50-02-2

Basic information

• Product Name: Dexamethasone
• Synonyms: 16alpha)-;16alpha)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-(11bet;16alpha-methyl-9alpha-fluoro-1,4-pregnadiene-11beta,17alpha,21-triol-2,20-dione;16-alpha-methyl-9-alpha-fluoro-1,4-pregnadiene-11-beta,17-alpha,21-triol-3,2;16-alpha-Methyl-9-alpha-fluoro-1,4-pregnadiene-11-beta,17-alpha,21-triol-3,20-dione;16-alpha-methyl-9-alpha-fluoro-11-beta,17-alpha,21-trihydroxypregna-1,4-dien;16alpha-Methyl-9alpha-fluoro-11beta-17alpha-21-trihydroxypregna-1,4-diene-3,20-dione;16-alpha-methyl-9-alpha-fluoro-1-dehydrocortisol
• CAS NO: 50-02-2
• Molecular Formula: C22H29FO5
• Molecular Weight: 392.46
• EINECS: 200-003-9
• Product Categories: Active Pharmaceutical Ingredients;Antitumors for Research and Experimental Use;Biochemistry;Hydroxyketosteroids;Steroids;Intermediates & Fine Chemicals;Pharmaceuticals;Isotope Labeled Compounds;Steroid and Hormone;Pharmaceutical intermediate;API;MAXIDEX;Hormone Drugs;Mainly used for anti-inflammatory and allergy;Pharmaceutical intermediates;pharmaceutical intermediate and medicine grade
• Mol File: 50-02-2.mol
• Article Data: 39

Chemical Properties

• Melting Point: 262-264 °C(lit.)
• Boiling Point: 568.2 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: off-white/powder
• Density: 1.1283 (estimate)
• Vapor Pressure: 2.81E-15mmHg at 25°C
• Refractive Index: 76 ° (C=1, Dioxane)
• Storage Temp.: 2-8°C
• Solubility: ethanol: 1 mg/mL
• PKA: 12.13±0.70(Predicted)
• Water Solubility: 10 mg/100 mL (25 ºC)
• Sensitive: Light Sensitive
• Stability: Stable. Combustible. Incompatible with strong oxidizing agents, strong bases, acid anhydrides, acid chlorides. May be light sens
• Merck: 14,2943
• BRN: 2066651
• CAS DataBase Reference: Dexamethasone(CAS DataBase Reference)
• NIST Chemistry Reference: Dexamethasone(50-02-2)
• EPA Substance Registry System: Dexamethasone(50-02-2)

Safety Data

• Hazard Codes: Xi,Xn,T,F
• Statements: 43-40-36/37/38-20/21/22-42/43-39/23/24/25-23/24/25-11
• Safety Statements: 36/37-45-36-26-22-16
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 2
• RTECS: TU3980000
• TSCA: Yes
• Hazardous Substances Data: 50-02-2(Hazardous Substances Data)

Usage

Anti-inflammatory effects

Dexamethasone reduces and prevents the tissue response to inflammation, thereby reducing the manifestations of inflammation. Hormones inhibit the accumulation of inflammatory cells, including macrophages and leukocytes, at sites of inflammation, and inhibit phagocytosis, the release of lysosomal enzymes, and the synthesis and release of inflammatory chemical mediators.

Description

Different sources of media describe the Description of 50-02-2 differently. You can refer to the following data:
1. Dexamethasone is an Anti-inflammatory glucocorticoid that is used to treat inflammatory and autoimmune conditions such as rheumatoid arthritis and bronchospasm. It is useful to study apoptosis, cell signaling pathways and gene expression. It is associated with marbofloxacin and clotrimazole and finds application in veterinary medicine to treat difficult ear infections in dogs. It is also used to treat horses with swelling of of distal limbs and general bruising in combination with trichlormethiazide. Dexamethasone induces the production of phospholipase A2 inhibitory protein (lipocortin). It also inhibits induction of nitric oxide synthase (IC50=5 nM). Dexamethasone has been shown to cause reduction in cyclin A and Cd k2 activity, inhibition of G1/S transition in osteoblasts and inhibition of phosphorylation of Rb protein in vitro. Dexamethasone has been observed to induce apoptosis in human thymocytes and eosinophils, but inhibits apoptosis in neutrophils in vitro. Dexamethasone is an activator of IDO. Dexamethasone Inhibits the expression of the inducible but not the constitutive nitric oxide synthase in vascular endothelial cells (IC50=5 nM). Dexamethasone regulates T cell survival, growth, and differentiation.Enhances active cation transport in aortic smooth muscle cells by stimulating the Na+-K+ pump. Has anti-inflammatory and anti-rheumatic properties. Induces apoptosis in human thymocytes. In general, 500-1000 nM of dexamethasone is sufficient to induce apoptosis following a 6-hour incubation at 37°C.
2. The activity of dexamethasone, as measured by glycogen deposition, is 20 times greater than that of hydrocortisone. It has five times the anti-inflammatory activity of prednisolone. Clinical data indicate that this compound has seven times the antirheumatic potency of prednisolone. It is roughly 30 times more potent than hydrocortisone. Its pharmacokinetics are presented in Table 33.3. Routes of metabolism for dexamethasone are similar to those for prednisolone, with its primary 6β-hydroxy metabolite being recovered in urine. Dexamethasone sodium phosphate is the water-soluble sodium salt of the 21-phosphate ester, with an IV half-life of less than 10 minutes because of rapid hydrolysis by plasma phosphatases. Peak plasma levels for dexamethasone usually are attained in approximately 10 to 20 minutes following its IV administered dose. A similar reaction occurs when the phosphate ester is applied topically or by inhalation.

Side Effects

Dexamethasone is a artificially synthetic glucocorticoid, belonging to a long-term glucocorticoid drugs. Glucocorticoids can promote the metabolism of the three major nutrients while preventing protein synthesis with long-term topical being able to causing more serious consequences. However, the adverse effects should be much smaller than oral medication. Common side effects of systemic corticosteroid include: It can cause stomach discomfort and increased sensitivity to stomach ulcers. It can Increase the appetite and results in a significant increase in body weight. Potential patients with diabetes: glucose intolerance in patients with aggravating existing diabetes. It can cause mental illness including personality changes, irritability, agitation, and mania. It can be used for the long-term treatment of osteoporosis: pathological fractures (such as hip). It can cause elevated liver enzymes, fatty liver degeneration (usually reversible). For patients of nephrotic syndrome, applying long-term high-dose medication is likely to cause large side effects such as gastrointestinal ulcers and avascular necrosis. For treatment of nephrotic syndrome, it is better to apply prednisone acetate tablets. Dexamethasone can be used for the treatment of high altitude cerebral edema and pulmonary edema. Upon climbing expeditions, people can apply it to alleviate altitude sickness. Combination with marbofloxacin and clotrimazole, etc. can be used for treating the ear infection and allergies of a dog or a bird.

Drug Reactions

Dexamethasone is a corticosteroid known as a glucocorticoid. Corticosteroids are meant to resemble a naturally occurring hormone produced in the adrenal cortex, cortisol. Corticosteroids act on the immune system by blocking the production of substances that trigger inflammatory and immune responses. Dexamethasone may react with these drugs: Amphotericin Aspirin Cyclophosphamide Cyclosporine Digoxin Daunorubicin HCl Doxorubicin HCl Insulin Mitotane Phenobarbital Phenytoin sodium Rifampin Rimadyl

Chemical Properties

White or almost white, crystalline powder.

Originator

Dexacen,Central,US,1977

Uses

Different sources of media describe the Uses of 50-02-2 differently. You can refer to the following data:
1. Glucocorticoid.
2. Dexamethasone is used for the same indications as all corticosteroids; however, it exhibits a significantly more powerful anti-inflammatory and anti-allergic action. It is used for circulatory collapse—shock during or after surgical operations, trauma, blood loss, myocardial infarction, and burns. It is also used in severe infections—toxemia, vascular collapse in meningococcosis, septicemia, diphtheria, typhoid fever, and peritonitis. It is used in severe allergic conditions—asthmatic status, laryngeal edema, severe anaphylactic reactions to medicinal drugs, and pyrogenic reactions.
3. Anti-inflammatory glucocorticoidDexamethasone is used to treat inflammatory and autoimmune conditions such as rheumatoid arthritis and bronchospasm. It is useful to study apoptosis, cell signaling pathways and gene expression. It is associated with marbofloxacin and clotrimazole and finds application in veterinary medicine to treat difficult ear infections in dogs. It is also used to treat horses with swelling of of distal limbs and general bruising in combination with trichlormethiazide. It is also an anti-inflammatory glucocorticoid.

Indications

Cushing’s disease is defined as hypercortisolism due to chronic overproduction of corticotrophin by a corticotroph adenoma. Cortisol’s lack of suppressibility during the administration of low doses of dexamethasone but suppressibility during high-dose dexamethasone is the key diagnostic finding in 99% of the patients with Cushing’s disease. This contrasts with the lack of glucocorticoid suppressibility typically found in patients with corticotrophin-independent hypercortisolism (Cushing’s syndrome). A judicious selection of the available tests may be necessary to obtain an accurate diagnosis in patients with Cushing’s syndrome.

Manufacturing Process

The preparation of dexamethasone acetate is described in US Patent 3,007,923 as follows. 1.5 cc of dimethylformamide and 1.5 cc of anhydrous hydrofluoric acid are admixed and treated with 480 mg of 9β,11β-epoxy-17αhydroxy-21-acetoxy-16α-methyl-?1,4-pregnadiene-3,20-dione (prepared according to E.P. Oliveto et al, J. Am. Chem. Soc., 80, 44331, 1958). The steroid dissolves in about 15 minutes. The reaction mixture is shaken for two hours at a temperature between 0 and +5°C, and then poured into 75 cc ofwater containing in suspension, 7.5 grams of sodium bicarbonate. The mixture is vacuum filtered, the filter cake washed and then dried at 100°C, yielding 460 mg of crude hexadecadrol contaminated with a small amount of the starting material. A single recrystallization from methylene chloride yields 370 mg of the pure product having a melting point of 170°C and 229°C. The mother liquor yields 62 mg of the starting material, and a remainder constituting a mixture of starting and final materials with little other contamination.

Brand name

Aeroseb-Dex (Allergan); Decadron (Merck); Dexone (Solvay Pharmaceuticals); Hexadrol (Organon); Maxidex (Alcon); Mymethasone (Morton Grove).

Therapeutic Function

9-Fluoro-11β,17-dihydroxy-21-acetoxy-16α-methylpregna1,4-diene-3,20-dione

General Description

Different sources of media describe the General Description of 50-02-2 differently. You can refer to the following data:
1. Dexamethasone, 9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione,is the 16 -isomer of betamethasone.Dexamethasone acetate, USP (21-acetate)Dexamethasone sodium phosphate, USP (21-sodiumphosphate).
2. Odorless white to off-white crystalline powder with a slightly bitter taste.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Dexamethasone may be sensitive to prolonged exposure to light. Dexamethasone is incompatible with strong oxidizers, strong acids, acid chlorides and acid anhydrides. Oxidation may occur with bases.

Fire Hazard

Flash point data for Dexamethasone are not available; however, Dexamethasone is probably combustible.

Biological Activity

Glucocorticoid; anti-inflammatory. Reduces levels of activated NF- κ B in immature dendritic cells (DCs) and inhibits differentiation into mature DCs.

Biochem/physiol Actions

Target IC50: 5 nM Inhibiting the expression of inducible but not constitutive nitric oxide synthase in vascular endothelial cells

Pharmacology

Dexamethasone is a corticosteroid with high glucocorticoid activity and virtually no mineralocorticoid activity. I ts mechanism of action as an antiemetic is unknown, but it is possible that either direct genomic or indirect non-genomic effects on 5-HT3 and GABAA receptors contribute to its antiemetic activity. Many of the original studies were carried out using 8– 10mg of dexamethasone phosphate, but smaller doses (2.5–4mg) provide equal antiemetic efficacy with minimal risk of adverse effects. Concerns relating to adrenal suppression and other steroid-induced adverse effects (including increased risk of bleeding) after a single dose of dexamethasone remain largely unfounded. O ne of the most unpleasant adverse effects of dexamethasone involves intense perineal stimulation after rapid i.v. injection.

Pharmacokinetics

The activity of dexamethasone, as measured by glycogen deposition, is 20 times greater than that of hydrocortisone. It has five times the anti-inflammatory activity of prednisolone. Clinical data indicate that this compound has seven times the antirheumatic potency of prednisolone. It is roughly 30 times more potent than hydrocortisone. Its pharmacokinetics are presented in Table 33.3. Routes of metabolism for dexamethasone are similar to those for prednisolone, with its primary 6β-hydroxy metabolite being recovered in urine. Dexamethasone sodium phosphate is the water-soluble sodium salt of the 21-phosphate ester, with an IV half-life of less than 10 minutes because of rapid hydrolysis by plasma phosphatases. Peak plasma levels for dexamethasone usually are attained in approximately 10 to 20 minutes following its IV administered dose. A similar reaction occurs when the phosphate ester is applied topically or by inhalation.

Clinical Use

Corticosteroid:Cerebral oedemaBacterial meningitis (unlicensed indication)Suppression of inflammatory and allergic disordersRheumatic diseaseCongenital adrenal hyperplasiaAnti-emetic (unlicensed indication)

Safety Profile

Poison by intraperitoneal and subcutaneous routes. An experimental teratogen. Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits toxic fumes of F-.

Synthesis

Dexamethasone, 9α-fluoro-16α-methyl-11β,17,21-trihydroxypregna- 1,4-dien-3,20-dione (27.1.51), or simply 9α-fluoro-16α-methylprednisolone. The distinctive characteristic of dexamethasone is the presence of a fluorine atom at C9 of the steroid ring. Dexamethasone is synthesized in a multistage process from 3α-acetoxy-16-pregnen- 11,20-dione, which is reacted with methylmagnesium bromide in the presence of lithium bromide to give 3α-hydroxy-16α-methylpregnan-11,20-dione (27.1.39), after which a 17α- hydroxyl group is added. This is done by a reaction with acetic anhydride in the presence of p-toluenesulfonic acid, forming the 3-acetoxy-17-enolacetate 27.1.40, which is epoxidized by perbenzoic acid 27.1.41, and the product is hydrolyzed by an alkali to give an oxyketone 27.1.42. Addition of another hydroxyl group at C21 is accomplished by subsequent bromination of a methyl group with molecular bromine, replacing the bromine atom with iodine, and reacting iodide with potassium acetate, which forms the corresponding acetoxyketone 27.1.43. The hydroxyl group at C3 is oxidized to a carbonyl by chromium(VI) oxide in pyridine, giving the 3,11,20-triketone 27.1.44, which again undergoes bromination by molecular bromine, but at position C4. Dehydrogenation of this compound is accomplished using semicarbazide, which results in the formation of an unsaturated triketone 27.1.45. In order to avoid formation of semicarbazones at the keto-groups at C3 and C20, the final product is treated with pyruvic acid. Semicarbazones are then specially formed at the keto-groups of C3 and C20, and the keto-group at C11 that does not take part in semicarbazone formation is reduced to hydroxyl group using sodium borohydride. After removing the protective semicarbzone groups, 21-O-acetoxy-16β-methylhydrocortisone (27.1.46) is formed. This is reacted with potassium acetate and transformed to the epoxide 27.1.49. Reacting this with hydrofluoric acid results in an opening of the epoxide ring, during which the fluorohydrin 27.1.50 is formed. Finally, microbiological dehydrogenation of this compound at C1–C2 and simultaneous deacetylation gives dexamethasone (27.1.51).

Veterinary Drugs and Treatments

Glucocorticoids have been used in an attempt to treat practically every malady that afflicts man or animal, but there are three broad uses and dosage ranges for use of these agents. 1) Replacement of glucocorticoid activity in patients with adrenal insufficiency, 2) as an antiinflammatory agent, and 3) as an immunosuppressive. Among some of the uses for glucocorticoids include treatment of: endocrine conditions (e.g., adrenal insufficiency), rheumatic diseases (e.g., rheumatoid arthritis), collagen diseases (e.g., systemic lupus), allergic states, respiratory diseases (e.g., asthma), dermatologic diseases (e.g., pemphigus, allergic dermatoses), hematologic disorders (e.g., thrombocytopenias, autoimmune hemolytic anemias), neoplasias, nervous system disorders (increased CSF pressure), GI diseases (e.g., ulcerative colitis exacerbations), and renal diseases (e.g., nephrotic syndrome). Some glucocorticoids are used topically in the eye and skin for various conditions or are injected intra-articularly or intralesionally. The above listing is certainly not complete. For specific dosages and indications refer to the Doses section. High dose dexamethasone use for shock or CNS trauma is controversial; recent studies have not demonstrated significant benefit and it actually may cause increased deleterious effects.

Drug interactions

Potentially hazardous interactions with other drugsAldesleukin: avoid concomitant use.Antibacterials: metabolism accelerated by rifamycins; metabolism possibly inhibited by erythromycin; concentration of isoniazid possibly reduced.Anticoagulants: efficacy of coumarins and phenindione may be altered.Antiepileptics: metabolism accelerated by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidoneAntifungals: increased risk of hypokalaemia with amphotericin - avoid; metabolism possibly inhibited by itraconazole and ketoconazole; caspofungin concentration possibly reduced (may need to increase dose).Antivirals: concentration of indinavir, lopinavir, saquinavir and telaprevir possibly reduced; avoid with rilpivirine; concentration possibly increased by ritonavir.Ciclosporin: rare reports of convulsions in patients on ciclosporin and high-dose corticosteroids.Cobicistat: concentration possibly increased by cobicistat.Cytotoxics: possibly decreases axitinib concentration, increase dose of axitinib.Diuretics: enhanced hypokalaemic effects of acetazolamide, loop diuretics and thiazide diuretics.Netupitant: concentration of dexamethasone increased - halve dexamethasone dose.Vaccines: high dose corticosteroids can impair immune response to vaccines; avoid concomitant use with live vaccines.

Metabolism

Corticosteroids are metabolised mainly in the liver but also in other tissues, and are excreted in the urine. The slower metabolism of the synthetic corticosteroids with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids. Up to 65% of a dose of dexamethasone is excreted in urine within 24 hours.

Purification Methods

Dexamethasone has been recrystallised from Et2O or small volumes of EtOAc. Its solubility in H2O is 10 mg/100mL at 25o; and is freely soluble in Me2CO, EtOH and CHCl3. [Arth et al. J Am Chem Soc 80 3161 1958; for the -methyl isomer see Taub et al. J Am Chem Soc 82 4025 1960, see Beilstein 8 IV 3501.]

References

1) Merck Index 14 2943

InChI:InChI=1/C22H29FO5/c1-12-8-16-15-5-4-13-9-14(25)6-7-19(13,2)21(15,23)17(26)10-20(16,3)22(12,28)18(27)11-24/h6-7,9,12,15-17,24,26,28H,4-5,8,10-11H2,1-3H3/t12-,15?,16+,17+,19+,20+,21+,22+/m1/s1

Synthetic route

C23H31FO4 → dexamethasone (50-02-2)

Conditions	Yield
Stage #1: C23H31FO4 In ethyl acetate at 0 - 10℃; Stage #2: With hydrogenchloride In water at 30 - 35℃; for 1h;	40%

betamethasone (1177-87-3) → dexamethasone (50-02-2)

Conditions	Yield
In ethanol at 24 - 26℃; for 96h; Penicillium decumbens ATCC 10436, potato dextrose broth;	5%
With methanol; sodium carbonate at 20℃; for 0.166667h; Temperature;

16α-methyl-9β,11β-oxido-17α,20;20,21-bismethylenedioxy-pregna-1,4-diene-3-one (1966-25-2) → dexamethasone (50-02-2)

Conditions	Yield
With hydrogen fluoride In tetrahydrofuran; ethanol at 0℃; for 20h;

(8S,10S,13S,14S,16R,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-7,8,12,14,15,16-hexahydro-6H-cyclopenta[a]phenanthren-3-one (13209-41-1) → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 74 percent / HCl / CH2Cl2 / Ambient temperature 2: 95 percent / 0.4M perchloric acid, N-bromoacetamide / dioxane / 15 h / Ambient temperature 3: 87 percent / potassium acetate / ethanol; dioxane / 19 h / Heating 4: 48percent hydrofluoric acid / ethanol; tetrahydrofuran / 20 h / 0 °C View Scheme

16α-methyl-17α,20;20,21-bismethylenedioxypregn-1,4,9(11)-triene-3-one (14518-56-0) → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / 0.4M perchloric acid, N-bromoacetamide / dioxane / 15 h / Ambient temperature 2: 87 percent / potassium acetate / ethanol; dioxane / 19 h / Heating 3: 48percent hydrofluoric acid / ethanol; tetrahydrofuran / 20 h / 0 °C View Scheme

9α-bromo-11β-hydroxy-16α-methyl-17α,20;20,21-bismethylenedioxy-pregna-1,4-diene-3-one (88509-22-2) → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / potassium acetate / ethanol; dioxane / 19 h / Heating 2: 48percent hydrofluoric acid / ethanol; tetrahydrofuran / 20 h / 0 °C View Scheme

C30H36O5Se (88509-18-6, 88509-19-7) → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 63 percent / sodium metaperiodate / tetrahydrofuran; methanol; H2O / 2.5 h / Ambient temperature 2: 95 percent / 0.4M perchloric acid, N-bromoacetamide / dioxane / 15 h / Ambient temperature 3: 87 percent / potassium acetate / ethanol; dioxane / 19 h / Heating 4: 48percent hydrofluoric acid / ethanol; tetrahydrofuran / 20 h / 0 °C View Scheme

16α-methyl-17α,20;20,21-bismethylenedioxy-pregn-4,9(11)-diene-3-one (80163-63-9, 88509-13-1, 88548-10-1) → dexamethasone (50-02-2)

Conditions

Yield

Multi-step reaction with 5 steps 1: 1.) LDA / 1.) THF, -78 deg C, 1 h then 0 deg C, 5 h; 2.) THF, -78 deg C, 3.5 h 2: 63 percent / sodium metaperiodate / tetrahydrofuran; methanol; H2O / 2.5 h / Ambient temperature 3: 95 percent / 0.4M perchloric acid, N-bromoacetamide / dioxane / 15 h / Ambient temperature 4: 87 percent / potassium acetate / ethanol; dioxane / 19 h / Heating 5: 48percent hydrofluoric acid / ethanol; tetrahydrofuran / 20 h / 0 °C View Scheme

2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl hydrogen (2-(2-(cyclooct-2-yn-1-yloxy)acetamido)ethyl)phosphoramidate → dexamethasone (50-02-2)

Conditions	Yield
With rat liver lysosomes In water; dimethyl sulfoxide; acetonitrile at 37℃; for 6h; Enzymatic reaction;

C24H35FNO8P → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 20 °C 2: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

C28H35FNO8P → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 20 °C 2: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

(9H-fluoren-9-yl)methyl (2-(((((2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethoxy)(hydroxy)phosphoryl)oxy)(hydroxy)phosphoryl)oxy)ethyl)carbamate → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: piperidine / dichloromethane / 3 h / 20 °C 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.67 h / 20 °C 2.2: 20 °C 3.1: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

C24H36FNO11P2 → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.67 h / 20 °C 1.2: 20 °C 2.1: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

2-(2-(cyclooct-2-yn-1-yloxy)acetamido)ethyl (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) dihydrogen pyrophosphate → dexamethasone (50-02-2)

Conditions	Yield
With rat liver lysosomes In water; dimethyl sulfoxide; acetonitrile at 37℃; for 6h; Enzymatic reaction;

(9H-fluoren-9-yl)methyl (4-(((((2-((8S,9R,10S,11S, 13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethoxy)(hydroxy)phosphoryl)oxy)(hydroxy)phosphoryl)oxy)phenyl)carbamate → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: piperidine / dichloromethane / 20 °C 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.33 h / 20 °C 2.2: 20 °C 3.1: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

C28H36FNO11P2 → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.33 h / 20 °C 1.2: 20 °C 2.1: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

4-(2-(cyclooct-2-yn-1-yloxy)acetamido)phenyl (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) dihydrogen pyrophosphate → dexamethasone (50-02-2)

Conditions	Yield
With rat liver lysosomes In water; dimethyl sulfoxide; acetonitrile at 37℃; for 6h; Enzymatic reaction;

tert-butyl (2-(((2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethoxy)(hydroxy)phosphoryl)oxy)ethyl)carbamate → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / ethyl acetate / 1 h 2: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 20 °C 3: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

((9H-fluoren-9-yl)methyl) (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) dihydrogen pyrophosphate → dexamethasone (50-02-2)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: piperidine / dichloromethane / 1.5 h / 20 °C 2.1: triethylamine; 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 20 °C 3.1: piperidine / dichloromethane / 1 h / 20 °C 4.1: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.1: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

(2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) trihydrogenpyrophosphate → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine; 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 20 °C 2.1: piperidine / dichloromethane / 1 h / 20 °C 3.1: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 4.1: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

(9H-fluoren-9-yl)methyl (2-(((((((2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethoxy)(hydroxy)phosphoryl)oxy)(hydroxy)phosphoryl)oxy)(hydroxy)phosphoryl)oxy)ethyl)carbamate → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: piperidine / dichloromethane / 1 h / 20 °C 2: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 3: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

2-amionethyl (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) trihydrogentriphosphate → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 2: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

2-(2-(cyclooct-2-yn-1-yloxy)acetamido)ethyl (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) trihydrogen triphosphate → dexamethasone (50-02-2)

Conditions	Yield
With rat liver lysosomes In water; dimethyl sulfoxide; acetonitrile at 37℃; for 6h; Enzymatic reaction;

2-(2-(cyclooct-2-yn-1-yloxy)acetamido)ethyl (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-Fluoro-11,17-dihydroxy-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)-2-oxoethyl) hydrogen phosphate → dexamethasone (50-02-2)

Conditions	Yield
With rat liver lysosomes In water; dimethyl sulfoxide; acetonitrile at 37℃; for 6h; Enzymatic reaction;

tert-butyl (4-(((2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethoxy)(hydroxy)phosphoryl)oxy)phenyl)carbamate → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / ethyl acetate / 1 h 2: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 20 °C 3: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

4-(2-(cyclooct-2-yn-1-yloxy)acetamido)phenyl (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) hydrogen phosphate → dexamethasone (50-02-2)

Conditions	Yield
With rat liver lysosomes In water; dimethyl sulfoxide; acetonitrile at 37℃; for 6h; Enzymatic reaction;

dexamethasone phosphate (312-93-6, 360-63-4) → dexamethasone (50-02-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / tert-butyl alcohol; water / 4 h / 100 °C 2: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine; 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 20 °C 2.1: piperidine / dichloromethane / 20 °C 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.33 h / 20 °C 3.2: 20 °C 4.1: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine; 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 20 °C 2.1: piperidine / dichloromethane / 3 h / 20 °C 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 0.67 h / 20 °C 3.2: 20 °C 4.1: rat liver lysosomes / water; acetonitrile; dimethyl sulfoxide / 6 h / 37 °C / Enzymatic reaction View Scheme

dexamethasone (50-02-2) + 4-Nitrophenyl chloroformate (7693-46-1) → dexamethasone 21-(p-nitrophenyl carbonate) (79360-11-5)

Conditions	Yield
With pyridine In chloroform Ambient temperature;	100%
With pyridine In dichloromethane at 20℃; for 0.4h; Sealed tube;	72%
With 4-methyl-morpholine In tetrahydrofuran at 20℃; for 24h;	55%
With 4-methyl-morpholine In tetrahydrofuran at 20℃; for 4h;
With pyridine at 20℃; for 2h; Concentration;

dexamethasone (50-02-2) + 5'-O-(4,4'-dimethoxytrityl)-2'-O-(tert-butyldimethylsilyl)uridine-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]phosphoramidite (144490-31-3, 118362-03-1, 131349-31-0, 131349-37-6) → (2R,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl (2-cyanoethyl) (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl)phosphite

Conditions	Yield
Stage #1: dexamethasone; 5'-O-(4,4'-dimethoxytrityl)-2'-O-(tert-butyldimethylsilyl)uridine-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]phosphoramidite With 5-(ethylthio)-1H-tetrazole In acetonitrile for 0.333333h; Stage #2: With tert.-butylhydroperoxide In acetonitrile at 20℃; for 1h;	100%

dexamethasone (50-02-2) + terephthalic acid mono-tert-butyl ester (20576-82-3) → tert-butyl (2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) terephthalate

Conditions	Yield
With pyridine; dmap; 1,2-dichloro-ethane at 20℃; for 18h; Inert atmosphere;	100%

dexamethasone (50-02-2) + Fmoc-Asp-O-t-Bu (129460-09-9, 134098-70-7) → 1-(tert-butyl) 4-(2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl) (((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartate

Conditions	Yield
With pyridine; dmap; 1,2-dichloro-ethane In dichloromethane at 20℃; for 18h; Inert atmosphere;	100%

dexamethasone (50-02-2) → 9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid (37927-01-8)

Conditions	Yield
Stage #1: dexamethasone With oxygen; potassium carbonate In methanol at 20℃; for 18h; Stage #2: With hydrogenchloride In water	99%
With periodic acid In ethanol; water for 16.5h;	97%
With sodium periodate; sulfuric acid In ethanol; water at 20℃; for 12h;	97%

dexamethasone (50-02-2) + tert-butyldimethylsilyl chloride (18162-48-6) → C28H43FO5Si

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 5h;	98.5%
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 4h;
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 4h;	24.9 g

succinic acid anhydride (108-30-5) + dexamethasone (50-02-2) → 4-(2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethoxy)-4-oxobutanoic acid

Conditions	Yield
With dmap In dichloromethane; acetonitrile at 20℃; for 2h;	98%
With dmap In tetrahydrofuran for 48h; Darkness;	94%
With pyridine; dmap at 20℃; Inert atmosphere;	90%

dexamethasone (50-02-2) + methanesulfonyl chloride (124-63-0) → Dexamethasone 21-mesylate (2265-22-7)

Conditions	Yield
With pyridine at 0 - 20℃; for 3h; Inert atmosphere;	96%
With pyridine at 4℃; for 16h; Inert atmosphere;	83%
With pyridine for 17h; Inert atmosphere; Cooling with ice;	83%

dexamethasone (50-02-2) + (12R)-hexanoyloxyoleic acid → 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-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)-2-oxoethyl (R,Z)-12-hexanoyloxyoleate

Conditions	Yield
Stage #1: (12R)-hexanoyloxyoleic acid With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.25h; Cooling with ice; Inert atmosphere; Stage #2: dexamethasone With dmap In dichloromethane for 17h; Cooling with ice; Inert atmosphere;	96%

dexamethasone (50-02-2) → disodium dexamethasone-21-phosphate

Conditions	Yield
Stage #1: dexamethasone With pyrophosphoryl chloride In tetrahydrofuran at -50℃; for 1h; Stage #2: With water In tetrahydrofuran at 20℃; pH=10; Stage #3: With sodium hydroxide In toluene pH=10; Solvent;	95.9%

dexamethasone (50-02-2) + (R,Z)-4-((12-(hexanoyloxy)octadec-9-en-1-yl)oxy)-4-oxobutanoic acid → C50H77FO10

Conditions	Yield
Stage #1: (R,Z)-4-((12-(hexanoyloxy)octadec-9-en-1-yl)oxy)-4-oxobutanoic acid With dicyclohexyl-carbodiimide In dichloromethane for 0.25h; Cooling with ice; Inert atmosphere; Stage #2: dexamethasone With dmap In dichloromethane for 14h; Cooling with ice;	95%

Upstream product

• 500219-69-2 {2-(4-chlorophenyl)-3-[4-(dimethylamino)phenyl]cyclopropyl}(2-furyl)methanone 
• 500219-68-1 (2-(4-chlorophenyl)-3-{4-nitrophenyl}cyclopropyl)(phenyl)methanone 
• 500219-62-5 N-cyclohexyl-3-oxo-2-(2-thienylmethyl)-1-isoindolinecarboxamide 
• 500219-61-4 2-benzyl-N-cyclohexyl-3-oxo-1-isoindolinecarboxamide 
• 500219-60-3 N-{[(4-methylphenyl)sulfonyl]methyl}-3-oxo-2-(2-thienylmethyl)-1-isoindolinecarboxamide 
• 500219-59-0 2-(4-chlorobenzyl)-N-{[(4-methylphenyl)sulfonyl]methyl}-3-oxo-1-isoindolinecarboxamide 
• 500219-17-0 2-amino-4-(2,4,5-trimethoxyphenyl)-4a,5,6,7-tetrahydro-1,3,3(4H)-naphthalenetricarbonitrile 
• 500219-15-8 ethyl 6-amino-8-(4-bromo-2-thienyl)-5,7,7-tricyano-3,7,8,8a-tetrahydro-2(1H)-isoquinolinecarboxylate 
• 500219-14-7 ethyl 6-amino-5,7,7-tricyano-8-(3,4-difluorophenyl)-3,7,8,8a-tetrahydro-2(1H)-isoquinolinecarboxylate 
• 500219-13-6 2-acetyl-6-amino-8-[2-(difluoromethoxy)phenyl]-2,3,8,8a-tetrahydro-5,7,7(1H)-isoquinolinetricarbonitrile 
• 500219-12-5 2-acetyl-6-amino-8-(4-tert-butylphenyl)-2,3,8,8a-tetrahydro-5,7,7(1H)-isoquinolinetricarbonitrile 
• 500219-11-4 6-amino-8-(4-bromo-2-thienyl)-2-isopropyl-2,3,8,8a-tetrahydro-5,7,7(1H)-isoquinolinetricarbonitrile 
• 500219-10-3 6-amino-8-(4-tert-butylphenyl)-2-isopropyl-2,3,8,8a-tetrahydro-5,7,7(1H)-isoquinolinetricarbonitrile 
• 500219-08-9 2-amino-6-tert-butyl-4-[2-(difluoromethoxy)phenyl]-4a,5,6,7-tetrahydro-1,3,3(4H)-naphthalenetricarbonitrile 

Downstream Products

• 4419-39-0 BECLOMETHASONE 

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