22884-10-2

Usage

Uses

1. Used in Pharmaceutical Industry:
Imidazol-1-yl-acetic acid is used as an intermediate in the synthesis of various pharmaceutical compounds, particularly for the production of zoledronic acid, a potent bone-resorbing drug used in the treatment of hypercalcemia, osteolytic bone metastases, and Paget's disease of bone.
2. Used in Chemical Research:
As an off-white solid with unique chemical properties, Imidazol-1-yl-acetic acid can be utilized in chemical research for the development of new compounds with potential applications in various fields, including medicine, agriculture, and materials science.
3. Used in Analytical Chemistry:
Imidazol-1-yl-acetic acid can be employed as a reference compound or standard in analytical chemistry for the calibration of instruments and the development of new analytical methods, particularly in the identification and quantification of related compounds in complex mixtures.
4. Used in Material Science:
The unique properties of Imidazol-1-yl-acetic acid may also find applications in material science, where it could be used to develop novel materials with specific properties, such as improved stability, reactivity, or selectivity in various chemical processes.

InChI:InChI=1/C5H6N2O2/c8-5(9)3-7-2-1-6-4-7/h1-2,4H,3H2,(H,8,9)

Synthetic route

methyl 2-(1H-imidazol-1-yl)acetate (25023-22-7) → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
In water	97%
With water-d2 at 80℃; for 12h; Rate constant;
With water for 6h; Heating;
With hydrogenchloride; water at -2 - 2℃; for 2h; pH=4 - 5;
With water In water for 5h; Reflux;

tert-butyl imidazol-1-ylaceatate (83468-75-1) → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
With water at 60 - 115℃; Product distribution / selectivity;	82.2%

N-ethylglycine (627-01-0) + isothiocyanoacetaldehyde diethyl acetal (13733-17-0) → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
With sulfuric acid; nitric acid

ethyl 2-(1H-imidazol-1-yl)acetate (17450-34-9) → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
hydrolysis;
With hydrogenchloride In water at 100℃; for 7h; pH=1.5;
With water
With ethanol In acetonitrile for 1h; Reflux;	12.78 g

chloroacetic acid ethyl ester (105-39-5) + 1-(Trimethylsilyl)imidazole (18156-74-6) → 1,3‐bis(carboxymethyl)imidazolium chloride + imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
Stage #1: chloroacetic acid ethyl ester; 1-(Trimethylsilyl)imidazole at 90 - 100℃; Stage #2: With water Further stages.;
Stage #1: chloroacetic acid ethyl ester; 1-(Trimethylsilyl)imidazole at 67 - 70℃; Stage #2: With water Further stages.;

methyl chloroacetate (96-34-4) + 1-(Trimethylsilyl)imidazole (18156-74-6) → 1,3‐bis(carboxymethyl)imidazolium chloride + imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
Stage #1: methyl chloroacetate; 1-(Trimethylsilyl)imidazole at 90 - 100℃; Stage #2: With water Further stages.;
Stage #1: methyl chloroacetate; 1-(Trimethylsilyl)imidazole at 67 - 70℃; Stage #2: With water Further stages.;

trimethylsilyl chloroacetate (18293-71-5) + 1-(Trimethylsilyl)imidazole (18156-74-6) → 1,3‐bis(carboxymethyl)imidazolium chloride + imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
Stage #1: trimethylsilyl chloroacetate; 1-(Trimethylsilyl)imidazole at 90 - 100℃; Stage #2: With water Further stages.;
Stage #1: trimethylsilyl chloroacetate; 1-(Trimethylsilyl)imidazole at 67 - 70℃; Stage #2: With water Further stages.;

3-Acetyl-1-ethoxycarbonylmethyl-3H-imidazol-1-ium; bromide → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: Na2CO3 / H2O 2: hydrolysis View Scheme

1H-imidazole (288-32-4) + methyl chloroacetate (96-34-4) → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
With potassium carbonate; potassium iodide In DMF (N,N-dimethyl-formamide); toluene at 25 - 65℃; for 3.66667 - 5.16667h; Stirring;
Stage #1: 1H-imidazole With potassium tert-butylate In tetrahydrofuran at 0 - 7℃; Inert atmosphere; Stage #2: methyl chloroacetate In tetrahydrofuran at 7 - 25℃; Inert atmosphere; Stage #3: With hydrogenchloride; water In methanol at 25℃; pH=4 - 5; Product distribution / selectivity;

Benzyl imidazol-1-ylacetate (134807-23-1) → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
With hydrogen; 5%-palladium/activated carbon In isopropyl alcohol at 20℃; for 2h; Product distribution / selectivity;
With hydrogenchloride; water at 65℃; for 4h; Product distribution / selectivity;

1H-imidazole (288-32-4) + bromoacetic acid (79-08-3) → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
In tetrahydrofuran; ethanol; water	1.22 g (7.5 mmol, 30%)

imidazole propionate → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
With water for 4 - 8h; Heating / reflux;

1H-imidazole (288-32-4) + methyl chloroacetate (96-34-4) → 1,3‐bis(carboxymethyl)imidazolium chloride + imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
Stage #1: 1H-imidazole With potassium carbonate; potassium iodide In N,N-dimethyl-formamide; toluene Stage #2: methyl chloroacetate In N,N-dimethyl-formamide; toluene at 25 - 65℃; Stage #3: With water for 0.5h;

1H-imidazole (288-32-4) + ethyl bromoacetate (105-36-2) → imidazol-1-ylacetic acid (22884-10-2)

Conditions	Yield
Stage #1: 1H-imidazole; ethyl bromoacetate Stage #2: With water

imidazol-1-ylacetic acid (22884-10-2) → 1-hydroxy-2-(imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (118072-93-8)

Conditions	Yield
Stage #1: imidazol-1-ylacetic acid With phosphoric acid; phosphorus trichloride In 1,2-propylene cyclic carbonate; PEG 600 (polyethylene glycol) at 40 - 60℃; Stage #2: With water In 1,2-propylene cyclic carbonate; PEG 600 (polyethylene glycol) at 85℃; for 18h; Product distribution / selectivity;	99%
Stage #1: imidazol-1-ylacetic acid With phosphorous acid; phosphorus trichloride In 1,2-propylene cyclic carbonate; PEG 600 at 40 - 60℃; Stage #2: With water In 1,2-propylene cyclic carbonate; PEG 600 at 85℃; for 18h; Product distribution / selectivity;	99%
With sulfolane; phosphonic Acid; 1-butyl-3-methylimidazolium Tetrafluoroborate; phosphorus trichloride at 75℃; for 3h; Reagent/catalyst; Green chemistry;	93%

imidazol-1-ylacetic acid (22884-10-2) + Fmoc-Pro-OH (71989-31-6) + N-Fmoc L-Phe (35661-40-6) + Fmoc-Asn-OH (71989-16-7) + Fmoc-L-Arg-OH (91000-69-0) + trifluoroacetic acid (76-05-1) → C44H62N16O8*C2HF3O2

Conditions	Yield
Stage #1: Fmoc-Asn-OH With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide for 2h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.333333h; Stage #3: imidazol-1-ylacetic acid; Fmoc-Pro-OH; N-Fmoc L-Phe; Fmoc-L-Arg-OH; trifluoroacetic acid Further stages;	97%

imidazol-1-ylacetic acid (22884-10-2) → zoledronic acid dihydrate

Conditions	Yield
Stage #1: imidazol-1-ylacetic acid With 1-butyl-3-methylimidazolium Tetrafluoroborate; phosphorous acid; phosphorus trichloride In sulfolane at 75℃; for 0.5h; Ionic liquid; Stage #2: With water at 105℃; for 1h; pH=1.8; Reagent/catalyst;	93%

imidazol-1-ylacetic acid (22884-10-2) + butan-1-ol (71-36-3) → butyl imidazol-1-yl-acetate hydrochloride

Conditions	Yield
With thionyl chloride In methanol	90%

imidazol-1-ylacetic acid (22884-10-2) + (E)-5-[2-4-(hydroxyphenyl)ethenyl]-1,3-benzenediol (501-36-0) → (E)-3-hydroxy-5-(4-hydroxystyryl)phenyl 2-(1H-imidazol-1-yl)acetate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 60℃; for 3h;	90%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 60℃; for 3h;	90%

imidazol-1-ylacetic acid (22884-10-2) + 2-nitro-1,4-phenylenediamine (5307-14-2) → N-(4-amino-3-nitrophenyl)-2-(1H-imidazol-1-yl)acetamide (1219483-65-4)

Conditions	Yield
With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In acetonitrile at 20℃; for 96h;	88%

imidazol-1-ylacetic acid (22884-10-2) + lead(II) nitrate → [[Pb(2-(1H-imidazole-1-yl)acetic acid)2(NO3)](NO3)]n

Conditions	Yield
In water aq. soln. of Pb(NO3)2 added to aq. soln. of 2-(1H-imidazole-1-yl)acetic acid with stirring; filtered, allowed to stand at room temp. for several d; elem. anal.;	80%

imidazol-1-ylacetic acid (22884-10-2) + 5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (1222103-97-0) → 5-{9-(Cyclopropylmethyl)-8-[4-(1H-imidazol-1-ylacetyl)piperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (1222104-33-7)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 17.5h;	79%

imidazol-1-ylacetic acid (22884-10-2) + silver nitrate → [Ag(2-(1H-imidazole-1-yl)acetic acid)(NO3)]n

Conditions	Yield
In water aq. soln. of AgNO3 added to aq. soln. of 2-(1H-imidazole-1-yl)acetic acid, stirred for 30 min at room temp.; filtered, allowed to stand at room temp. for wk; elem. anal.;	78%

imidazol-1-ylacetic acid (22884-10-2) + cadmium(II) chloride (10108-64-2) → [Cd(2-(1H-imidazole-1-yl)acetate)2]n

Conditions	Yield
With NaOH In water aq. soln. of ligand added to aq. soln. of CdCl2, aq. soln. of NaOH addedto pH 7, stirred for 30 min; filtered, left to stand at room temp., slow evapd. for 3 d; elem. anal.;	75%

imidazol-1-ylacetic acid (22884-10-2) + zinc(II) nitrate (10196-18-6) → [Zn(2-(1H-imidazole-1-yl)acetate)2]n

Conditions	Yield
With NaOH In water aq. soln. of ligand added to aq. soln. of Zn(NO3)2, stirred for 30 min, aq. soln. of NaOH added to pH 7; filtered, left to stand at room temp., slow evapd. for 5 d; elem. anal.;	72%

imidazol-1-ylacetic acid (22884-10-2) + C2HF3O2*C21H27N3O4 (1386274-53-8) → 1-(4-(4-(3-(benzyloxy)-2-nitrophenoxy)butyl)piperazin-1-yl)-2-(1H-imidazol-1-yl)ethanone (1372616-31-3)

Conditions	Yield
Stage #1: C2HF3O2*C21H27N3O4 With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 0.166667h; Inert atmosphere; Stage #2: imidazol-1-ylacetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere;	72%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 16h; Inert atmosphere;	72%

imidazol-1-ylacetic acid (22884-10-2) + [2,2]bipyridinyl (366-18-7) + copper(II) choride dihydrate → 4Cu(2+)*4C10H8N2*4Cl(1-)*4C5H5N2O2(1-)*4H2O

Conditions	Yield
In ethanol; water at 20 - 120℃; for 72h; pH=4; Autoclave;	72%

imidazol-1-ylacetic acid (22884-10-2) + 3A-amino-3A-deoxy-β-cyclodextrin (125827-01-2) → C47H75N3O35

Conditions	Yield
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide	65.9%

imidazol-1-ylacetic acid (22884-10-2) + (2AS,3AS)-3A-amino-3A-deoxy-3A-β-cyclodextrin (125827-01-2, 117194-77-1) → C47H75N3O35

Conditions	Yield
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide	65.7%

imidazol-1-ylacetic acid (22884-10-2) + silver nitrate → [Ag(2-(1H-imidazole-1-yl)acetate)]n (934965-86-3)

Conditions	Yield
With NaOH In water aq. soln. of NaOH added to aq. soln. of ligand to pH 7, aq. soln. of AgNO3 added slowly; filtered, slow evapd. for 1 wk; elem. anal.;	65%

2-Aminomethylthiophene (27757-85-3) + imidazol-1-ylacetic acid (22884-10-2) + Cyclohexyl isocyanide (931-53-3) + 2-methylphenyl aldehyde (529-20-4) → C25H30N4O2S (1355324-07-0)

Conditions	Yield
Stage #1: 2-Aminomethylthiophene; 2-methylphenyl aldehyde In methanol at 20℃; for 0.5h; Stage #2: imidazol-1-ylacetic acid In methanol at 20℃; for 0.166667h; Stage #3: Cyclohexyl isocyanide In methanol at 20℃;	64%

imidazol-1-ylacetic acid (22884-10-2) + (2S,3S)-3-methyl-2-methylaminopentanoic acid benzyl ester → C19H25N3O3

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;	61.2%

imidazol-1-ylacetic acid (22884-10-2) + 3,4-bis((4-methoxybenzyl)oxy)aniline (1225208-71-8) → C27H27N3O5 (1225209-30-2)

Conditions	Yield
Stage #1: imidazol-1-ylacetic acid; 3,4-bis((4-methoxybenzyl)oxy)aniline With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 2h; Stage #2: In N,N-dimethyl-formamide for 1h;	58%

imidazol-1-ylacetic acid (22884-10-2) + 1,2-diamino-benzene (95-54-5) → 2-[(1H-imidazol-1-yl)-methyl]-1H-benzimidazole

Conditions	Yield
With polyphosphoric acid	57%

imidazol-1-ylacetic acid (22884-10-2) + 5-(phenylsulfonyl)-N-piperidine-4-yl-2-(trifluoromethyl)benzenesulfonamide hydrochloride → N-[1-(1H-imidazol-1-ylacetyl)piperidin-4-yl]-5-(phenylsulfonyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride (1095322-83-0)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72h;	55%

imidazol-1-ylacetic acid (22884-10-2) + lead(II) nitrate → bis(2-(1H-imidazol-1-yl)acetate)bis(nitrato)lead(IV)

Conditions	Yield
With NaOH In water byproducts: NaNO3; equimol., to a Soln. of N compd. (pH ca. 7-8 by NaOH) slowly added a soln. of metal salt, refluxed for 4 h; ppt. extd. (water), filtered, stored at room temp.; elem. anal., TGA, powder XRD;	51%

imidazol-1-ylacetic acid (22884-10-2) + 3-amino-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]propan-1-one (1619971-96-8) → N-{3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}-2-(1H-imidazol-1-yl)acetamide (1619971-53-7)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 16h;	49%

imidazol-1-ylacetic acid (22884-10-2) + 4-(thiophen-3-yl)aniline (834884-74-1) → 2-(1H-imidazol-1-yl)-N-(4-(thiophen-3-yl)phenyl)acetamide

Conditions	Yield
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h;	42%

imidazol-1-ylacetic acid (22884-10-2) + 4-amino-2-methyl-1-phenylbenzene (63019-97-6) → C18H17N3O

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 36h;	40%

imidazol-1-ylacetic acid (22884-10-2) + heptatriaconta-6,9,28,31-tetraen-19-ol → (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 2-(1H-imidazol-1-yl)acetate (1346932-66-8)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap In dichloromethane for 16h; Inert atmosphere; Reflux;	39%

imidazol-1-ylacetic acid (22884-10-2) + (6Z,9Z,28Z,31Z)-heptatriacont-6,9,28,31-tetraene-19-ol (1169768-28-8) → (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 2-(1H-imidazol-1-yl)acetate (1346932-66-8)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane for 16h; Inert atmosphere; Reflux;	39%

imidazol-1-ylacetic acid (22884-10-2) + benzaldehyde (100-52-7) → 3-(1H-imidazol-1-yl)-2H-chromen-2-one

Conditions	Yield
Stage #1: imidazol-1-ylacetic acid; benzaldehyde With acetic anhydride; triethylamine at 100 - 170℃; Microwave irradiation; Stage #2: With sodium hydroxide In methanol; water at 20℃;	39%

Upstream product

• 627-01-0 N-ethylglycine 
• 13733-17-0 isothiocyanoacetaldehyde diethyl acetal 
• 25023-22-7 methyl 2-(1H-imidazol-1-yl)acetate 
• 105-39-5 chloroacetic acid ethyl ester 
• 18156-74-6 1-(Trimethylsilyl)imidazole 
• 96-34-4 methyl chloroacetate 
• 18293-71-5 trimethylsilyl chloroacetate 
• 288-32-4 1H-imidazole 
• 79-08-3 bromoacetic acid 
• 105-36-2 ethyl bromoacetate 
• 134807-23-1 Benzyl imidazol-1-ylacetate 
• 17450-34-9 ethyl 2-(1H-imidazol-1-yl)acetate 
• 83468-75-1 tert-butyl imidazol-1-ylaceatate 

Downstream Products

• 886042-54-2 methyl 14-cyclohexyl-3-fluoro-6-(1H-imidazol-1-ylacetyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate 
• 1355324-07-0 C₂₅H₃₀N₄O₂S 
• 94937-88-9 2-[(1H-imidazol-1-yl)-methyl]-1H-benzimidazole 
• 904894-54-8 zoledronic acid dihydrate 

Relevant academic research and scientific papers

Pharmacological evaluation of imidazole-derived bisphosphonates on receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation and function

Bisphosphonates (BPs) have been commonly used in the treatment of osteolytic bone lesions, such as osteoporosis and osteogenesis imperfecta. However, serious side-effects can occur during the therapy. To search for novel potent BPs with lower side-effects, a series of imidazole-containing BPs (zoledronic acid [ZOL]; ZOL derivatives by substitution of the hydrogen at the 2-position on the imidazole ring with a methyl [MIDP], ethyl [EIDP], n-propyl [PIDP], or n-butyl group [BIDP]) were developed and the effects on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation were investigated using the murine macrophage RAW 264.7 cells at the protein, gene, and morphological and functional levels. Influences of these BPs on the cell growth and proliferation of RAW 264.7 were also studied in order to determine cytotoxicity. The results showed that PIDP significantly inhibited the RANKL-induced osteoclast formation in a dose-dependent fashion without inducing cytotoxicity under the concentration of 12.5?μM. It exerted remarkable suppressive effects on the development of actin rings, the bone resorption, and the expressions of osteoclastogenesis-related gene and protein markers. The down-regulation of c-Jun N-terminal kinase (JNK), protein kinase B (Akt), and inhibitor of nuclear factor kappa-B (IκB) phosphorylation in the early signaling event and subsequent inhibition of the expression of c-Fos and nuclear factor of activated T cells (NFATc1) might be involved in these effects. All these results indicated that PIDP might be a promising drug to treat bone-related disorders.

One-pot preparation method for imidazol-1-yl-acetic acid

The invention discloses a one-pot preparation method for imidazol-1-yl-acetic acid. The preparation method comprises the following specific steps: 1) dissolving imidazole in a solvent, and then carrying out an N-alkylation reaction on the formed solution and an N-alkylation reagent to obtain methyl imidazol-1-yl-acetate or ethyl imidazol-1-yl-acetate in a reaction intermediate state; and 2) addinghydrous ethanol into a reaction solution obtained in the step 1), continuing heating for a hydrolysis reaction, carrying out cooling for crystallization after the reaction is finished, and carrying out filtering and drying to obtain imidazol-1-yl-acetic acid. According to the method, the starting raw material imidazole is used as an alkali, so the use of a phase transfer catalyst is avoided; theimidazol-1-yl-acetic acid is prepared by the one-pot method, so steps are few, operation is simple, raw material variety is few, post-treatment is simple, reaction yield is high, product purity is high, reaction conditions are mild, cost is low, and safety is good; and the method accords with the trend of green chemical industry and is suitable for industrial production.

Imidazole heterocyclic diphosphonic acid compound as well as preparation method and application thereof

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to an imidazole heterocyclic diphosphonic acid compound as well as a preparation method and application thereof. The imidazole heterocyclic diphosphonic acid compound has a larger non-toxic concentration range for an osteoclast precursor, and can significantly inhibit the formation of osteoclasts at the same time; the imidazole heterocyclic diphosphonic acid compound can damage actin ring to the utmost extent, thus having an obvious inhibiting effect on the osteoclasts and further being used as an osteoclast inhibitor; the imidazole heterocyclic diphosphonic acid compound solves the problems that diphosphonate in the prior art is low in inhibiting effect on the osteoclasts, high in toxicity and large in side effects.

CEPHALOSPORIN HAVING CATECHOL GROUP

The present invention provides Cephem compounds which have a wide antimicrobial spectrum and have potent antimicrobial activity against beta-lactamase producing Gram negative bacteria as follows: A compound of the formula: wherein, X is N, CH or C-Cl; T is S or the like; A and G are lower alkylene or the like; B is a single bond or the like; D is a single bond, -NR7-, -CO-, -CO-NR7-, -NR7-CO-, -NR7-CO-NR7-, or the like; E is optionally substituted lower alkylene; F is a single bond or optionally substituted phenylene; R3, R4, R5 and R6 each is independently hydrogen, halogene, nitrile, or the like; or an ester, a compound protected at the amino on the ring in the 7-side chain, a pharmaceutically acceptable salt, or a solvate thereof.

Process for Making Zoledronic Acid

Processes for making zoledronic acid can be advantageously carried out in a solvent/diluent that comprises a mixture of (i) a polyalkylene glycol and (ii) a cyclic carbonate of the formula (3) wherein n is an integer from 2 to 4, and R1 and R2 each independently represent a hydrogen or a C1-C4 alkyl group.

Process for making zoledronic acid

The invention relates to a process a process, which comprises: reacting in a solvent/diluent a compound of formula (2) or a salt or ester thereof with a phosphonation agent to form phosphonated intermediates; and subsequently hydrolyzing said intermediates to form a compound of formula (1) or a salt or hydrate thereof wherein said solvent/diluent comprises a mixture of (i) a polyalkylene glycol and (ii) a cyclic carbonate of the formula (3) wherein n is an integer from 2 to 4, and R1 and R2 each independently represent a hydrogen or a C1-C4 alkyl group and to the use of intermediates therein.

PROCESS FOR MANUFACTURING BISPHOSPHONIC ACIDS

A manufacturing process for the preparation of bisphosphonic acids and in particular zoledronic acid is provided wherein diglyme, monoglyme, or a mixture thereof, is utilized to produce a homogenous, water soluble, solid reaction mass that upon cooling, dissolving in water and stripping results in a high purity product and comparatively good yield.

PROCESSES FOR THE PREPARATION OF PURE ZOLEDRONIC ACID

The invention relates to processes for the preparation of pure zoledronic acid or pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions that include the pure zoledronic acid.

N-alkylation of N-trimethylsilylimidazole

The reaction of N-trimethylsilylimidazole with alkyl chloroacetates is studied. This process yields a mixture of N-alkylation and quarternization products in the ratio dependent on the reaction conditions. The reaction mechanism is discussed. 1H NMR data show that high melting point and low solubility of 1-imidazolylacetic acid in organic solvents are evidently caused by the formation of strong intermolecular hydrogen bonds, whereas in water zwitterionic structures with the protonation of both nitrogen atoms are formed.

A PROCESS FOR THE PREPARATION OF 2-(IMIDAZOL-1-YL)-1-HYDROXYETHANE-1, 1-DIPHOSPHONIC ACID

The present invention provides a process for preparation of 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid, compound of formula (1), said process comprising (a) reacting imidazole with chloroacetyl chloride and benzyl alcohol in homogenous system in one pot to obtain benzyl 1-imidazolylacetate, compound of formula (3); (b) debenzylating benzyl 1-imidazolylacetate, a compound of formula (3) to imidazole 1-ylacetic acid, compound of formula (2) and (c) converting compound of formula (2) to compound of formula (1).