80474-14-2

Basic information

• Product Name: Fluticasone propionate
• Synonyms: s-fluoromethyl-6alpha,9alpha-difluoro-11beta-hydroxy-16alpha-methyl-3-oxo-17alpha-propionyloxyandrosta-1,4-diene-17beta-carbothioate;-17-(1-oxopropoxy)-,s-(fluoromethyl)ester,(6-alpha,11-beta,16-alpha,17-alph;androsta-1,4-diene-17-carbothioicacid,6,9-difluoro-11-hydroxy-16-methyl-3-oxo;cci18781;fluticasone17-propionate;flutide;(6A,11B,16A,17A)-6,9-DIFLUORO-11-HYDROXY-16-METHYL-3-OXO-17-(1-OXOPROPOXY)ANDROSTA-1,4-DIENE-17-CARBOTHIOIC ACID FLUOROMETHYL ESTER;(6 ALPHA,11 BETA,16 ALPHA,17 ALPHA)-6,9-DIFLUORO-11-HYDROXY-16-METHYL-3-OXO-17-(1-OXOPROPOXY)ANDROSTA-1,4-DIENE-17-CARBOTHIOIC ACID FLUOROMETHYL ESTER
• CAS NO: 80474-14-2
• Molecular Formula: C₂₅H₃₁F₃O₅S
• Molecular Weight: 500.57
• EINECS: 1308068-626-2
• Product Categories: Biochemistry;Hydroxyketosteroids;Steroids;Intermediates & Fine Chemicals;Pharmaceuticals;Fluticasone;Steroid and Hormone;HIVID;Hormone Drugs
• Mol File: 80474-14-2.mol

Chemical Properties

• Melting Point: 275 °C
• Boiling Point: 568.3 °C at 760 mmHg
• Flash Point: 297.5 °C
• Appearance: white/solid
• Density: 1.32 g/cm³
• Vapor Pressure: 1.52E-14mmHg at 25°C
• Refractive Index: 31 ° (C=1, Dioxane)
• Storage Temp.: Store at RT
• Solubility: DMSO: ≥10 mg/mL
• PKA: 12.53±0.70(Predicted)
• Merck: 14,4211
• CAS DataBase Reference: Fluticasone propionate(CAS DataBase Reference)
• NIST Chemistry Reference: Fluticasone propionate(80474-14-2)
• EPA Substance Registry System: Fluticasone propionate(80474-14-2)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 2
• RTECS: BV7980000
• Hazardous Substances Data: 80474-14-2(Hazardous Substances Data)

Usage

Preparation

Fluticasone propionate, synthesized by Glaxo Wellcome and launched in 1993, is a trifluorinated glucocorticosteroid. It shows good topical antiinflammatory activity and is commonly used as a safe and effective inhaled treatment for asthma and allergic rhinitis.Fluticasone propionate can be synthesized from 9 by using BrCH2F,2a ClCH2F,5a or S-(monofluoromethyl) diarylsulfonium tetrafluoroborate 5f,g directly. Using BrCH2F can get an ideal yield; however, BrCH2F is costly and will destroy to the ozone layer. In addition, 9 reacted with BrCH2Cl or Br2CH2 and then by an anion exchange with AgF,2c,5e KF, or tetrabutylammonium fluoride5b to afford 1 in a low yield.Improved Synthesis of Fluticasone Propionate

Manufacturing Process

A solution of S-iodomethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo17α-propionyloxyandrosta-1,4-diene-17β-carbothioate (310 mg) in acetonitrile (10 ml) was stirred with silver fluoride (947 mg) for 3 days at room temperature in the dark. Ethyl acetate (100 ml) was added and the mixture was filtered through kieselguhr. The filtrate was washed successively with 2 N hydrochloric acid, water, saturated brine, then dried. The solvent was removed and the residue was subjected to column chromatography in chloroform then chloroform-acetone (19:1). The product was eluted with ethyl acetate and crystallised on concentration of the solution to give S-fluoromethyl 6α,9αdifluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene17β-carbothioate (0.075 g); melting point 272-273°C (dec.), [α]D= +30° (c 0.35).

Therapeutic Function

Glucocorticoid

Biological Activity

High affinity, selective glucocorticoid receptor agonist (K d = 0.5 nM). Potently stimulates glucocorticoid receptor-mediated transactivation of gene expression and enhances human eosinophil apoptosis (EC 50 = 3.7 nM) in vitro . Inhibits mast cell accumulation in nasal mucosa following topical administration. Lipophilic, clinically-used anti-inflammatory agent with low oral bioavailability.

Biochem/physiol Actions

Fluticasone propionate is a second generation glucocorticoid. Used as an anti-inflammatory agent for asthma. Shown to enhance eosinophil apoptosis in a concentration-dependent manner via the glucocorticoid receptor.

Mechanism of action

Fluticasone propionate has a unique C-20 thioflouromethyl group, and that, in combination with the 17α-propionate ester, gives it 36-fold the glucocorticoid receptor affinity as compared to beclomethasone dipropionate and twofold the affinity as compared to budesonide. The 9α-flouro group increases both glucocorticoid and mineralocorticoid activities, and the 6α-flouro group enhances only the glucocorticoid action. Studies have determined that the effectiveness of inhaled fluticasone propionate results from a local rather than a systemic effect.

Side effects

In controlled US studies, more than 3,300 patients with seasonal allergic, perennial allergic, or perennial nonallergic rhinitis received treatment with intranasal fluticasone propionate. In general, adverse reactions in clinical studies have been primarily associated with irritation of the nasal mucous membranes, and the adverse reactions were reported with approximately the same frequency by patients treated with the vehicle itself. The complaints did not usually interfere with treatment. Less than 2% of patients in clinical trials discontinued because of adverse events; this rate was similar for vehicle placebo and active comparators.Systemic corticosteroid side effects were not reported during controlled clinical studies up to 6 months’ duration with FLONASE Nasal Spray. If recommended doses are exceeded, however, or if individuals are particularly sensitive or taking FLONASE Nasal Spray in conjunction with administration of other corticosteroids, symptoms of hypercorticism, e.g., Cushing syndrome, could occur.PRESCRIBING INFORMATION

Veterinary Drugs and Treatments

While there are topical forms of fluticasone, most veterinary interests are in the inhaled versions of the drug. The aerosol for pulmonary inhalation appears to be effective in treating feline asthma, recurrent airway obstruction (RAO, heaves) or inflammatory airway disease (IAD) in horses, and dogs with chronic tracheobronchial disease. While the majority of small animal use has been with fluticasone, there are several other aerosol corticosteroids for inhalation (beclomethasone dipropionate, flunisolide, and triamcinolone acetonide) that theoretically could be used for the same purpose. The nasal inhalation corticosteroid products may be useful for allergyrelated chronic rhinosinusitis in cats and dogs.

Metabolism

Interestingly, less than 1% of the swallowed dose is bioavailable, in contrast to the fact that the majority of the inhaled dose is systemically available and highly protein bound. Fluticasone propionate is not a prodrug and is extensively metabolized by the liver. The only detectable metabolite is the 17β-carboxylic acid derived from CYP3A4 oxidation. This metabolite has 2,000-fold less affinity for the glucocorticoid receptor than the parent drug. Elimination is through both the feces and the urine, with the relative amounts determined by the route of administration. Fluticasone propionate is available in aerosol and powder inhalation formulations.

Dosage

Adults: The recommended starting dosage in adults is 2 sprays (50 mcg of fluticasone propionate each) in each nostril once daily (total daily dose, 200 mcg). The same dosage divided into 100 mcg given twice daily (e.g., 8 a.m. and 8 p.m.) is also effective. After the first few days, patients may be able to reduce their dosage to 100 mcg (1 spray in each nostril) once daily for maintenance therapy. Some patients (12 years of age and older) with seasonal allergic rhinitis may find as-needed use of 200 mcg once daily effective for symptom control (see Clinical Trials). Greater symptom control may be achieved with scheduled regular use.

InChI:InChI=1/C22H27F3O4S/c1-11-6-13-14-8-16(24)15-7-12(26)4-5-19(15,2)21(14,25)17(27)9-20(13,3)22(11,29)18(28)30-10-23/h4-5,7,11,13-14,16-17,27,29H,6,8-10H2,1-3H3/t11-,13+,14+,16+,17+,19+,20+,21+,22+/m1/s1

Synthetic route

S-hydroxymethyl 6α,9α-difluoro-16α-methyl-3-oxo-11β-hydroxy-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate (709002-83-5) → flixotide (80474-14-2)

Conditions	Yield
With diethylamino-sulfur trifluoride In tetrahydrofuran at -20℃; for 0.333333h;	68%
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at -60℃; for 0.166667h;	35%

6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methylpregna-3-oxo-1,4-diene-17β-thiocarboxylic acid diisopropylethylamine salt + R32 (593-70-4) → flixotide (80474-14-2)

Conditions	Yield
In acetonitrile at 5 - 50℃; under 975.098 Torr; for 22.5h;	60%
In acetonitrile at 5 - 50℃; under 760.051 - 975.098 Torr; for 22.5h;	60%

bromofluoromethane (373-52-4) + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
With potassium hydrogencarbonate In N,N-dimethyl-formamide at -10 - 20℃; for 2h;	91.7%
With potassium carbonate In acetone at -5 - 0℃; for 2 - 5h; Product distribution / selectivity;	84.51%
Stage #1: 17-propionate carbothioic acid With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: bromofluoromethane In acetone at 0 - 5℃;	80%

S-iodomethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate (80474-67-5) → flixotide (80474-14-2)

Conditions	Yield
With calcium fluoride; silver fluoride In acetonitrile at -15 - -10℃; for 48h;	75%
With silver fluoride In acetonitrile for 4h; Ambient temperature;	74%
With calcium fluoride; silver fluoride In acetonitrile at -15 - -10℃; for 48h; Product distribution / selectivity;	60%
With silver fluoride In acetonitrile at 0 - 5℃; for 75h; Product distribution / selectivity;	40%
Multi-step reaction with 2 steps 1: 74.2 percent / acetonitrile / 1.17 h / 20 °C 2: 43 percent Spectr. / KF, KI, aminopolyether 2.2.2 / acetonitrile / 0.58 h / 100 °C / 1050.08 Torr View Scheme

fluoroiodomethane (373-53-5) + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
With caesium carbonate In acetonitrile at 20℃; for 6h; chemoselective reaction;	82%
With potassium hydrogencarbonate In N,N-dimethyl-formamide at 22 - 25℃; for 0.25h;	67.1%
With potassium carbonate; sodium hydrogensulfite In acetone at -10℃;

C27H30F6O6S (1414857-56-9) → flixotide (80474-14-2)

Conditions	Yield
With methanol; ammonia at 0℃; for 0.0833333h;
With ammonia In methanol at 0℃; for 0.0833333h;	0.041 g

S-fluoromethyl 6α-fluoro-9β,11β-epoxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (192191-49-4) → flixotide (80474-14-2)

Conditions	Yield
With hydrogen fluoride In water at -20℃; for 7h;

6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylic acid triethylamine salt + R32 (593-70-4) → flixotide (80474-14-2)

Conditions	Yield
In acetonitrile at 5 - 50℃; under 975.098 Torr; for 22.5h;

6α,9α-difluoro-11β-hydroxy-17α-propionyloxy-16α-methyl-pregna-3-oxo-1,4-diene-17β-thiocarboxylic acid N-methylpiperidine salt + R32 (593-70-4) → flixotide (80474-14-2)

Conditions	Yield
In acetonitrile at 5 - 50℃; under 975.098 Torr; for 22.5h;

diethylammonium 6α,9α-difluoro-16α-methyl-3-oxo-11β-hydroxy;-17α-propionyloxyandrosta-1,4-diene-17β-thiocarboxylate + R32 (593-70-4) → flixotide (80474-14-2)

Conditions	Yield
In acetonitrile at 5 - 50℃; under 975.098 Torr; for 22.5h;

C4H9NO*C24H30F2O5S + R32 (593-70-4) → flixotide (80474-14-2)

Conditions	Yield
In acetonitrile at 5 - 50℃; under 975.098 Torr; for 22.5h;

C12H23N*C24H30F2O5S + R32 (593-70-4) → flixotide (80474-14-2)

Conditions	Yield
In acetonitrile at 5 - 50℃; under 975.098 Torr; for 22.5h;

C6H13N*C24H30F2O5S + R32 (593-70-4) → flixotide (80474-14-2)

Conditions	Yield
In acetonitrile at 5 - 50℃; under 975.098 Torr; for 22.5h;

P-(monofluoromethyl)triphenylphosphonium tetrafluoroborate (96385-23-8) + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
With caesium carbonate In acetonitrile at 20℃;

N-(monofluoromethyl)-N-phenyl-dimethylammonium triflate (1351445-70-9) + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
With caesium carbonate In acetonitrile at 20℃;

N-(monofluoromethyl)-N-phenyldimethylammonium tetrafluoroborate + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
With caesium carbonate In acetonitrile at 20℃;

R32 (593-70-4) + N-ethyl-N,N-diisopropylamine (7087-68-5) + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
Stage #1: N-ethyl-N,N-diisopropylamine; 17-propionate carbothioic acid In acetonitrile for 0.25h; Stage #2: Stage #3: R32 In acetonitrile at 5 - 50℃; under 975.098 Torr; for 22.5h;

R32 (593-70-4) + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
base;
With potassium thiosulfate; 2-methylacrylic acid 3-hydroxypropyl ester at 10℃;

6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (1351451-82-5) → flixotide (80474-14-2)

Conditions	Yield
With 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate); silver nitrate In water; acetone at 45℃; for 3h; Temperature; Solvent; Time; Inert atmosphere; Green chemistry;	83%

17β-[(N,N-dimethylcarbamoyl)thio]formyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-one androstone-1,4-diene (105638-31-1) → flixotide (80474-14-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: Et2NH / Heating 2: 67.1 percent / KHCO3 / dimethylformamide / 0.25 h / 22 - 25 °C View Scheme
Multi-step reaction with 2 steps 1: Et2NH / Heating 2: 9.4 percent / K2CO3 / dimethylformamide / 1 h / -5 - 0 °C View Scheme
Multi-step reaction with 4 steps 1: Et2NH / Heating 2: 67 percent / NaHCO3 / N,N-dimethyl-acetamide / 2 h 3: 85 percent / NaI / acetone / Heating 4: 74 percent / AgF / acetonitrile / 4 h / Ambient temperature View Scheme

6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylic acid (65429-42-7) → flixotide (80474-14-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / 20 °C 2: Et2NH / Heating 3: 67.1 percent / KHCO3 / dimethylformamide / 0.25 h / 22 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / 20 °C 2: Et2NH / Heating 3: 9.4 percent / K2CO3 / dimethylformamide / 1 h / -5 - 0 °C View Scheme
Multi-step reaction with 5 steps 1: Et3N / CH2Cl2 / 20 °C 2: Et2NH / Heating 3: 67 percent / NaHCO3 / N,N-dimethyl-acetamide / 2 h 4: 85 percent / NaI / acetone / Heating 5: 74 percent / AgF / acetonitrile / 4 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1.1: sodium iodide; triethylamine / tetrahydrofuran / 4 h / 70 - 75 °C 2.1: morpholine / 3 h / 20 °C 3.1: potassium carbonate / acetone / 0.5 h / 20 °C 3.2: 0 - 5 °C View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine; sodium iodide / acetone; water / 6 h / 10 - 30 °C 1.2: 1 h / 0 °C 2.1: potassium carbonate / methanol / 5 h / 25 °C / Inert atmosphere 3.1: triethylamine / acetone / 5 h / 25 °C 3.2: 0 °C / pH 1 - 1.5 4.1: silver nitrate; 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) / acetone; water / 3 h / 45 °C / Inert atmosphere; Green chemistry View Scheme

6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid (28416-82-2) → flixotide (80474-14-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: dimethylformamide / 4 h / Ambient temperature 2: H2S / dimethylformamide 3: Et3N / CH2Cl2 / 0.75 h 4: Et2NH / acetone / 1 h 5: 67.1 percent / KHCO3 / dimethylformamide / 0.25 h / 22 - 25 °C View Scheme
Multi-step reaction with 5 steps 1: dimethylformamide / 4 h / Ambient temperature 2: H2S / dimethylformamide 3: Et3N / CH2Cl2 / 0.75 h 4: Et2NH / acetone / 1 h 5: 9.4 percent / K2CO3 / dimethylformamide / 1 h / -5 - 0 °C View Scheme
Multi-step reaction with 7 steps 1: dimethylformamide / 4 h / Ambient temperature 2: H2S / dimethylformamide 3: Et3N / CH2Cl2 / 0.75 h 4: Et2NH / acetone / 1 h 5: 67 percent / NaHCO3 / N,N-dimethyl-acetamide / 2 h 6: 85 percent / NaI / acetone / Heating 7: 74 percent / AgF / acetonitrile / 4 h / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / acetone / 3 h / 0 - 5 °C 1.2: 2.5 h / 40 - 45 °C 2.1: sodium iodide; triethylamine / tetrahydrofuran / 4 h / 70 - 75 °C 3.1: morpholine / 3 h / 20 °C 4.1: potassium carbonate / acetone / 0.5 h / 20 °C 4.2: 0 - 5 °C View Scheme
Multi-step reaction with 5 steps 1.1: triethylamine / acetone / 4 h / 10 - 25 °C 1.2: 10 - 25 °C 1.3: 0 °C / pH 1 - 1.5 2.1: triethylamine; sodium iodide / acetone; water / 6 h / 10 - 30 °C 2.2: 1 h / 0 °C 3.1: potassium carbonate / methanol / 5 h / 25 °C / Inert atmosphere 4.1: triethylamine / acetone / 5 h / 25 °C 4.2: 0 °C / pH 1 - 1.5 5.1: silver nitrate; 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) / acetone; water / 3 h / 45 °C / Inert atmosphere; Green chemistry View Scheme

17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 67 percent / NaHCO3 / N,N-dimethyl-acetamide / 2 h 2: 85 percent / NaI / acetone / Heating 3: 74 percent / AgF / acetonitrile / 4 h / Ambient temperature View Scheme
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 3 h / 20 °C 2: triethylamine / dmap / tetrahydrofuran / 20 °C 3: trifluoroacetic acid / 2 h / 20 °C 4: xenon fluoride / dichloromethane / 48 h / -10 °C 5: ammonia; methanol / 0.08 h / 0 °C View Scheme
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 3 h / 20 °C 2: triethylamine; dmap / tetrahydrofuran / 20 °C 3: trifluoroacetic acid / 2 h / 20 °C 4: xenon difluoride / dichloromethane / 48 h / -10 °C 5: ammonia / methanol / 0.08 h / 0 °C View Scheme

bromofluoromethane (373-52-4) + 17β-[(N,N-dimethylcarbamoyl)thio]formyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-one androstone-1,4-diene (105638-31-1) → flixotide (80474-14-2)

Conditions	Yield
Stage #1: 17β-[(N,N-dimethylcarbamoyl)thio]formyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-one androstone-1,4-diene With sodium hydrogensulfide In ISOPROPYLAMIDE at 0 - 20℃; for 4h; Stage #2: bromofluoromethane In ISOPROPYLAMIDE at -5℃; for 1h; Stage #3: With dihydrogen peroxide In ISOPROPYLAMIDE; water at 20℃; for 0.5h; Product distribution / selectivity;
Stage #1: 17β-[(N,N-dimethylcarbamoyl)thio]formyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-one androstone-1,4-diene With methanol; potassium carbonate at 20℃; for 5.5h; Stage #2: bromofluoromethane at -5 - 0℃; for 7.5h; Product distribution / selectivity;

Propionic acid (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-(toluene-4-sulfonyloxymethylsulfanylcarbonyl)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester (192191-50-7) → flixotide (80474-14-2) + S-iodomethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate (80474-67-5) + C49H60F4O10S2

Conditions	Yield
With potassium fluoride; aminopolyether 2.2.2; potassium iodide In acetonitrile at 100℃; under 1050.08 Torr; for 0.583333h;	A 43 % Spectr. B 21 % Spectr. C 24 % Spectr.

S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulphonium tetrafluoroborate + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
With caesium carbonate In dichloromethane at 20℃; Product distribution / selectivity;

S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflate + 17-propionate carbothioic acid (80474-45-9) → flixotide (80474-14-2)

Conditions	Yield
With caesium carbonate In dichloromethane at 20℃; Product distribution / selectivity;

S-chloromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate (80486-69-7) → flixotide (80474-14-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 90.1 percent / NaI / acetone / 2 h / Heating 2: 74.2 percent / acetonitrile / 1.17 h / 20 °C 3: 43 percent Spectr. / KF, KI, aminopolyether 2.2.2 / acetonitrile / 0.58 h / 100 °C / 1050.08 Torr View Scheme
Multi-step reaction with 2 steps 1: 85 percent / NaI / acetone / Heating 2: 74 percent / AgF / acetonitrile / 4 h / Ambient temperature View Scheme

6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid (80473-92-3) → flixotide (80474-14-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / 0.75 h 2: Et2NH / acetone / 1 h 3: 67.1 percent / KHCO3 / dimethylformamide / 0.25 h / 22 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / 0.75 h 2: Et2NH / acetone / 1 h 3: 9.4 percent / K2CO3 / dimethylformamide / 1 h / -5 - 0 °C View Scheme
Multi-step reaction with 5 steps 1: Et3N / CH2Cl2 / 0.75 h 2: Et2NH / acetone / 1 h 3: 67 percent / NaHCO3 / N,N-dimethyl-acetamide / 2 h 4: 85 percent / NaI / acetone / Heating 5: 74 percent / AgF / acetonitrile / 4 h / Ambient temperature View Scheme

(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-Difluoro-11,17-dihydroxy-17-(imidazole-1-carbonyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-cyclopenta[a]phenanthren-3-one → flixotide (80474-14-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: H2S / dimethylformamide 2: Et3N / CH2Cl2 / 0.75 h 3: Et2NH / acetone / 1 h 4: 67.1 percent / KHCO3 / dimethylformamide / 0.25 h / 22 - 25 °C View Scheme
Multi-step reaction with 4 steps 1: H2S / dimethylformamide 2: Et3N / CH2Cl2 / 0.75 h 3: Et2NH / acetone / 1 h 4: 9.4 percent / K2CO3 / dimethylformamide / 1 h / -5 - 0 °C View Scheme
Multi-step reaction with 6 steps 1: H2S / dimethylformamide 2: Et3N / CH2Cl2 / 0.75 h 3: Et2NH / acetone / 1 h 4: 67 percent / NaHCO3 / N,N-dimethyl-acetamide / 2 h 5: 85 percent / NaI / acetone / Heating 6: 74 percent / AgF / acetonitrile / 4 h / Ambient temperature View Scheme

3-(tert-butyloxycarbonylamino)propionic acid (3303-84-2) + flixotide (80474-14-2) → C33H44F3NO8S

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 168h; Cooling with ice;	99%

flixotide (80474-14-2) → (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-((hydroxyhydrophosphoryl)oxy)-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate

Conditions	Yield
With triethylamine; phosphorus trichloride In tetrahydrofuran at -78 - 20℃; for 26h;	94%

Elaidic acid (112-79-8) + flixotide (80474-14-2) → Fluticasone propionate 11beta-elaidic acid ester (1059627-22-3)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 164h;	79%

2-(triphenylmethylthio)ethanoic acid (34914-36-8) + flixotide (80474-14-2) → 11-O-[2-(tritylmercapto)acetyl]fluticasone propionate

Conditions	Yield
With dmap In dichloromethane at 20℃;	71%

BOC-glycine (4530-20-5) + flixotide (80474-14-2) → C32H42F3NO8S

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;	63%

3-[(tert-butoxycarbonyl)amino]-2-fluoropropanoic acid + flixotide (80474-14-2) → C33H43F4NO8S

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 168h; Cooling with ice;	63%

Upstream product

• 373-53-5 fluoroiodomethane 
• 80474-45-9 17-propionate carbothioic acid 
• 373-52-4 bromofluoromethane 
• 65429-42-7 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carboxylic acid 
• 80473-92-3 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid 
• 593-70-4 R₃₂ 
• 192191-49-4 S-fluoromethyl 6α-fluoro-9β,11β-epoxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate 
• 709002-83-5 S-hydroxymethyl 6α,9α-difluoro-16α-methyl-3-oxo-11β-hydroxy-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate 
• 7087-68-5 N-ethyl-N,N-diisopropylamine 
• 105638-31-1 17β-[(N,N-dimethylcarbamoyl)thio]formyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-one androstone-1,4-diene 
• 96385-23-8 P-(monofluoromethyl)triphenylphosphonium tetrafluoroborate 
• 1351445-70-9 N-(monofluoromethyl)-N-phenyl-dimethylammonium triflate 
• 1414857-52-5 C₃₀H₄₀F₂O₇S 
• 1414857-53-6 C₃₂H₃₉F₅O₈S 

Relevant articles and documents

Fluticasone propionate synthesis method

The embodiments of the invention provide a fluticasone propionate synthesis method, which comprises: a thioesterification reaction: adding a first intermediate, an first organic alkali, dimethylaminothioformyl chloride, sodium iodide and a first organic solvent into a reaction kettle, carrying out a reaction, adding a polar aprotic solvent and water after the reaction, carrying out cooling crystallizing, filtering, washing, and drying to obtain a second intermediate; an alcoholysis reaction: adding the second intermediate, a first inorganic alkali and a second organic solvent into a reaction kettle, carrying out a reaction, adding water or water and an extracting agent after the reaction, extracting, taking the water phase, adding hydrochloric acid in a dropwise manner, crystallizing, filtering, washing, and drying to obtain a third intermediate; and a substitution esterification reaction: adding the third intermediate, a second inorganic alkali and a third organic solvent into a reaction kettle, adding fluorobromomethane, adding hydrochloric acid in a dropwise manner, crystallizing, filtering, washing, and drying to obtain fluticasone propionate. According to the embodiments of the invention, the low-cost production can be realized, and the reaction yield and the purity are high.

Direct and Chemoselective Electrophilic Monofluoromethylation of Heteroatoms (O-, S-, N-, P-, Se-) with Fluoroiodomethane

The commercially available fluoroiodomethane represents a valuable and effective electrophilic source for transferring the CH2F unit to a series of heteroatom-centered nucleophiles under mild basic conditions. The excellent manipulability offered by its liquid physical state (bp 53.4 °C) enables practical and straightforward one-step nucleophilic substitutions to retain the chiral information embodied, thus allowing it to overcome de facto the requirement for fluoromethylating agents with no immediate access. The high-yielding methodology was successfully applied to a variety of nucleophiles including a series of drugs currently in the market.

Preparation method of fluticasone propionate

The invention provides a preparation method of fluticasone propionate. The preparation method comprises the following steps that (1) a compound 5 is hydrolyzed in the presence of a base and an alcoholsolvent to obtain a compound 6; and (2) the compound 6 reacts with fluorohalomethane to obtain fluticasone propionate (compound 1) under the condition that a reducing salt is used as a catalyst. According to the preparation method of fluticasone propionate, the reducing inorganic salt is used as the catalyst to greatly reduce the formation of impurities, such as disulfide impurities, sulfhydryl oxide impurities and haloalkylate impurities introduced by sulfhydryl oxides.

Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates

As part of an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel pyrophosphate ester linker was discovered to enable the targeted delivery of glucocorticoids. As small molecules, these highly soluble phosphate ester drug linkers were found to have ideal orthogonal properties: robust plasma stability coupled with rapid release of payload in a lysosomal environment. Building upon these findings, site-specific ADCs were made between this drug linker combination and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. Full characterization of these ADCs enabled procession to in vitro proof of concept, wherein ADCs 1-22 and 1-37 were demonstrated to afford potent, targeted delivery of glucocorticoids to a representative cell line, as measured by changes in glucocorticoid receptor-mediated gene mRNA levels. These activities were found to be antibody-, linker-, and payload-dependent. Preliminary mechanistic studies support the notion that lysosomal trafficking and enzymatic linker cleavage are required for activity and that the utility for the pyrophosphate linker may be general for internalizing ADCs as well as other targeted delivery platforms.

PROCESS FOR PREPARING FLUTICASONE PROPIONATE/FUROATE

The present invention relates to an improved process for the preparation of substituted Fluticasone derivatives. The invention also reveals the processes for the purification of Fluticasones and related intermediates to provide the highly pure product.

Improved synthesis of fluticasone propionate

A novel process for the preparation of fluticasone propionate (1), a corticosteroid, is reported. In this paper, compound 2 was used as starting material to prepare 6 by using NaClO or NaBrO which was much cheaper than H 5IO6 as an oxidizing agent. Furthermore, toxic, expensive, and pollutive BrCH2F was replaced by AgNO3 and Selectfluor in decarboxylative fluorination.

Method for the Production of Fluoromethyl Esters of Androstan-17 beta Carboxylic Acids

Described herein are processes for the preparation of monofluoromethylated organic biologically active compounds, starting from protected intermediates and/or reagents to obtain compounds such as fluticasone propionate and fluticasone furoate, in presence of decarboxylating reagents XeF2 and BrF3, or using FCH2SH as a reagent.

METHOD FOR THE PRODUCTION OF FLUOROMETHYL - ESTERS OF ANDROSTAN- 17 - BETA - CARBOXYLIC ACIDS

The present invention relates to a method of preparing an organic biologically active compound of formula (I), wherein R1, R2, R3, R4,. X1, X2 and X3 are as defined in the specification, to certain novel intermediates obtainable from such a method and their use.

METHOD FOR MONOFLUOROMETHYLATION OF ORGANIC SUBSTRATES TO PREPARE BIOLOGICALLY ACTIVE ORGANIC COMPOUNDS

The present invention describes a process for the preparation of monofluoromethylated organic biologically active compounds using monofluoromethylated reagents. Fluticasone Propionate and Fluticasone Furoate can be prepared using, for example, S-monofluoromethyl-S-phenyl-2,3,4,5- tetramethylphenylsulfonium tetrafluoroborate as monofluoromethylating reagent instead of bromofluoromethane.

NOVEL PROCESS AND INTERMEDIATES

The present invention relates to a process for the preparation of steroidal 17β-carboxylic thioates. More particularly the present invention relates to a convenient and efficient synthesis of steroidal 17β-carboxylic thioates, such as fluticasone propionate I, using soluble mixed fluorides to introduce fluorine by displacing an appropriate leaving group X in compounds II resulting in selective and controlled fluorination. The present invention also relates to intermediates II and their preparation.