83-43-2

Usage

Originator

Medrol,Upjohn,US,1957

Manufacturing Process

The following process description is taken from US Patent 2,897,218. Six 100- ml portions of a medium in 250-ml Erlenmeyer flasks containing 1% glucose, 2% corn steep liquor (60% solids) and tap water was adjusted to a pH of 4.9. This medium was sterilized for 45 minutes at 15 psi pressure and inoculated with a one to two day growth of Septomyxa affinis ATCC 6737. The Erlenmeyer flasks were shaken at room temperature at about 24°C for a period of 3 days.At the end of this period, this 600-ml volume was used as an inoculum for ten liters of the same glucose-corn steep liquor medium which in addition contained 10 ml of an antifoam (a mixture of lard oil and octadecanol). The fermentor was placed into the water bath, adjusted to 28°C, and the contents stirred (300 rpm) and aerated (0.5 liter air/10 liters beer). After 17 hours of incubation, when a good growth developed and the acidity rose to pH 6.7, 2 g of 6α-methylhydrocortisone plus 1 g of 3-ketobisnor-4-cholen-22-al, dissolved in 115 ml of dimethylformamide, was added and the incubation (conversion) carried out at the same temperature and aeration for 24 hours (final pH 7.9).The mycelium (56 g dry weight) was filtered off and the steroidal material was extracted with methylene chloride, the methylene extracts evaporated to dryness, and the resulting residue chromatographed over a Florisil column. The column was packed with 200 g of Florisil and was developed with five 400-ml fractions each of methylene chloride, Skellysolve B-acetone mixtures of 9:1, 8:2, 7:3, 1:1, and methanol. The fraction eluted with Skellysolve Bacetone (7:3) weighed 1.545 g and on recrystallization from acetone gave, in three crops, 928 mg of product of MP 210° to 235°C. The sample prepared for analysis melted at 245° to 247°C.

Therapeutic Function

Glucocorticoid

Biological Activity

methylprednisolone is a synthetic glucocorticoid receptor agonist, used to achieve prompt suppression of inflammation.cllinical trials: in patients with acute spinal cord injury diagnosed in national acute spinal cord injury study (nascis) centers within 8 hours of injury, methylprednisolone treatment for 48 hours improved motor recovery at 6 weeks (p= 0.09) and 6 months (p= 0.07) after injury[6]. in patients with acute spinal-cord injury, methylprednisolone (30 mg/kg) followed by infusion at 5.4 mg/kg/hour for 23 hours improved neurologic recovery. among patients treated with methylprednisolone (30 mg/kg), mortality at 14 days was significantly increasedsecondary infection[7]. methylprednisolone has entered

Mechanism of action

Methylprednisolone is an analog of prednisolone that exhibits a more prolonged effect than prednisolone and cortisone; it has practically no mineralocorticosteroid activity and is better tolerated.

Clinical Use

Adding a 6α-methyl group to prednisolone increases the glucocorticoid activity and effectively abolishes mineralocorticoid action. It has fivefold the glucocorticoid activity of hydrocortisone (prednisolone has fourfold the glucocorticoid activity) and none of its mineralocorticoid properties. It is used almost exclusively as a systemic product and is available as the free alcohol for oral administration and as various esters.

Safety Profile

Moderately toxic by intraperitoneal route. A steroid hormone. Human systemic effects include arrhythmias, blood pressure lowering, heart rate changes, increased body temperature, pulse rate increase, respiratory depression. When heated to decomposition it emits acrid smoke and irritating fumes.

Synthesis

Methylprednisolone, 11β,17α,21-trihydroxy-6α-methylpregna-1, 4-dien-3,20-dione (27.1.38), differs from prednisolone in the presence of a methyl group at position C6 of the steroid skeleton of the molecule. This seemingly simple difference in structure requires a different approach to synthesis. It is synthesized from hydrocortisone (27.1.8), the carbonyl group of which initially undergoes ketalization by ethylene glycol in the presence of traces of acid, during which the double bond at position C4– C5 is shifted to position C5– C6, giving the diethyleneketal 27.1.34. The product is oxidized to an epoxide (27.1.35) using perbenzoic acid. Next, the resulting epoxide is reacted with methylmagnesium bromide, and subsequent removal of the ketal protection by hydrogen reduction gives the 5-hydroxy-6-methyl derivative of dihydrocortisone 27.1.36. The resulting β-hydroxyketone is dehydrated using an alkaline, and then the resulting 6α-methylcortisone (27.1.37) undergoes microbiological dehydration at position C1–C2, giving the desired methylprednisolone (27.1.38).

in vitro

methylprednisolone (2-10 mg/kg) significantly inhibited tnf production. high doses of methylprednisolone (50 mg/kg) increased lps-induced il-10 levels. methylprednisolone (0.01-100 μg/ml) increased the biosynthesis of il-10 in lps-activated mouse peritoneal macrophages [1]. in wg patients and controls, methylprednisolone (mp) down-regulated the spontaneous and the staphylococcal enterotoxin b (seb)-induced release of chemokines from peripheral blood mononuclear cells (pbmc)[2]. treatment with 0.25 mm methylprednisolone inhibited acantholysis in skin cultures directly [3].

in vivo

methylprednisolone (30 mg/kg, i.v.) given immediately after sci reduced tnf-α expression by 55% (p<0.01) and nf-kb binding activity. methylprednisolone suppressed the post-traumatic inflammatory activity caused by tnf-alpha-nf-kb cascade[4]. intravenously administration of mp (30 mg/kg) reduced the number of ed1-positive cells by 82% in the rostral cord stump and 66% in the caudal stump. in the adult rat, mp administration shortly after spinal cord transection resulted in a long-term reduction of ed1-positive cells and spinal tissue loss, reduced dieback of vestibule spinal fibres, and a transient sprouting of vestibule spinal fibres near the lesion at 1 and 2 weeks post-lesion. mp treatment also significantly reduced the tissue loss in both cord stumps at 2, 4 and 8 week post-injury[5].

Drug interactions

Metabolism in the liver occurs primarily via the CYP3A4 enzyme to inactive metabolites, which are excreted in the urine Aldesleukin: avoid concomitant use. Antibacterials: metabolism accelerated by rifampicin; metabolism inhibited by erythromycin and possibly clarithromycin; concentration of isoniazid possibly reduced. Anticoagulants: efficacy of coumarins and phenindione may be altered. Antiepileptics: metabolism accelerated by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone. Antifungals: increased risk of hypokalaemia with amphotericin - avoid; metabolism inhibited by ketoconazole and possibly itraconazole. Antivirals: concentration possibly increased by ritonavir. Ciclosporin: rare reports of convulsions in patients on ciclosporin and high-dose corticosteroids; levels of ciclosporin increased with high dose methylprednisolone. Cobicistat: concentration possibly increased by cobicistat. Diuretics: enhanced hypokalaemic effects of acetazolamide, loop diuretics and thiazide diuretics. Vaccines: high dose corticosteroids can impair immune response to vaccines; avoid with live vaccines.

Metabolism

Metabolism in the liver occurs primarily via the CYP3A4 enzyme to inactive metabolites, which are excreted in the urine

Purification Methods

Recrystallise medrol from EtOAc. The UV has max at in 95% EtOH 243nm ( 14,875). The 21-acetoxy derivative has m 205-208o (from EtOAc), and [] D +95o ( c 1, CHCl3). [Spero et al. J Am Chem Soc 78 6213 1956; Fried et al. J Am Chem Soc 81 1235 1959; 1H NMR: Slomp & McGarvey J Am Chem Soc 81 2200 1959, Beilstein 8 IV 3498.]

references

[1] marchant a, amraoui z, gueydan c, et al. methylprednisolone differentially regulates il‐10 and tumour necrosis factor (tnf) production during murine endotoxaemia[j]. clinical & experimental immunology, 1996, 106(1): 91-96.[2] torheim e a, yndestad a, bjerkeli v, et al. increased expression of chemokines in patients with wegener's granulomatosis modulating effects of methylprednisolone in vitro[j]. clinical & experimental immunology, 2005, 140(2): 376-383.[3] swanson d l, dahl m v. methylprednisolone inhibits pemphigus acantholysis in skin cultures[j]. journal of investigative dermatology, 1983, 81(3): 258-260.[4] xu j, fan g, chen s, et al. methylprednisolone inhibition of tnf-α expression and nf-kb activation after spinal cord injury in rats[j]. molecular brain research, 1998, 59(2): 135-142.[5] oudega m, vargas c g, weber a b, et al. [j]. european journal of neuroscience, 1999, 11(7): 2453-2464.long‐term effects of methylprednisolone following transection of adult rat spinal cord[6] bracken m b, shepard m j, holford t r, et al. administration of methylprednisolone for 24 or 48 hours or tirilazadmesylate for 48 hours in the treatment of acute spinal cord injury: results of the third national acute spinal cord injury randomized controlled trial[j]. jama, 1997, 277(20): 1597-1604.[7] bracken m b, shepard m j, collins w f, et al. a randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: results of the second national acute spinal cord injury study[j]. new england journal of medicine, 1990, 322(20): 1405-1411.

InChI:InChI=1/C22H30O5/c1-12-8-14-15-5-7-22(27,18(26)11-23)21(15,3)10-17(25)19(14)20(2)6-4-13(24)9-16(12)20/h4,6,9,12,14-15,17,19,23,25,27H,5,7-8,10-11H2,1-3H3/t12-,14?,15?,17-,19?,20-,21-,22-/m0/s1

Synthetic route

methylprednisolone acetate (53-36-1) → Methylprednisolone (83-43-2)

Conditions	Yield
Hydrolysis;
With potassium hydroxide In methanol; dichloromethane at 10 - 15℃; for 0.333333h; Inert atmosphere;

(20Ξ)-11β-hydroxy-6α-methyl-17,20;20,21-bis-methylenedioxy-pregna-1,4-dien-3-one (117888-35-4) → Methylprednisolone (83-43-2)

Conditions	Yield
With formic acid

methylprednisolone acetate (53-36-1) → Methylprednisolone (83-43-2) + 17α-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione (86401-94-7)

Conditions	Yield
With aq. buffer In N,N-dimethyl-formamide at 25℃; Rate constant; Mechanism; pH dependence;

17α-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione (86401-94-7) → Methylprednisolone (83-43-2) + methylprednisolone acetate (53-36-1)

Conditions	Yield
With aq. buffer In N,N-dimethyl-formamide at 25℃; Rate constant; Mechanism; pH dependence;

6α-methylprednisolone-21-hydrogen succinate (2921-57-5) → Methylprednisolone (83-43-2)

Conditions	Yield
With tetramethyl ammoniumhydroxide; tetrazolium blue In ethanol Rate constant; Ambient temperature; reaction of corticosteroids and their hemisuccinate esters with blue tetrazolium under USP assay conditions, hydrolysis of esters, effect of water content, kinetic study by HPLC;
With water In acetonitrile at 25℃; Rate constant;
In water at 25℃; Rate constant; rate constants for hydrolysis;

6α-methylprednisolone-21-hydrogen succinate (2921-57-5) → Methylprednisolone (83-43-2) + 6α-methylprednisolone 17-hemisuccinate (77074-42-1)

Conditions	Yield
With aq. buffer In N,N-dimethyl-formamide at 25℃; Rate constant; Mechanism; pH dependence;

6α-methylprednisolone 17-hemisuccinate (77074-42-1) → Methylprednisolone (83-43-2) + 6α-methylprednisolone-21-hydrogen succinate (2921-57-5)

Conditions	Yield
With aq. buffer In N,N-dimethyl-formamide at 25℃; Rate constant; Mechanism; pH dependence;

6α-methylprednisolone 21-hemiadipate (85847-50-3) → Methylprednisolone (83-43-2)

Conditions	Yield
With water In acetonitrile at 25℃; Rate constant;

6α-methylprednisolone 21-hemisuberate (85847-51-4) → Methylprednisolone (83-43-2)

Conditions	Yield
With water In acetonitrile at 25℃; Rate constant;

17,21-dihydroxy-pregn-4-ene-3,11,20-trione (53-06-5, 10007-36-0, 15779-07-4, 35446-72-1, 104713-00-0) → Methylprednisolone (83-43-2)

Conditions

Yield

Multi-step reaction with 9 steps 1: aqueous hydrochloric acid; chloroform 2: benzene; toluene-4-sulfonic acid 3: peroxybenzoic acid; benzene / Behandeln unter Ausschluss von Licht, Behandeln des Reaktionsprodukts mit Ameisensaeure und Erwaermen des danach isolierten Reaktionsprodukts mit wss.-methanol. Kalilauge 4: toluene-4-sulfonic acid 5: benzene; diethyl ether 6: pyridine; thionyl chloride / Erwaermen des Reaktionsprodukts mit Lithiumalanat in Aether und Benzol 7: acetone; toluene-4-sulfonic acid 8: acetic acid; tert-butyl alcohol; selenium dioxide 9: aqueous formic acid View Scheme

11β,21-dihydroxy-6α-methyl-pregna-4,17(20)c-dien-3-one (3386-04-7, 14423-17-7) → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: Dehydrierung durch Septomyxa affinis und anschliessende Acetylierung 2: diacetoxy-phenyl-iodan; OsO4; tert-butyl alcohol / Reagens 4: Pyridin 3: Hydrolysis View Scheme

21-acetoxy-11β-hydroxy-6α-methyl-pregna-1,4,17(20)c-trien-3-one (1968-76-9) → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: diacetoxy-phenyl-iodan; OsO4; tert-butyl alcohol / Reagens 4: Pyridin 2: Hydrolysis View Scheme

(20Ξ)-11β-hydroxy-6α-methyl-17,20;20,21-bis-methylenedioxy-pregn-4-en-3-one (123292-91-1) → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; tert-butyl alcohol; selenium dioxide 2: aqueous formic acid View Scheme

17α,20;20,21-bismethylenedioxypregn-4-ene-3,11-dione (3607-68-9) → Methylprednisolone (83-43-2)

Conditions

Yield

Multi-step reaction with 8 steps 1: benzene; toluene-4-sulfonic acid 2: peroxybenzoic acid; benzene / Behandeln unter Ausschluss von Licht, Behandeln des Reaktionsprodukts mit Ameisensaeure und Erwaermen des danach isolierten Reaktionsprodukts mit wss.-methanol. Kalilauge 3: toluene-4-sulfonic acid 4: benzene; diethyl ether 5: pyridine; thionyl chloride / Erwaermen des Reaktionsprodukts mit Lithiumalanat in Aether und Benzol 6: acetone; toluene-4-sulfonic acid 7: acetic acid; tert-butyl alcohol; selenium dioxide 8: aqueous formic acid View Scheme

(20Ξ)-17,20;20,21-bis-methylenedioxy-5α-pregnane-3,6,11-trione (55701-21-8) → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: toluene-4-sulfonic acid 2: benzene; diethyl ether 3: pyridine; thionyl chloride / Erwaermen des Reaktionsprodukts mit Lithiumalanat in Aether und Benzol 4: acetone; toluene-4-sulfonic acid 5: acetic acid; tert-butyl alcohol; selenium dioxide 6: aqueous formic acid View Scheme

(20Ξ)-3,3-ethanediyldioxy-6-methyl-17,20;20,21-bis-methylenedioxy-pregn-5-en-11β-ol → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetone; toluene-4-sulfonic acid 2: acetic acid; tert-butyl alcohol; selenium dioxide 3: aqueous formic acid View Scheme

6-methyl-11-oxo-3-pyrrolidino-pregna-3,5,17(20)c-trien-21-oic acid methyl ester (1968-77-0) → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: LiAlH4; diethyl ether / Behandeln des Reaktionsprodukts mit wss.-methanol.Alkalilauge 2: Dehydrierung durch Septomyxa affinis und anschliessende Acetylierung 3: diacetoxy-phenyl-iodan; OsO4; tert-butyl alcohol / Reagens 4: Pyridin 4: Hydrolysis View Scheme

(8′S,9′S,10′R,13′S,14′S,17′R)-10′,13′-dimethyl-1′,2′,4′,7′,8′,9′,10′,12′,13′,14′,15′,16′-dodecahydro-11′H-trispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,4''-[1,3]dioxolane-5'',4'''-[1,3]dioxolan]-11′-one (52248-40-5) → Methylprednisolone (83-43-2)

Conditions

Yield

Multi-step reaction with 7 steps 1: peroxybenzoic acid; benzene / Behandeln unter Ausschluss von Licht, Behandeln des Reaktionsprodukts mit Ameisensaeure und Erwaermen des danach isolierten Reaktionsprodukts mit wss.-methanol. Kalilauge 2: toluene-4-sulfonic acid 3: benzene; diethyl ether 4: pyridine; thionyl chloride / Erwaermen des Reaktionsprodukts mit Lithiumalanat in Aether und Benzol 5: acetone; toluene-4-sulfonic acid 6: acetic acid; tert-butyl alcohol; selenium dioxide 7: aqueous formic acid View Scheme

(20Ξ)-3,3-ethanediyldioxy-6β-hydroxy-6α-methyl-17,20;20,21-bis-methylenedioxy-5α-pregnan-11-one (123885-50-7) → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine; thionyl chloride / Erwaermen des Reaktionsprodukts mit Lithiumalanat in Aether und Benzol 2: acetone; toluene-4-sulfonic acid 3: acetic acid; tert-butyl alcohol; selenium dioxide 4: aqueous formic acid View Scheme

(20Ξ)-3,3-ethanediyldioxy-17,20;20,21-bis-methylenedioxy-5α-pregnane-6,11-dione (107157-45-9) → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: benzene; diethyl ether 2: pyridine; thionyl chloride / Erwaermen des Reaktionsprodukts mit Lithiumalanat in Aether und Benzol 3: acetone; toluene-4-sulfonic acid 4: acetic acid; tert-butyl alcohol; selenium dioxide 5: aqueous formic acid View Scheme

HYCp45 → C16H27NO11 + Methylprednisolone (83-43-2)

Conditions	Yield
With sodium hydroxide In water-d2 at 37℃; pH=7.0;

C26H42O6 → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sulfuric acid / tetrahydrofuran / pH 2 - 3 2.1: D-glucose; potassium dihydrogenphosphate / water; methanol / 50 h 3.1: iodine; calcium oxide / methanol; dichloromethane 3.2: 2 h / 45 - 50 °C 4.1: potassium hydroxide / methanol; dichloromethane / 0.33 h / 10 - 15 °C / Inert atmosphere View Scheme

11β,17-dihydroxy-6α-methyl-pregn-4-ene-3,20-dione (7055-53-0) → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: D-glucose; potassium dihydrogenphosphate / water; methanol / 50 h 2.1: iodine; calcium oxide / methanol; dichloromethane 2.2: 2 h / 45 - 50 °C 3.1: potassium hydroxide / methanol; dichloromethane / 0.33 h / 10 - 15 °C / Inert atmosphere View Scheme

17-hydroxy-pregn-4-ene-3,11,20-trione (1882-82-2) → Methylprednisolone (83-43-2)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: trimethyloxosulfonium bromide; orthoformic acid triethyl ester / 5 h 2.1: sodium tetrahydroborate / tetrahydrofuran / 12 h 3.1: phthalic anhydride; dihydrogen peroxide / ethyl acetate / 6 h 4.1: magnesium / tetrahydrofuran / 4 h 5.1: sulfuric acid / tetrahydrofuran / pH 2 - 3 6.1: D-glucose; potassium dihydrogenphosphate / water; methanol / 50 h 7.1: iodine; calcium oxide / methanol; dichloromethane 7.2: 2 h / 45 - 50 °C 8.1: potassium hydroxide / methanol; dichloromethane / 0.33 h / 10 - 15 °C / Inert atmosphere View Scheme

3,3;20,20-bis-ethanediyldioxy-17-hydroxy-pregn-5-en-11-one (74332-34-6) → Methylprednisolone (83-43-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 12 h 2.1: phthalic anhydride; dihydrogen peroxide / ethyl acetate / 6 h 3.1: magnesium / tetrahydrofuran / 4 h 4.1: sulfuric acid / tetrahydrofuran / pH 2 - 3 5.1: D-glucose; potassium dihydrogenphosphate / water; methanol / 50 h 6.1: iodine; calcium oxide / methanol; dichloromethane 6.2: 2 h / 45 - 50 °C 7.1: potassium hydroxide / methanol; dichloromethane / 0.33 h / 10 - 15 °C / Inert atmosphere View Scheme

3,3;20,20-bis-ethanediyldioxy-pregn-5-ene-11β,17-diol (41870-77-3) → Methylprednisolone (83-43-2)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: phthalic anhydride; dihydrogen peroxide / ethyl acetate / 6 h 2.1: magnesium / tetrahydrofuran / 4 h 3.1: sulfuric acid / tetrahydrofuran / pH 2 - 3 4.1: D-glucose; potassium dihydrogenphosphate / water; methanol / 50 h 5.1: iodine; calcium oxide / methanol; dichloromethane 5.2: 2 h / 45 - 50 °C 6.1: potassium hydroxide / methanol; dichloromethane / 0.33 h / 10 - 15 °C / Inert atmosphere View Scheme

C25H38O7 → Methylprednisolone (83-43-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: magnesium / tetrahydrofuran / 4 h 2.1: sulfuric acid / tetrahydrofuran / pH 2 - 3 3.1: D-glucose; potassium dihydrogenphosphate / water; methanol / 50 h 4.1: iodine; calcium oxide / methanol; dichloromethane 4.2: 2 h / 45 - 50 °C 5.1: potassium hydroxide / methanol; dichloromethane / 0.33 h / 10 - 15 °C / Inert atmosphere View Scheme

Methylprednisolone (83-43-2) + methanesulfonyl chloride (124-63-0) → 2-((6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl methanesulfonate (51474-81-8)

Conditions	Yield
With pyridine at 0 - 10℃;	95%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	81%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;

ethyl orthoacetate (58924-88-2) + Methylprednisolone (83-43-2) → 6α-methylprednisolone 17α,21-ethyl orthoacetate + 17α,21-diacetoxy-11β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione (86413-24-3)

Conditions	Yield
With sodium carbonate; toluene-4-sulfonic acid In N-methyl-acetamide; water; ethyl acetate	A 92.5% B n/a

methyl orthovalerate (856317-97-0) + Methylprednisolone (83-43-2) → 6α-methylprednisolone 17α,21-methyl orthovalerate + 11β,21-dihydroxy-6α-methyl-17α-valeroyloxy-1,4-pregnadiene-3,20-dione (86413-38-9)

Conditions	Yield
With sodium carbonate; toluene-4-sulfonic acid In N-methyl-acetamide; water; ethyl acetate	A n/a B 91.7%

methyl orthoisovalerate + Methylprednisolone (83-43-2) → 6α-methylprednisolone 17α,21-methyl orthoisovalerate + 11β,21-dihydroxy-17α-isovaleryloxy-6α-methyl-1,4-pregnadiene-3,20-dione (86413-32-3)

Conditions	Yield
With sodium carbonate; toluene-4-sulfonic acid In N-methyl-acetamide; water; ethyl acetate	A 82.8% B n/a

3-sulfopropanoic acid (44826-45-1) + Methylprednisolone (83-43-2) → 21-<<3-sulfo-1-oxopropyl>oxy>-11β,17-dihydroxy-6α-methylpregna-1,4-diene-3,20-dione

Conditions	Yield
With pyridine; dicyclohexyl-carbodiimide for 16h;	70%

Methylprednisolone (83-43-2) → 17α,21-dihydroxy-6α-methylpregna-1,4-diene-3,11,20-trione (111264-84-7, 91523-05-6)

Conditions	Yield
With pyridine; N-bromoacetamide

Methylprednisolone (83-43-2) → 11β,17α-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione (6870-94-6)

Conditions	Yield
ueber mehrere Stufen;

Upstream product

• 53-36-1 methylprednisolone acetate 
• 117888-35-4 (20Ξ)-11β-hydroxy-6α-methyl-17,20;20,21-bis-methylenedioxy-pregna-1,4-dien-3-one 
• 86401-94-7 17α-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione 
• 2921-57-5 6α-methylprednisolone-21-hydrogen succinate 
• 77074-42-1 6α-methylprednisolone 17-hemisuccinate 
• 85847-50-3 6α-methylprednisolone 21-hemiadipate 
• 85847-51-4 6α-methylprednisolone 21-hemisuberate 
• 53-06-5 17,21-dihydroxy-pregn-4-ene-3,11,20-trione 
• 3607-68-9 17α,20;20,21-bismethylenedioxypregn-4-ene-3,11-dione 
• 55701-21-8 (20Ξ)-17,20;20,21-bis-methylenedioxy-5α-pregnane-3,6,11-trione 
• 1968-77-0 6-methyl-11-oxo-3-pyrrolidino-pregna-3,5,17⁽²⁰⁾c-trien-21-oic acid methyl ester 
• 52248-40-5 (8′S,9′S,10′R,13′S,14′S,17′R)-10′,13′-dimethyl-1′,2′,4′,7′,8′,9′,10′,12′,13′,14′,15′,16′-dodecahydro-11′H-trispiro[[1,3]dioxolane-2,3′-cyclopenta[a]phenanthrene-17′,4''-[1,3]dioxolane-5'',4'''-[1,3]dioxolan]-11′-one 
• 107157-45-9 (20Ξ)-3,3-ethanediyldioxy-17,20;20,21-bis-methylenedioxy-5α-pregnane-6,11-dione 
• 41870-77-3 3,3;20,20-bis-ethanediyldioxy-pregn-5-ene-11β,17-diol 

Downstream Products

• 111264-84-7 17α,21-dihydroxy-6α-methylpregna-1,4-diene-3,11,20-trione 
• 6870-94-6 11β,17α-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione 
• 437-99-0 21-fluoro-11β,17-dihydroxy-6α-methyl-pregna-1,4-diene-3,20-dione 
• 53-36-1 methylprednisolone acetate 
• 85198-29-4 6α-methylprednisolone-17α,21-methyl orthobenzoate 
• 85198-27-2 6α-Methylprednisolone 17α,21-ethyl orthopropanoate 
• 171611-77-1 17α-acetoxy-9α-fluoro-6α-methylprogesterone 
• 86282-02-2 11β,21-dihydroxy-17α-methoxyacetoxy-6α-methyl-1,4-pregnadiene-3,20-dione 
• 89472-50-4 11β,21-dihydroxy-6α-methyl-17α-(methylthio)acetoxy-1,4-pregnadiene-3,20-dione 
• 85198-34-1 17α-benzoyloxy-21-chloro-11β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione 
• 387-65-5 11β,17α,20α,21-tetrahydroxy-6α-methylpregna-1,4-diene-3-one 
• 387-66-6 11β,17α,20β,21-tetrahydroxy-6α-methylpregna-1,4-diene-3-one 
• 1625-39-4 11β,17α,21-trihydroxy-6α-methylpregna-4-ene-3,20-dione 
• 359-80-8 9,21-difluoro-11β,17-dihydroxy-6α-methyl-pregna-1,4-diene-3,20-dione 

Relevant academic research and scientific papers

Kinetics of drug release from a hyaluronan-steroid conjugate investigated by NMR spectroscopy

The methylprednisolone steroid ester of hyaluronan was hydrolyzed under physiological conditions in vitro, and the kinetics of drug release was investigated by NMR spectroscopy. Transverse relaxation times are correlated with the molecular rotational free

A methylprednisolone production process and production apparatus (by machine translation)

The invention discloses a methylprednisolone production device, including connected according to the procedure of the reaction, shui xifu, centrifugal filtration equipment, the concentrator, [...], biological fermentation tank, drying apparatus, the drying apparatus comprises an outer cylinder, the drying cylinder, the inner cylinder; the bottom surface of the outer cylinder is provided with a motor, the rotation of the motor shaft is provided with a exhaust fan blade, type impeller, vortex impeller; exhaust fan leaf is arranged on the bottom surface of the drying cylinder between the cylinder and the outer cylinder; drum type impeller is arranged on the drying cylinder between the cylinder and an inner cylinder; vortex impeller is arranged on the bottom of the inner drum; [...] is set with infrared heating in; on the inner end center provided with a feed port; the outer tube side wall comprises an inner wall and the outer wall; the inner wall and the outer wall of the annular cavity formed between the interlayer; outlet at upper end of the sandwich cavity is provided with an annular baffle plate; the baffle plate is provided with a vent; the upper end of the baffle is provided with a rotatable air purifies the link. This invention can reduce the methylprednisolone intermediate product in the production process of the preparation time, realize methylprednisolone rapid high-quality production. (by machine translation)

Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor

Methods for reducing or preventing transplant rejection in the eye of an individual are described, comprising: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.

Mucosal adhesive device for long-acting delivery of pharmaceutical combinations in oral cavity

Mucosal adhesive devices are provided for use in the oral cavity for therapy against infections. The devices are dosage units which comprise a combination of antimicrobial agents such as antifungal agents and anti-inflammatory agents, optionally also a local anesthetic. The dosage units yield a gradual and relatively constant release of the pharmaceuticals over at least a 12-hour period.

High molecular weight prodrug derivatives of antiinflammatory drugs

Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.

Amine containing ester prodrugs of corticosteroids

Novel solution stable ester prodrugs of corticosteroids of the formula STR1

Sulfonate containing ester prodrugs of corticosteroids

Novel solution stable ester prodrugs of corticosteroids of the formula STR1 and their salts.

Carboxyl group catalysis of acyl transfer reactions in corticosteroid 17- and 21-monoesters

Succinate esters, although frequently employed as water-soluble prodrugs of poorly soluble parent drugs, are not sufficiently stable to allow long-term storage in solution. Intramolecular catalysis of ester hydrolysis by the terminal succinate carboxyl group is a contributing factor to this instability. Methylprednisolone 21-succinate has recently been reported to undergo both hydrolysis and 21 ? 17 acyl migration in aqueous solutions. Intramolecular catalysis by the terminal carboxyl group is seen in both reactions, but the catalytic mechanisms are not well understood. While acyl migration can only be catalyzed via the carboxyl group acting as a general acid or general base, hydrolysis may undergo either nucleophilic or general acid-base catalysis. To gain further insight into the catalytic mechanism, hydrolysis of methyl-prednisolone 21-succinate was carried out in aniline buffers to trap any succinic anhydride (as the anilide) that would form if the catalysis were nucleophilic. The nucleophilic mechanism was shown to account for only 15-20% of the overall catalysis. Comparisons of the rates of the intramolecularly catalyzed reactions of methylprednisolone 21- and 17-succinate were made with the same reactions of methylprednisolone-21- and 17-acetate catalyzed intermolecularly by acetate ion. Interestingly, intramolecular catalysis appears to favor acyl migration over hydrolysis. Hence, the hydrolysis of methylprednisolone 21-succinate is faster in basic solutions (pH > 7.4), while acyl migration becomes the dominant reaction in the catalyzed region of the pH profile between pH 3.6 and 7.4. Arguments are presented to account for these differences in catalytic efficiency in terms of the transition-state structures for the two reactions.

Water-soluble steroid compounds

Beta-cyclodextrin forms a water-soluble complex or inclusion compound with steroid compounds having a molecular structure smaller than the interior cavity in the doughnut-shaped molecular structure of beta-cyclodextrin. The resulting inclusion compounds can be used for a variety of applications including aqueous topical ophthalmic preparations and topical dermatological ointments.

Influence of premicellar and micellar association on the reactivity of methylprednisolone 21-hemiesters in aqueous solution

Self-association of drug molecules at formulation concentrations can have a major impact on formulation properties. In this study a homologous series of methylprednisolone 21-hemiesters were found to undergo self-association in aqueous solution. The effect of aggregate formation on the solution degradation of these compounds was examined. To determine the nature and extent of association of these steroidal esters, partition coefficients between butyronitrile and aqueous buffer (pH 8.5) were measured as a function of ester concentration. The partitioning data were found to be consistent with dimer formation at low concentration followed by true micelle formation at higher concentration. Chain length increases favored micelle formation, but appeared to have little effect on dimerization. The first-order rate constants for ester hydrolysis and 21 → 17 acyl migration in aqueous buffer (pH 8.5) were also found to be dependent on ester concentration. The kinetic data are consistent with a model which assumes stabilization by both dimer and micelle formation, the limiting factor at high concentration being the reactivity of the ester in the micelles. The degree of stabilization due to self-association was found to increase with chain length.