40391-99-9

Usage

Chemical Properties

White Solid

Uses

anticancer

InChI:InChI=1/C3H11NO7P2/c4-2-1-3(5,12(6,7)8)13(9,10)11/h5H,1-2,4H2,(H2,6,7,8)(H2,9,10,11)

Synthetic route

3-amino propanoic acid (107-95-9) → pamidronate (40391-99-9)

Conditions	Yield
With methanesulfonic acid; phosphorous acid; phosphorus trichloride at 65 - 70℃; Inert atmosphere;	99%
Stage #1: 3-amino propanoic acid With phosphorus trichloride In methanesulfonic acid at 80 - 85℃; Stage #2: With water In methanesulfonic acid at 105℃; for 4h;	85%
With phosphonic Acid; phosphorus trichloride In chlorobenzene at 100℃; for 3h; Inert atmosphere;	82%

[3-(benzyloxycarbonylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid (948317-73-5) → pamidronate (40391-99-9)

Conditions	Yield
With hydrogen; palladium on activated charcoal In methanol for 24h;	90%

[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-hydroxy-1-phosphonopropyl]phosphonic acid (917092-03-6) → pamidronate (40391-99-9)

Conditions	Yield
With hydrazine hydrate In water at 20℃; for 0.5h;	67%
With hydrogenchloride In water for 5.5h; Reflux;

pamidronate (40391-99-9) → 3-amino-1-hydroxypropane-1,1-diphosphonic acid disodium salt

Conditions	Yield
With sodium methylate In ethanol	99.6%
With sodium methylate In methanol	97.9%
With sodium hydroxide In water

copper(II) carbonate + pamidronate (40391-99-9) + water (7732-18-5) → 2Cu(2+)*2H3NC2H4C(OH)(PO3)PO3H(2-)*H2O=[Cu2(H3NC2H4C(OH)(PO3)PO3H)2]*H2O

Conditions	Yield
In water High Pressure; equimol., heatd at 70°C in a closed flask for for 3 wk; crysts. decanted, dried (air); elem. anal.;	95%

formaldehyd (50-00-0) + pamidronate (40391-99-9) → olpadronate (63132-39-8)

Conditions	Yield
With formic acid for 17h; Heating;	92%

6-maleimidohexanoic acid N-hydroxylsuccinimide ester (55750-63-5) + pamidronate (40391-99-9) → (3‐{[6‐(2,5‐dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)hexanoyl]amino}‐1‐hydroxypropane‐1,1‐diyl)bis(phosphonic acid)

Conditions	Yield
With sodium hydroxide In water; acetone at 20℃; pH=8 - 9;	88%

pamidronate (40391-99-9) → disodium-1,3-dihydroxypropane-1,1-diphosphonate

Conditions	Yield
With sodium nitrite In Na2 -salt; water	85%

pamidronate (40391-99-9) + water (7732-18-5) + copper(II) nitrate → 3Cu(2+)*2C3NH8P2O7(3-)*2H2O=Cu3(C3NH8P2O7)2*2H2O

Conditions	Yield
With NaOH In water High Pressure; a mixt. of Cu-contg. compd. (0.5 mmol), ligand (0.5 mmol) and water adjusted to pH 4.2 with NaOH aq. soln. was sealed in a Teflon-lined autoclave and heated at 160°C for 3 d; slow cooling to room temp.; crystals were filtered off and washed with water; elem. anal.;	85%

4-chloroquinazoline (5190-68-1) + pamidronate (40391-99-9) → [1-hydroxy-3-(quinazolin-4-ylamino)propane-1,1-diyl]bis(phosphonic acid)

Conditions	Yield
Stage #1: 4-chloroquinazoline; pamidronate With potassium carbonate In water at 95℃; for 24h; Reflux; Stage #2: With hydrogenchloride In water at 5℃; for 24h; pH=1;	82%

pamidronate (40391-99-9) + phenyl isothiocyanate (103-72-0) + formamide (77287-34-4, 77287-35-5, 60100-09-6) + triethylamine (121-44-8) → bis(triethylammonium) <1-hydroxy-3-(3-phenylthioureido)propylidene>bisphosphonate formamide

Conditions	Yield
In acetonitrile Ambient temperature;	77%

2-chloropyrimidine (1722-12-9) + pamidronate (40391-99-9) → [1-hydroxy-3-(pyrimidin-2-ylamino)propane-1,1-diyl]bis(phosphonic acid)

Conditions	Yield
Stage #1: 2-chloropyrimidine; pamidronate With potassium carbonate In water at 90 - 180℃; for 23h; Reflux; Stage #2: With hydrogenchloride In water at 5℃; for 48h; pH=1;	71%

zinc(II) nitrate (10196-18-6) + pamidronate (40391-99-9) + water (7732-18-5) → Zn(2+)*C3NH9P2O7(2-)*H2O=Zn(C3NH9P2O7)*H2O

Conditions	Yield
With NaOH In water High Pressure; a mixt. of Zn-contg. compd. (0.5 mmol), ligand (0.5 mmol) and water adjusted to pH 3.6 with NaOH aq. soln. was sealed in a Teflon-lined autoclave and heated at 160°C for 3 d; slow cooling to room temp.; crystals were filtered off and washed with water; elem. anal.;	70%

samarium(III) oxide + pamidronate (40391-99-9) → samarium(III) 3-ammonium-1-hydroxypropylidene-1,1-diphosphonate

Conditions	Yield
With hydrogenchloride In water at 160℃; for 48h; pH=0.65; Autoclave;	68%

pamidronate (40391-99-9) + [Pt(OSO3)(cis-1,4-diaminocyclohexane)(water)] (164654-62-0) + water (7732-18-5) → [(cis-Pt(1,4-diaminocyclohexane))2(3-ammonium-1-hydroxypropane-1,1-diylbisphosphonate)]HSO4*6water

Conditions	Yield
With Ba(OH)2*8H2O In water byproducts: BaSO4; addn. of barium hydroxide to aq. soln. of phosphonic acid deriv., addn. of aq. soln. of platinum compd., stirring at room temp. for 48 h; filtration, concg., addn. of aq. H2SO4 to pH 1, treating with acetone, keeping at 4°C for 2 h, filtration, drying in vac., elem. anal.;	65.1%

formaldehyd (50-00-0) + pamidronate (40391-99-9) → α-hydroxy-γ-propylidenediphosphonic acid

Conditions	Yield
With hydrogenchloride; phosphonic Acid In water at 115 - 120℃; for 3h;	64%

Nd2O5 + pamidronate (40391-99-9) → neodimium(III) 3-ammonium-1-hydroxypropylidene-1,1-diphosphonate

Conditions	Yield
With hydrogenchloride In water at 160℃; for 48h; pH=0.47; Autoclave;	63%

2-chloroquinazoline (6141-13-5) + pamidronate (40391-99-9) → [1-hydroxy-3-(quinazolin-2-ylamino)propane-1,1-diyl]bis(phosphonic acid)

Conditions	Yield
Stage #1: 2-chloroquinazoline; pamidronate With potassium carbonate In water at 90 - 180℃; for 22h; Reflux; Stage #2: With hydrogenchloride In water at 5℃; for 24h; pH=1;	62%

cobalt(II) nitrate hexahydrate + pamidronate (40391-99-9) → Co(2+)*C3NH9P2O7(2-)*H2O=Co(C3NH9P2O7)*H2O (898547-48-3)

Conditions	Yield
With NaOH In water High Pressure; a mixt. of Co-contg. compd. (0.5 mmol), ligand (0.5 mmol) and water adjusted to pH 2.8 with NaOH aq. soln. was sealed in a Teflon-lined autoclave and heated at 160°C for 3 d; slow cooling to room temp.; crystals were filtered off and washed with water; elem. anal.;	60%

manganese(II) nitrate hexahydrate + pamidronate (40391-99-9) → Mn(2+)*C3NH9P2O7(2-)*H2O=Mn(C3NH9P2O7)*H2O (898547-50-7)

Conditions	Yield
With NaOH In water High Pressure; a mixt. of Mn-contg. compd. (0.5 mmol), ligand (0.5 mmol) and water adjusted to pH 2.8 with NaOH aq. soln. was sealed in a Teflon-lined autoclave and heated at 160°C for 3 d; slow cooling to room temp.; crystals were filtered off and washed with water; elem. anal.;	60%

3-maleimidopropionic acid N-hydroxysuccinimide ester (55750-62-4) + pamidronate (40391-99-9) → (3‐{[3‐(2,5‐dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)propanoyl]amino}‐1‐hydroxypropane‐1,1‐diyl)bis(phosphonic acid)

Conditions	Yield
With sodium hydroxide In water; acetone at 20℃; pH=8 - 9;	60%

Thiram (137-26-8) + pamidronate (40391-99-9) → disodium <3-(3,3-dimethylthioureido)-1-hydroxypropylidene>bisphosphonate trihydrate (140846-28-2)

Conditions	Yield
With triethylamine In methanol for 8h; Heating;	50%

nickel(II) nitrate hexahydrate + pamidronate (40391-99-9) → Ni2(C3NH10P2O7)4(H2O)2*2H2O

Conditions	Yield
In water High Pressure; a mixt. of Ni-contg. compd. (0.5 mmol), ligand (0.5 mmol) and water (pH 1.7) was sealed in a Teflon-lined autoclave and heated at 160°C for 3 d; slow cooling to room temp.; crystals were washed with water; elem. anal.;	50%

europium(III) oxide + pamidronate (40391-99-9) → europium(III) 3-ammonium-1-hydroxypropylidene-1,1-diphosphonate

Conditions	Yield
With hydrogenchloride In water at 160℃; for 36h; pH=0.58; Autoclave;	50%

4-chloro-2-phenylquinazoline (6484-25-9) + pamidronate (40391-99-9) → [1-hydroxy-3-((2-phenylquinazolin-4-yl)amino)propane-1,1-diyl]bis(phosphonic acid)

Conditions	Yield
Stage #1: 4-chloro-2-phenylquinazoline; pamidronate With potassium carbonate In water at 90 - 180℃; for 23h; Reflux; Stage #2: With hydrogenchloride In water at 5℃; for 48h; pH=1;	46%

pamidronate (40391-99-9) + pyridoxal 5'-phosphate (54-47-7) → ammonium salt 3-(N-[5'-phospho]pyridoxylamino)-1-hydroxypropyliden-1,1-bisphosphonic acid

Conditions	Yield
Stage #1: pamidronate; pyridoxal 5'-phosphate With triethylamine In ethanol; water at 20℃; for 1h; Stage #2: With sodium tetrahydroborate at 20℃; for 1h; Stage #3: With ammonia In water	44%

pamidronate (40391-99-9) + o-chlorobenzoyl chloride (609-65-4) → C10H14ClNO8P2 (790204-13-6)

Conditions	Yield
Stage #1: pamidronate; o-chlorobenzoyl chloride With sodium hydroxide In water at -10℃; for 6h; Stage #2: With hydrogenchloride In water pH=1;	41%

praseodymium oxide + pamidronate (40391-99-9) → praseodimium(III) 3-ammonium-1-hydroxypropylidene-1,1-diphosphonate

Conditions	Yield
With hydrogenchloride In water at 160℃; for 48h; pH=0.74; Autoclave;	41%

Upstream product

• 107-95-9 3-amino propanoic acid 
• 948317-73-5 [3-(benzyloxycarbonylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid 
• 917092-03-6 [3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-hydroxy-1-phosphonopropyl]phosphonic acid 
• 111-87-5 octanol 

Downstream Products

• 63132-39-8 olpadronate 
• 948317-73-5 [3-(benzyloxycarbonylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid 
• 790204-13-6 C₁₀H₁₄ClNO₈P₂ 
• 775280-99-4 C₁₀H₁₅NO₈P₂ 

Relevant academic research and scientific papers

The synthesis of pamidronic derivatives in different solvents: An optimization and a mechanistic study

The synthesis of pamidronic acid and sodium pamidronate dihydrate from β-alanine and P-reagents (phosphorus trichloride and phosphorous acid) was investigated at 75°C in different solvents, and the preparation was optimized. In sulfolane, the use of 2 equiv of phosphorus trichloride and phosphorous acid was found the optimum to lead to pamidronic acid in a yield of 63%. In methanesulfonic acid, 3.2 equiv of phosphorus trichloride was necessary without any phosphorous acid to give pamidronate dihydrate in the best yield (57%) after hydrolysis and pH adjustment. In the first case, the P-nucleophile may be (HO)2P-O-PCl-O-P(OH)2 or (HO)2P-O- PCl2, whereas in the second case, the P-reactant is probable Cl 2P-O-S(O)2Me. It can be said that the mechanism proposed for the formation of pamidronic acid is highly influenced by the solvent used, as it determines the necessary P-reagent(s). Our results promote the "on purpose" planning of the synthesis of dronates.

Efficient synthesis of pamidronic acid using an ionic liquid additive

An efficient method was developed for the synthesis of pamidronic acid involving the reaction of β-alanine with three equivalents of phosphorus trichloride and two equivalents of phosphorous acid at 75 °C in the presence of 0.3 or 0.6 equivalents of [BMIM][PF6] as an additive.

Biocompatible organic coatings based on bisphosphonic acid RGD‐derivatives for PEO‐modified titanium implants

Currently, significant attention is attracted to the problem of the development of the specific architecture and composition of the surface layer in order to control the biocompatibility of implants made of titanium and its alloys. The titanium surface properties can be tuned both by creating an inorganic sublayer with the desired morphology and by organic top coating contributing to bioactivity. In this work, we developed a composite biologically active coatings based on hybrid molecules obtained by chemical crosslinking of amino acid bisphosphonates with a linear tripeptide RGD, in combination with inorganic porous sublayer created on titanium by plasma electrolytic oxidation (PEO). After the addition of organic molecules, the PEO coated surface gets nobler, but corrosion currents increase. In vitro studies on proliferation and viability of fibroblasts, mesenchymal stem cells and osteoblastlike cells showed the significant dependence of the molecule bioactivity on the structure of bisphosphonate anchor and the linker. Several RGDmodified bisphosphonates of β–alanine, γ–aminobutyric and ε–aminocaproic acids with BMPS or SMCC linkers can be recommended as promising candidates for further in vivo research.

The synthesis of hydroxymethylenebisphosphonic- (dronic-) and acyl-ethoxycarbonyl-methylphosphonate derivatives

Recent results on the synthesis of substituted hydroxymethylenebisphosphonic acids (A and B), as well as acylated ethoxycarbonyl-methylphosphonate derivatives (C and D) are summarized. In the first part, solvent mixtures were applied in the preparation of known dronic acids, while in the second series of experiments, new acyl species were synthesized.

Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis

Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC50 of 0.31 μM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.

Copolymers having gem-bisphosphonate groupings

A copolymer includes a main hydrocarbon chain and side groups including carboxylic groups and polyoxyalkylate groups. The copolymer further includes gem-bisphosphonate groups. A composition, such as n admixture for suspensions of mineral particles, includes the copolymer. The copolymer can be used for fluidifying suspensions of mineral particles and maintaining the fluidity of such suspensions. The copolymer can also be used for reducing the sensitivity of hydraulic compositions to clays and alkaline sulfates.

AMIDE-LINKED EP4 AGONIST-BISPHOSPHONATE COMPOUNDS AND USES THEREOF

The present invention relates to EP4 agonist-bisphosphonate conjugates or related compounds and uses thereof. Said conjugates or related compounds may be used to provide delivery of an EP4 agonist or related compound to a desired site of action, such as a bone. Bisphosphonate moieties, linked to the EP4 agonists via amide linkers, have been implicated in the inhibition of bone resorption and bone targeting.

Efficient synthesis of pamidronic acid using an ionic liquid additive

An efficient method was developed for the synthesis of pamidronic acid involving the reaction of β-alanine with three equivalents of phosphorus trichloride and two equivalents of phosphorous acid at 75 ° C in the presence of 0.3 or 0.6 equivalents of [BMIM][PF6] as an additive.

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.

Non-hydrolysable analogues of inorganic pyrophosphate as inhibitors of hepatitis C virus RNA-dependent RNA-polymerase

Inorganic pyrophosphate (PPi) is the product of the polymerization reaction catalyzed by DNA-and RNA-polymerases. A number of novel non-hydrolsable PPi analogues was synthesized; some of them inhibited the polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore based on a non-hydrolysable methylenediphosphonate backbone has been developed. The structure-activity relationship analysis of 12 bisphosphonates is presented and the structural features crucial for NS5B polymerase activity inhibition are stated. Pleiades Publishing, Ltd., 2012.