100643-71-8

Basic information

• Product Name: Desloratadine
• Synonyms: DESLORATADINE;DESLORATIDINE;8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5h-benzo[5,6]cyclohepta[1,2-b]pyridine;8-CHLORO-6,11-DIHYDRO-11-(4-PIPERIDINYLIDENE)-5H-BENZO[5,6]CYCLOHEPTA[1,2-B]PYRIDINE;AKOS 92131;SCH-34117;Aerius;Dis-loratadine
• CAS NO: 100643-71-8
• Molecular Formula: C₁₉H₁₉ClN₂
• Molecular Weight: 310.82
• EINECS: 1308068-626-2
• Product Categories: Active Pharmaceutical Ingredients;Antihistaminic;Various Metabolites and Impurities;Intermediates & Fine Chemicals;Metabolites;Pharmaceuticals;Heterocycles;Metabolites & Impurities;API;FLUVENT;Other APIs;Inhibitors
• Mol File: 100643-71-8.mol

Chemical Properties

• Melting Point: 150-151°C
• Boiling Point: 467.9 °C at 760 mmHg
• Flash Point: 236.8 °C
• Appearance: Beige solid
• Density: 1.221 g/cm³
• Vapor Pressure: 6.25E-09mmHg at 25°C
• Refractive Index: 1.625
• Storage Temp.: 2-8°C
• Solubility: DMSO: >10mg/mL
• PKA: 10.27±0.20(Predicted)
• Merck: 14,2922
• CAS DataBase Reference: Desloratadine(CAS DataBase Reference)
• NIST Chemistry Reference: Desloratadine(100643-71-8)
• EPA Substance Registry System: Desloratadine(100643-71-8)

Safety Data

• WGK Germany: 3
• RTECS: DE8011000
• Hazardous Substances Data: 100643-71-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Desloratadine is used as an antihistamine for the symptomatic relief of allergic conditions, including seasonal allergic rhinitis and chronic urticaria (hives). It works by blocking the effects of histamine, a natural substance produced during an allergic reaction, without causing drowsiness.
Desloratadine is used as a histamine H1-receptor antagonist for the relief of nasal and non-nasal symptoms associated with seasonal allergic rhinitis, such as watery eyes, runny nose, itching eyes/nose, sneezing, and itching.
Desloratadine is used as an anti-inflammatory agent to inhibit the generation and release of inflammatory mediators from basophils and mast cells.
Desloratadine is used as a non-sedating antihistamine for the symptomatic treatment of pruritus and reduction in the number and size of hives in chronic idiopathic urticaria patients aged 6 months and older.
In Research:
Desloratadine has been used in cellular studies to test its effect on embryoid body development in an in vitro gastrulation model of P19C5 stem cells.
Desloratadine has been used as an antihistamine mimic in rats to study its effects on the central nervous system and other physiological responses.
Desloratadine has been used to treat lung cancer (A549) and glioblastoma (U87) cells in various cellular studies, exploring its potential as a therapeutic agent for cancer treatment.

Originator

Sepracor (US)

Indications

Desloratadine (Clarinex) is an active metabolite of loratadine. A 5 mg daily dose has been shown to be effective. There is no evidence that it offers any advantage over loratadine. Fexofenadine (like its parent compound terfenadine) may rarely promote cardiac arrhythmias (24). No significant difference in efficacy has been noted in the nonsedating H1 blockers. Combinations of nonsedating antihistamines in the morning and sedating antihistamines in the evening may be more cost effective than increasing doses of the nonsedating agent.

Manufacturing Process

To a solution of 10.9 g (0.1 mole) of ethylchloroformate in 300 ml of anhydrous benzene is added dropwise, with stirring at room temperature, a solution of 16.2 g (0.05 M) of 11-(N-methyl-4-piperidylidene)-8-chloro-6,11- dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine in 200 ml of benzene. The solution is stirred and is heated under reflux overnight (16-20 hours). The mixture is cooled and is poured into ice water and the organic layer is separated, washed with water, dried, and then concentrated to dryness. The residue is triturated with petroleum ether and a white solid of 8-chloro-6,11- dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6 ]cyclohepta[1,2-b]pyridine having a melting point of 128-130°C is recrystallized from isopropyl ether after decolorization with decolorizing carbon.To 12 g of sodium hydroxide in 30 ml ethyl alcohol (70%) add 6 g of 8-chloro6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5Hbenzo[5,6]cyclohepta[1,2-b]pyridine and reflux with stirring for 24 hours. After about the first 6-8 hours an additional 30 ml of 70% ethyl alcohol may be added. Remove about 50% of the solvent by distillation in vacuo. Add a small amount of ice water and acidify with glacial acetic acid. Extract with chloroform (6-8 times), since the product precipitates from the acetic acid solution as a thick emulsion which cannot be filtered. Concentrate the chloroform extracts to a small volume and precipitate the product with hexane to give crude 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5Hbenzo[5,6]cyclohepta[1,2-b]pyridine acetic acid salt, m.p. 197-200°C. Recrystallize from benzene-hexane to obtain the product, m.p. 199-200°C. Yield 4.0-4.5 g.

Therapeutic Function

Antiallergic

Biochem/physiol Actions

Desloratadine is a selective and nonsedating histamine H1 receptor antagonist, an active metabolite of loratadine (Claritin), used to relieve hay fever and allergy symptoms with less drowsiness than other antihistamines; does not significantly inhibits cardiac K+ channels at clinically achievable blood levels. Free from antimuscarinic/anticholinergic effects.

Clinical Use

Desloratadine was launched as an improved version of Schering-Plough's Claritin? (Loratadine), for the treatment of nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR). Desloratadine can be prepared by a 7-step synthesis starting with a Ritter reaction on 2-cyano-3-picoline and involving successively alkylation with 3- chlorobenzyl chloride, dehydration, Grignard reaction with the piperidine magnesium chloride, intramolecular cyclization in strong acidic medium, and finally demethylation of the piperidine. Desloratadine (the descarboethoxyloratadine) is a biologically active metabolite of the second-generation antihistamine Ioratadine. Desloratadine is a nonsedating competitive histamine H1 receptor antagonist with increased potency and improved safety as compared to Ioratadine. When compared with other H1 antagonists as an inhibitor of histamine-induced calcium flux in CHO cells, desloratadine was found to be more potent than most H1 antagonists (such as the widely used terfenadine, fexofenadine, cetirizine, Ioratadine and astemizole) in this assay. Desloratadine is also a potent antagonist of muscarinic M1 and M3 receptors (not M2) indicating anticholinergic activity. These effects may be the explanation for the unexpected decongestant effects of desloratadine reported in clinical trials. Desloratadine appears to be devoid of significant effects on potassium channels and does not appear to suffer from adverse interaction with cytochrome P450 inhibitors. Clinical studies have shown that it does not induce sedation or cardiac arrhythmias and does not potentiate the effects of alcohol. Apparent total body clearance is in the range of 114-201 l/h and the mean elimination half life is 19-34.6 h in human. Desloratadine is available as 5-mg tablets, which is the once-daily recommended dose for adults and children above 12 years. It may be taken without regard to food. The treatment not only improved symptoms of SAR but also improved patient ratings of nasal congestion. The FDA also has issued an "approvable" letter for this agent for the treatment of chronic idiopathic urticaria (ClU).

References

[1] https://www.drugbank.ca [2] Raif S. Geha, Eli O. Meltzer (2001) Desloratadine: A new, nonsedating, oral antihistamine, The Journal of Allergy and Clinical Immunology,107, 751-762

InChI:InChI=1/C19H19ClN2/c20-16-5-6-17-15(12-16)4-3-14-2-1-9-22-19(14)18(17)13-7-10-21-11-8-13/h1-2,5-6,9,12,21H,3-4,7-8,10-11H2

Synthetic route

loratadine (79794-75-5) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
In ethanol; water Reflux; Inert atmosphere; Alkaline conditions;	98.5%
With C22H40N4(2+)*2BF4(1-) In toluene at 80℃; for 0.666667h;	98.5%
With sodium hydroxide In ethanol; water at 100 - 105℃; for 5h; Concentration; Solvent; Time; Temperature; Autoclave; Inert atmosphere; Large scale;	96%

8-chloro-6,11-dihydro-11-(4-piperidinylydene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine carbon dioxide adduct → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Stage #1: 8-chloro-6,11-dihydro-11-(4-piperidinylydene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine carbon dioxide adduct In ethanol for 1h; Heating / reflux; Stage #2: In methanol; acetone Heating / reflux;	63%

N-tert-butyl-3-methylpyridine-2-carboxamide (32998-95-1) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: 1.) n-BuLi / 1.) THF, -40 deg C 2: POCl3 / Heating 3: 2.) aq. HCl / 1.) THF, reflux 4: CF3SO3H / Heating 5: Et3N / toluene / Heating 6: aq. KOH / Heating View Scheme

3-[2-(3-chlorophenyl)ethyl]-2-pyridine-carbonitrile (31255-57-9) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2.) aq. HCl / 1.) THF, reflux 2: CF3SO3H / Heating 3: Et3N / toluene / Heating 4: aq. KOH / Heating View Scheme

3-<2-(3-chlorophenyl)ethyl>-N-(1,1-dimethylethyl)-2-pyridinecarboxamide (107285-30-3) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: POCl3 / Heating 2: 2.) aq. HCl / 1.) THF, reflux 3: CF3SO3H / Heating 4: Et3N / toluene / Heating 5: aq. KOH / Heating View Scheme

{3-[2-(3-Chloro-phenyl)-ethyl]-pyridin-2-yl}-(1-methyl-piperidin-4-yl)-methanone (130642-50-1) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: CF3SO3H / Heating 2: Et3N / toluene / Heating 3: aq. KOH / Heating View Scheme

1-Chloro-3-chloromethyl-benzene (620-20-2) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: 1.) n-BuLi / 1.) THF, -40 deg C 2: POCl3 / Heating 3: 2.) aq. HCl / 1.) THF, reflux 4: CF3SO3H / Heating 5: Et3N / toluene / Heating 6: aq. KOH / Heating View Scheme

N-methyldesloratadine (38092-89-6) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / toluene / Heating 2: aq. KOH / Heating View Scheme
With potassium hydroxide In ethanol; water
With potassium hydroxide In ethanol; water
Multi-step reaction with 2 steps 1: triethylamine / toluene / 3 h / Reflux 2: potassium hydroxide / ethanol / 6 h / Reflux View Scheme

8-chloro-6,11-dihydro-11-(1-cyano-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (100643-73-0) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
In hydrogenchloride; water; acetic acid	11.5 grams (93%)

8-Chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine acetic acid salt → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
With potassium carbonate; pyrographite In chloroform; water for 0.5h; pH=~ 10 - 12; Product distribution / selectivity;
Stage #1: 8-Chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine acetic acid salt With pyrographite In water at 20℃; for 1h; Stage #2: With potassium carbonate In water at 65 - 70℃; for 6 - 12h; pH=10 - 12; Product distribution / selectivity;

8-chloro-5,6-dihydro-11H-Benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (31251-41-9) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrahydrofuran / Reflux 2: sulfuric acid / 4.5 h / 20 °C 3: triethylamine / toluene / 3 h / Reflux 4: potassium hydroxide / ethanol / 6 h / Reflux View Scheme

(1-methyl-4-piperidyl)magnesium chloride (63463-36-5) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrahydrofuran / Reflux 2: sulfuric acid / 4.5 h / 20 °C 3: triethylamine / toluene / 3 h / Reflux 4: potassium hydroxide / ethanol / 6 h / Reflux View Scheme

8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol (38089-93-9) → descarboethoxyloratadine (100643-71-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / 4.5 h / 20 °C 2: triethylamine / toluene / 3 h / Reflux 3: potassium hydroxide / ethanol / 6 h / Reflux View Scheme

descarboethoxyloratadine (100643-71-8) + propoxycarbonyl chloride (109-61-5) → Propyl-4-(8-chlor-5,6-dihydro-11H-benzo-<5,6>-cyclohepta-<1,2-b>-pyridin-11-ylidin)-1-piperidincarboxylat

Conditions	Yield
In toluene at 50℃; for 1h;	100%
With N-ethyl-N,N-diisopropylamine In dichloromethane for 2h;

(2R)-2-phenylbutanoic acid (938-79-4) + descarboethoxyloratadine (100643-71-8) → (R)-1-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-2-phenyl-butan-1-one

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h;	100%

4-Nitrophenyl isocyanate (100-28-7) + descarboethoxyloratadine (100643-71-8) → 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-(4-nitrophenyl)piperidine-1-carboxamide

Conditions	Yield
In tetrahydrofuran at 20℃; for 3h;	100%

descarboethoxyloratadine (100643-71-8) + Tert-butyl isocyanate (1609-86-5) → N-(t-butyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxamide

Conditions	Yield
In tetrahydrofuran at 20℃; for 3h;	100%

descarboethoxyloratadine (100643-71-8) + phenyl isocyanate (103-71-9) → 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-phenylpiperidine-1-carboxamide (169252-51-1)

Conditions	Yield
In tetrahydrofuran at 20℃; for 3h;	99%

descarboethoxyloratadine (100643-71-8) + phenylacetyl chloride (103-80-0) → 1-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-phenylethan-1-one

Conditions	Yield
In dichloromethane at 20℃; for 7h;	98%
With pyridine In tetrahydrofuran for 48h; Ambient temperature;	36%
With N-ethyl-N,N-diisopropylamine In dichloromethane for 2h;

carbon dioxide (124-38-9) + descarboethoxyloratadine (100643-71-8) → 8-chloro-6,11-dihydro-11-(4-piperidinylydene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine carbon dioxide adduct

Conditions	Yield
In acetone at 50℃; for 3h; Product distribution / selectivity; Heating / reflux;	97.5%
In methanol; acetone at 20 - 40℃; Product distribution / selectivity;	96%
In isopropyl alcohol; acetone at 20 - 40℃; Product distribution / selectivity;	95.2%
In ethanol; acetone at 20 - 45℃; for 0.5h; Product distribution / selectivity;	94.3%
In acetone; butan-1-ol at 20 - 40℃; Product distribution / selectivity;	94.3%

descarboethoxyloratadine (100643-71-8) + 3-nitrobenzenesulphonyl chloride (121-51-7) → 8-Chloro-11-(1-((3-nitrophenyl)sulfonyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine (1423771-99-6)

Conditions	Yield
Stage #1: descarboethoxyloratadine With triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 3-nitrobenzenesulphonyl chloride In dichloromethane for 2h;	97%
With triethylamine In dichloromethane at 20℃; for 6h;	97.2%
With triethylamine In dichloromethane at 0℃; for 2h;

4-(methylthio)benzoic acid (13205-48-6) + descarboethoxyloratadine (100643-71-8) → [4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-(4-methylsulfanyl-phenyl)-methanone (169252-29-3)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h;	97%

Tropic acid (529-64-6) + descarboethoxyloratadine (100643-71-8) → 1-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-3-hydroxy-2-phenyl-propan-1-one (169250-67-3)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h;	97%

descarboethoxyloratadine (100643-71-8) + 3,5-ditrifluoromethylisocyanate (16588-74-2) → N-(3,5-bis(trifluoromethyl)phenyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxamide

Conditions	Yield
In tetrahydrofuran at 20℃; for 3h;	97%

descarboethoxyloratadine (100643-71-8) + 4-Nitrobenzenesulfonyl chloride (98-74-8) → 8-Chloro-11-(1-((4-nitrophenyl)sulfonyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine

Conditions	Yield
With pyridine at -5℃; for 12h;	96%
Stage #1: descarboethoxyloratadine With triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-Nitrobenzenesulfonyl chloride In dichloromethane for 2h;	88%
With potassium carbonate In toluene Ambient temperature;
With dmap In pyridine at 20℃;
With triethylamine In dichloromethane at 0℃; for 2h;

descarboethoxyloratadine (100643-71-8) + 4-Methoxyphenyl isocyanate (5416-93-3) → 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-(4-methoxyphenyl)piperidine-1-carboxamide

Conditions	Yield
In tetrahydrofuran at 20℃; for 3h;	96%

5-methylnicotinic acid (3222-49-9) + descarboethoxyloratadine (100643-71-8) → [4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-(5-methyl-pyridin-3-yl)-methanone

Conditions	Yield
With boric acid In toluene Concentration; Reflux;	95%
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 18h; Ambient temperature;	44%

descarboethoxyloratadine (100643-71-8) + 3-methoxycarbonylbenzyl bromide (1129-28-8) → methyl 3-[4-(8-chloro-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-ylmethyl]benzoate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 70℃;	95%

descarboethoxyloratadine (100643-71-8) + 4-nitro-benzoyl chloride (122-04-3) → (4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)(4-nitrophenyl)methanone

Conditions	Yield
Stage #1: descarboethoxyloratadine With triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-nitro-benzoyl chloride In dichloromethane for 2h;	95%
With triethylamine In dichloromethane at 0℃; for 2h;

di-tert-butyl dicarbonate (24424-99-5) + descarboethoxyloratadine (100643-71-8) → tert-butyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 5h;	94%
With N-ethyl-N,N-diisopropylamine In dichloromethane for 2h;

1-bromo-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethane-1-sulfonyl fluoride + descarboethoxyloratadine (100643-71-8) → (E)-2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethene-1-sulfonyl fluoride

Conditions	Yield
In 1,4-dioxane at 20℃; stereoselective reaction;	94%

4-tolylacetic acid (622-47-9) + descarboethoxyloratadine (100643-71-8) → 1-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-2-p-tolyl-ethanone

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h;	93%

m-methylphenylacetic acid (621-36-3) + descarboethoxyloratadine (100643-71-8) → 1-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-2-m-tolyl-ethanone

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h;	93%

descarboethoxyloratadine (100643-71-8) + p-trifluoromethyl-phenylisocyanate (1548-13-6) → 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide

Conditions	Yield
In tetrahydrofuran at 20 - 23℃; for 6h;	93%

descarboethoxyloratadine (100643-71-8) + 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (157688-46-5) → t-butyl 4-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)-2-oxoethyl)piperidine-1-carboxylate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 24h;	93%

carbon dioxide (124-38-9) + descarboethoxyloratadine (100643-71-8) → 0.5CO2*C19H19ClN2

Conditions	Yield
In ethanol; ethyl acetate at 5℃; for 2h; Product distribution / selectivity;	92.5%
In ethyl acetate for 0.5h;

5-bromo-3-pyridinecarboxylic acid (20826-04-4) + descarboethoxyloratadine (100643-71-8) → (5-Bromo-pyridin-3-yl)-[4-(8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-methanone

Conditions	Yield
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 18h; Ambient temperature;	92%

C11H12NO4(1-)*K(1+) + descarboethoxyloratadine (100643-71-8) → C29H30ClN3O2

Conditions	Yield
With manganese(IV) oxide; copper(l) iodide; zinc diacetate In N,N-dimethyl-formamide at 30℃; for 20h; Inert atmosphere; Sealed tube; chemoselective reaction;	92%

pentafluorophenyl isocyanate (1591-95-3) + descarboethoxyloratadine (100643-71-8) → 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-(perfluorophenyl)piperidine-1-carboxamide

Conditions	Yield
In tetrahydrofuran at 20℃; for 3h;	92%

descarboethoxyloratadine (100643-71-8) + 3-Phenylpropionic acid (501-52-0) → 1-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-3-phenyl-propan-1-one

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h;	91%

3,4-dihydroxyphenylacetate (102-32-9) + descarboethoxyloratadine (100643-71-8) → 1-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-2-(3,4-dihydroxy-phenyl)-ethanone

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h;	90.3%

erythro-2-phenyl-3-methylpentanoic acid (7782-37-8) + descarboethoxyloratadine (100643-71-8) → 1-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-3-methyl-2-phenyl-pentan-1-one

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h;	90%

Upstream product

• 38089-93-9 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol 
• 63463-36-5 (1-methyl-4-piperidyl)magnesium chloride 
• 31251-41-9 8-chloro-5,6-dihydro-11H-Benzo[5,6]cyclohepta[1,2-b]pyridin-11-one 
• 100643-73-0 8-chloro-6,11-dihydro-11-(1-cyano-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 
• 38092-89-6 N-methyldesloratadine 
• 620-20-2 1-Chloro-3-chloromethyl-benzene 
• 130642-50-1 {3-[2-(3-Chloro-phenyl)-ethyl]-pyridin-2-yl}-(1-methyl-piperidin-4-yl)-methanone 
• 107285-30-3 3-<2-(3-chlorophenyl)ethyl>-N-(1,1-dimethylethyl)-2-pyridinecarboxamide 
• 31255-57-9 3-[2-(3-chlorophenyl)ethyl]-2-pyridine-carbonitrile 
• 32998-95-1 N-tert-butyl-3-methylpyridine-2-carboxamide 
• 79794-75-5 loratadine 

Downstream Products

• 117810-61-4 N-formyldesloratadine 
• 158876-82-5 rupatadine 
• 1373612-33-9 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-phenyl-1-piperidinecarbothioamide 
• 1373612-35-1 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-(2-methoxyphenyl)-1-piperidinecarbothioamide 
• 1373612-32-8 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-cyclohexyl-1-piperidinecarbothioamide 
• 1373612-34-0 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-(2-methylphenyl)-1-piperidinecarbothioamide 
• 1402084-78-9 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-cyano-N'-cyclohexyl-1-piperidinecarboximidamide 
• 1402084-79-0 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-N-cyano-N'-(1-phenylethyl)-1-piperidinecarboximidamide 

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Relevant articles and documents

Loratadine analogues as MAGL inhibitors Dedicated to Dr. Sameer Agarwal, principal scientist at Zydus Research Centre (ZRC, India)

Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50 = 46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50 = 7.24 μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC50 = 1.79 μM). Additionally, compound 12a retained H1 antagonistic affinity (pA2 = 6.81) but did not show cannabinoid receptor activity, when tested at concentrations ≤10 μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.

A new addition compound of desloratadine with carbon dioxide

The addition compound of 8-chloro-6,11-dihydro-11-(4-pip-eridylidene)-5H- benzo[5,6]cyclohepta[1,2-b]pyridine (descarboet-hoxyloratadine, desloratadine) with CO2, in molar ratio 2:1, is described. This unique form of desloratadine drug substance can be prepared in exceedingly high purity by a simple process from crude desloratadine. The addition compound is a useful intermediate in the manufacturing process of desloratadine Form I polymorph. An improved, environmental friendly manufacturing process for the synthesis of desloratadine starting from loratadine is also disclosed here.

Preparation method of desloratadine

The invention discloses a preparation method of desloratadine, according to the preparation method, loratadine is taken as a raw material, reaction is carried out at a mild temperature, the reaction time is short, especially the yield can reach 98% or above, and the purity can reach 99.90% or above.

Desloratadine preparation method

The invention discloses a desloratadine preparation method. The method comprises the following steps: firstly reacting methyl desloratadine with chloroethyl chloroformate to prepare chloroethoxycarbonyl desloratadine, and then heating in methanol to remove chloroethoxycarbonyl to obtain desloratadine. The method is mild in reaction condition, simple and easy to implement, and the obtained product is high in purity and few in impurity, and can be used for industrial mass production.

Preparation method of desloratadine

The invention provides a preparation method of desloratadine. The preparation method comprises the following steps: dissolving desloratadine in an ionic liquid, and reacting while stirring to obtain desloratadine; the ionic liquid is a mixture of 1-butyl-3-methylimidazolium propionate ionic liquid and ionic liquid shown as a formula I in the specification. The method is simple, easy to operate, high in yield, simple in aftertreatment, environmentally friendly and high in safety.

Late-Stage Lead Diversification Coupled with Quantitative Nuclear Magnetic Resonance Spectroscopy to Identify New Structure-Activity Relationship Vectors at Nanomole-Scale Synthesis: Application to Loratadine, a Human Histamine H1Receptor Inverse Agonist

An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 μmol). The approach delivers multiple analogues from a single lead at nanomole-scale amounts as DMSO-d6 stock solutions with a known structure and concentration for in vitro pharmacology and absorption, distribution, metabolism, and excretion testing. To demonstrate the feasibility of this approach, we have used the antihistamine agent loratadine (1). Twenty-six analogues of loratadine were isolated and fully characterized by NMR. Informative SAR analogues were identified, which display potent affinity for the human histamine H1 receptor and improved metabolic stability.

Desloratadine crystal form IV and preparation method thereof (by machine translation)

The invention provides a novel crystal form of desloratadine and a preparation method thereof. The preparation method comprises the following steps: dissolving desloratadine in tetrahydrofuran, adding water dropwise to the system, filtering the dropwise addition, obtaining a filter cake, and drying to obtain the desloratadine crystal. The crystal form has the advantages of high purity and good stability, has superiority in the production of the process, and is suitable for long-term storage of the preparation process. (by machine translation)

Method of preparing rupatadine fumarate through microchannel reaction device

The invention discloses a method of preparing rupatadine fumarate through a microchannel reaction device. A process is optimized on a known path of synthesis for rupatadine fumarate; the microchannelreaction device helps greatly shorten the reaction time and provide high throughput and good product quality stability; high continuity is good for continuous scaled production; operating is simple, safety is high, and separating is easy; the defects of the traditional synthetic path can be effectively overcome; the yield is significantly increased, up to 90%. Desloratadine prepared in the production process is subjected to continuous separation and continuous liquid separation; the solution is added directly to next reaction to obtain rupatadine; the yield is not reduced, and the operation issimplified.

Preparation method for desloratadine

The invention provides a green synthesis method for desloratadine, which achieves a yield of more than 90% and a purity of more than 99.9%. A reaction is carried out in a specific medium, that is, an ionic liquid with a specific structure. The ionic liquid can be used as a medium independently or be used in combination with other component solvents, and can be recovered and cyclically used, and therefore is green and environment-friendly. After-treatment is simple and convenient.

A ground of loratadine preparation method (by machine translation)

The present invention provides a yield of 90% or more, purity 99.9% or more green synthetically loratadine method. In a specific medium, i.e. a particular structure of the reaction is carried out in the ionic liquid. The ionic liquid may be used alone as the media, can also be combined with other component solvent use, and can be recycled, and environmental protection. After treatment is simple, post-processing is simple and convenient. (by machine translation)