6) → sodium alendronate (121268-17-5)

Conditions	Yield
Stage #1: tetraethyl 2-N-phthalimide-1-hydroxybutylidene-1,1-bisphosphonate With hydrogenchloride Heating; Stage #2: With sodium hydroxide pH=4.3 - 4.4;	90%

2-pyrrolidinon (616-45-5) → sodium alendronate (121268-17-5)

Conditions	Yield
Stage #1: 2-pyrrolidinon With phosphorus trichloride In water at 65 - 110℃; for 7.33333 - 7.41667h; Stage #2: With methanesulfonic acid; phosphorus trichloride at 60 - 75℃; for 9h; Stage #3: With sodium hydroxide; water Product distribution / selectivity; more than 3 stages;	82%
Stage #1: 2-pyrrolidinon With water; phosphorus trichloride at 65 - 110℃; for 7.33333 - 7.41667h; Heating / reflux; Stage #2: With methanesulfonic acid; phosphorus trichloride at 60 - 75℃; for 9h; Stage #3: With sodium hydroxide; methanesulfonic acid; water Product distribution / selectivity; more than 3 stages;	82%
Stage #1: 2-pyrrolidinon With methanesulfonic acid; water; phosphorus trichloride at 20 - 110℃; for 3.33333 - 8.41667h; Heating / reflux; Stage #2: With methanesulfonic acid at 60 - 75℃; for 9h; Stage #3: With sodium hydroxide; methanesulfonic acid; water Product distribution / selectivity; more than 3 stages;	81%

4-amino-1-hydroxybutylidenebisphosphonic acid (66376-36-1) → sodium alendronate (121268-17-5)

Conditions	Yield
With sodium carbonate In water for 3h; Heating;	79%
With sodium hydroxide In water at 0 - 5℃; for 3h; pH=4.3;
With sodium hydroxide In water at 30 - 70℃;

sodium hydroxide (1310-73-2) → sodium alendronate (121268-17-5)

Conditions	Yield
Stage #1: 4-amino-n-butyric acid With phosphorous acid; phosphorus trichloride In acetonitrile at 55 - 75℃; for 6 - 9h; Stage #2: With water In acetonitrile at 60 - 100℃; for 4 - 6h; Stage #3: sodium hydroxide at 55 - 65℃; pH=4.4 - 4.8;	69.6%

C13H31NO8P2Si → sodium alendronate (121268-17-5)

Conditions	Yield
Stage #1: C13H31NO8P2Si With hydrogenchloride In water for 17h; Reflux; Stage #2: With sodium hydroxide In water at 25℃; pH=4.3;	26.84 g

carbon disulfide (75-15-0) + sodium alendronate (121268-17-5) → sodium alendronate dithiocarbamate

Conditions	Yield
Stage #1: sodium alendronate With sodium hydroxide In water Cooling with ice; Stage #2: carbon disulfide In water for 24h; Cooling with ice;	95%
With sodium hydroxide In water at 0℃; for 24h;	94%

C18H26N4O12 + sodium alendronate (121268-17-5) → C18H34N4O16P2

Conditions	Yield
With triethylamine In water at 20℃; for 24h;	92%

2,5-dioxopyrrolidin-1-yl pent-4-ynoate (132178-37-1) + sodium alendronate (121268-17-5) → 1-hydroxy-4-pent-4-ynamidobutane-1,1-diyldiphosphonic acid (952615-43-9)

Conditions	Yield
Stage #1: sodium alendronate With sodium hydroxide In water pH=8.5; Stage #2: 2,5-dioxopyrrolidin-1-yl pent-4-ynoate In water; acetonitrile at 22℃; for 8h; pH=8.5;	89.9%

4-nitro-benzoyl chloride (122-04-3) + sodium alendronate (121268-17-5) → Na(1+)*C11H15N2O10P2(1-)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 2h; pH=11;	86%

2,3-bis(benzyloxy)benzoyl chloride (69146-58-3) + sodium alendronate (121268-17-5) → 4-N-(2,3-dibenzyloxybenzoyl)aminobutane-1-hydroxy-1,1-bisphosphonic acid disodium

Conditions	Yield
With sodium hydroxide In tetrahydrofuran at 20℃; for 6h;	81.2%

diethylenetriaminepentaacetic dianhydride (23911-26-4) + sodium alendronate (121268-17-5) → C22H43N5O22P4(2-)*2Na(1+)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 60℃; for 12h; pH=8; Inert atmosphere;	80%

6-azidohexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (866363-70-4) + sodium alendronate (121268-17-5) → [4-(6-azidohexanamido)-1-hydroxy-1-(hydroxy-oxido-phosphoryl)butyl]phosphonic acid sodium salt

Conditions	Yield
With sodium hydroxide In water; acetonitrile at 20℃; pH=Ca. 8.5;	80%
With sodium hydroxide In water; acetonitrile at 20℃; for 25h; pH=8 - 8.5;	70%

tert-butoxycarbonyl-L-proline N-hydroxysuccinimide ester (3392-10-7) + sodium alendronate (121268-17-5) → C14H28N2O10P2

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In water; N,N-dimethyl-formamide at 20℃; for 96h;	75%

6-aza-5,9-dioxo-9-(1,2-didehydrodibenzo[b,f]azocin-5(6H)-yl)nonanoic acid succinimidyl ester (1393350-27-0) + sodium alendronate (121268-17-5) → C23H26N2O9P2

Conditions	Yield
With sodium hydroxide In water; dimethyl sulfoxide at 5℃; Darkness;	66%

5-(1H-imidazol-1-yl)pentanoic acid (68887-65-0) + sodium alendronate (121268-17-5) → [1-hydroxy-4-(5-imidazol-1-ylpentanoylamino)-1-phosphonobutyl]phosphonic acid

Conditions	Yield
Stage #1: sodium alendronate With N-ethyl-N,N-diisopropylamine In water at 20℃; for 0.5h; Stage #2: 5-(1H-imidazol-1-yl)pentanoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In water; N,N-dimethyl-formamide	42%

trans-4-cycloocten-yl 2,5-dioxo-1-pyrrolidinyl ester carbonic acid + sodium alendronate (121268-17-5) → [4-(cyclooct-4-enyloxycarbonylamino)-1-hydroxy-1-phosphonobutyl]phosphonic acid

Conditions	Yield
With triethylamine In water; dimethyl sulfoxide Darkness;	25%

copper(II) nitrate trihydrate + galium(III) nitrate monohydrate + ethanol (64-17-5) + C17H26N6O5 + sodium alendronate (121268-17-5) + sodium hydroxide (1310-73-2) → C21H34CuGaN7O12P2*4NO3(1-)*4Na(1+)*7.1C2H6O

Conditions	Yield
Stage #1: copper(II) nitrate trihydrate; galium(III) nitrate monohydrate; C17H26N6O5 In water for 0.25h; Stage #2: sodium alendronate In water for 0.25h; Stage #3: ethanol; sodium hydroxide Further stages;	23%

sodium alendronate (121268-17-5) + 3,5-dihexadecyloxybenzoic acid chloride (41696-89-3) → 4-N-(3,5-ditetradecyloxybenzoyl)-aminobutane-1-hydroxy-1,1-bisphosphonic acid disodium salt

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; diethyl ether; water at 20℃; for 6h;	13%

benzyl chloroformate (501-53-1) + sodium alendronate (121268-17-5) → 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (134399-26-1)

Conditions	Yield
With sodium hydroxide at 20℃; for 36h;

sodium alendronate (121268-17-5) → 4-amino-1-hydroxybutylidenebisphosphonic acid (66376-36-1)

Conditions	Yield
With hydrogenchloride; ethanol; water at 20 - 50℃; for 2h;

sodium alendronate (121268-17-5) → alendronate monosodium trihydrate

Conditions	Yield
With water at 58 - 60℃; pH=4.3 - 4.4;

2-chloromethylpyridine hydrochloride (6959-47-3) + sodium alendronate (121268-17-5) → C16H21N3O7P2(2-)*2Na(1+)

Conditions	Yield
With sodium hydroxide In water at 20℃; for 40h; pH=12.1;	> 90 %Chromat.

tetra(n-butyl)ammonium hydroxide (2052-49-5) + sodium alendronate (121268-17-5) → sodium tris(tetrabutylammonium) alendronate

Conditions	Yield
In water

sodium alendronate (121268-17-5) → calcium alendronate monohydrate

Conditions	Yield
With calcium chloride; sodium hydroxide In water at 90℃; for 2h; Reagent/catalyst; Temperature; Time; Concentration;

sodium alendronate (121268-17-5) + Methacryloyl chloride (920-46-7) → methacrylamide alendronate

Conditions	Yield
With 4-methoxy-phenol; sodium hydroxide In water at 5 - 20℃; for 3h;

sodium alendronate (121268-17-5) + β‐cyclodextrin (7585-39-9) → C42H70O35*C4H12NO7P2(1-)*Na(1+)

Conditions	Yield
In water for 0.05h;

formaldehyd (50-00-0) + sodium alendronate (121268-17-5) + acetylacetone (123-54-6) → C15H24NO9P2(1-)*Na(1+)

Conditions	Yield
In aq. acetate buffer pH=5; Solvent; Temperature; Time; pH-value; Hantzsch Dihydropyridine Synthesis; Heating;

sodium alendronate (121268-17-5) + 4-Nitrobenzenesulfonyl chloride (98-74-8) → Na(1+)*C10H15N2O11P2S(1-)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 2h; pH=10 - 11;

Upstream product

• 66376-36-1 4-amino-1-hydroxybutylidenebisphosphonic acid 
• 1310-73-2 sodium hydroxide 
• 56-12-2 4-amino-n-butyric acid 
• 616-45-5 2-pyrrolidinon 
• 183959-44-6 tetraethyl 2-N-phthalimide-1-hydroxybutylidene-1,1-bisphosphonate 

Downstream Products

• 134399-26-1 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid 
• 66376-36-1 4-amino-1-hydroxybutylidenebisphosphonic acid 

Relevant articles and documents

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Bisphosphonates (BPs) have interesting antitumor effects as well in vitro as in vivo, despite their poor bioavailability in the organism after oral ingestion. To overcome this problem and reduce drug doses and secondary effects, we report the chemical synthesis of new bioconjugates. They were built with a nitrogen-containing BP as the drug covalently coupled to the carboxymethyldextran. This polysaccharide was used as a carrier, in order to increase BP lifetime in bloodstream and to target tumor cells which have a strong affinity with dextran. The efficiency of our vectorization system was biologically proved in vitro and in vivo on mammalian carcinoma models in mice.

Analysis of supramolecular interactions in alendroniate alkali metal salts: synthesis, structure, and properties of novel sodium alendronate polymorph

A new polymorph of anhydrous sodium alendronate, C4H12NO7P2Na, has been synthesized and characterized by single crystal X-ray diffraction as well as infrared spectroscopy and thermal analysis. The title compound crystallizes in the monoclinic P21/c space group. Asymmetric unit consists of one alendronic anion and one sodium cation. An interplay of classical strong O-H…O, N-H…O and non-classical weak C-H…O hydrogen bonds creates 3D framework in the crystal. Contrary to previously reported sodium alendronate salts, in which Na+ cation is surrounded by six-coordinated sphere, in compound (1), the Na+ cation is five-coordinated in a distorted trigonal-bipyramidal geometry. In order to provide a detailed investigation of the molecular arrangement in view of intermolecular interactions, the title compound was compared with alendronic acid and other known alkali metal alendronate salts, retrieved from the Cambridge Crystal Structure Database. The intercontacts were qualitatively and quantitatively compared using Hirshfeld surface analysis. It highlights that strong O…H/H…O and subtle H…H contacts play an influential role in the total surface area. The Me+…H/H…Me+ and Me+…O/O…Me+ contacts are meaningful as well. These evidently simple systems show a diverse complexity. Moreover, the powder X-ray diffraction, DSC, thermogravimetry/derivative thermogravimetry, and FT-IR results are also reported.

Investigation of the effect of medium in the preparation of alendronate: till now the best synthesis in the presence of an ionic liquid additive

The synthesis of the drug alendronate from γ-aminobutyric acid and phosphorus trichloride/phosphorous acid as the P-reagents is revisited using methanesulfonic acid and sulfolane as solvents and ionic liquids (ILs) as additives according to a novel approach. Besides elaborating efficient synthetic methods with a record yield of up to 80%, the misleading literature data were also clarified. It is a novel trend to use ILs as only catalysts or additives and not as solvents.

ORGANIC-INORGANIC HYBRID SOLID HAVING A MODIFIED OUTER SURFACE

The present invention concerns metal-organic hybrid solids having a modified outer surface. These solids can be used, for example, for the storage and vectoring of molecules of interest such as pharmaceutically active ingredients, compounds of interest in cosmetics and markers, for example contrast agents. These solids have good results in terms of active drug loading capacities, biocompatibility, stability and controlling the release of the active ingredients encapsulated.

The synthesis of risedronic acid and alendronate applying phosphorus oxychloride and phosphorous acid in methanesulfonic acid

The synthesis of risedronic acid and alendronate from 3-pyridylacetic acid and γ-aminobutyric acid, respectively, using phosphorus oxychloride and phosphorous acid as the P-reagents and methanesulfonic acid as the solvent was optimized, and the role of phosphorus oxychloride and phosphorous acid in the reaction was clarified.

Microwave-assisted efficient synthesis of bisphosphonate libraries: A useful procedure for the preparation of bisphosphonates containing nitrogen and sulfur

Microwave-assisted rapid and efficient procedure for the synthesis of bisphosphonate and their libraries is described in solvent-free medium. Bisphosphonates having nitrogen and sulfur are synthesized following this new procedure. This procedure is simple and can be useful for the generation of compound libraries of a class of bone-resorptive inhibitors such as N- and N-, S- containing bisphosphonates.

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NOVEL PROCESS

The present invention relates to a process for the preparation of bisphosphonic acids and salts thereof, in particular monosodium salts thereof. The invention also relates to the conversion of the bisphosphonic acids to their sodium salts using an aqueous-organic solvent system. The present invention further relates to the conversion of variable hydrate forms of risedronic acid monosodium salt into a pharmaceutically acceptable hemipentahydrate form by crystallization using an aqueous-organic solvent system.

AN IMPROVED PROCESS FOR THE PREPARATION OF BISPHOSPHONIC ACID

The present invention is to relate an improved process using anisole as solvent for the preparation of compound of formula (I) and its pharmaceutically acceptable salts thereof. wherein R represents-NR1R2, or formula (II), a group n = 1,2,3,4 and 5, where R1 and R2 may be same or different and independently represents hydrogen, or C1-6 alkyl;