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Lirafugratinib

September 26, 2026 3:00 am / Leave a comment

Lirafugratinib

CAS No.:2549174-42-5
Formula:C₂₈H₂₄FN₇O₂
Molecular Weight:509.53

FDA 2026, APPROVALS 2026, Lyrfigtu, RLY-4008, RLY 4008, 23SEPT2026

N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (lirafugratinib)

To adults with previously treated unresectable, locally advanced or metastatic cholangiocarcinoma harboring a fibroblast growth factor receptor 2 gene fusion or other rearrangement

Lirafugratinib (RLY-4008) is an orally active, irreversible and highly selective FGFR2 inhibitor with an IC₅₀ of 3 nM. Lirafugratinib covalently binds to Cys491. Lirafugratinib targets FGFR2 primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs.

Lirafugratinib (Lyrfigtu) received FDA approval on September 23, 2026, for adults with previously treated, unresectable or metastatic cholangiocarcinoma involving FGFR2 gene fusions or rearrangements.

Overview & Mechanism

Drug Class: An oral, selective, and irreversible FGFR2 small-molecule inhibitor.
Developer/Marketed By: Developed by Relay Therapeutics and commercialized globally by Elevar Therapeutics.
How it Works: Covalently targets the FGFR2 kinase domain to inhibit tumor-driving signaling while sparing other FGFR proteins to limit off-target effects.

Efficacy

Clinical Trial: Assessed in the phase 1/2 REFOCUS trial (NCT04526106) involving 116 previously treated, FGFR-inhibitor-naive patients.
Key Metrics: Demonstrated an objective response rate of 46%, a median duration of response of 11.8 months, and a median progression-free survival of 11.3 months.

Dosing & Administration

Recommended Dose: 70 mg orally once daily on a continuous basis until disease progression or unacceptable toxicity.

Safety & Warnings

Common Adverse Events: Hand-foot syndrome, stomatitis, nail issues, and ocular/retinal toxicities.
Special Warnings: Includes precautions for ocular toxicity, hyperphosphatemia, soft tissue mineralization, and embryo-fetal risks

PAPER

https://pmc.ncbi.nlm.nih.gov/articles/PMC10861881

SEE https://pmc.ncbi.nlm.nih.gov/articles/instance/10861881/bin/pnas.2317756121.sapp.pdf

N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide (lirafugratinib)

5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with 5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (10.0 g,
47.16 mmol), Cs2CO3 (22.99 g, 70.75 mmol), DMF (120 mL) and a stirbar. Iodomethane (8.03 g,
56.59 mmol) was added, and the solution was stirred for 1 h at room temperature. The reaction mixture was diluted with H2O (300 mL), and the aqueous phase was extracted with ethyl acetate
(300 mL) three times. The combined organic layers were washed with saturated brines, dried
over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was
purified by HPLC. Concentration in vacuo resulted in 5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine (5 g, 47.1 % ) as an off-white solid.

5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-
amine (5 g, 22.12 mmol), DCM (50 mL) and TFA (2 mL) and a stirbar. 1-iodopyrrolidine-2,5-
dione (5.97 g, 26.54 mmol) was added, and the solution was stirred for 2 h at room temperature.
The reaction mixture was diluted with Na2SO3 solution (200 mL), and the aqueous phase was
extracted with DCM (200 mL) three times. The combined organic layers were washed with
saturated brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting
crude material was purified by HPLC. Concentration in vacuo resulted in 5-bromo-6-iodo-7-
methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4 g, 51.3 %) as a yellow solid.

tert-butyl (4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate

A resealable reaction vial was charged with 5-bromo-6-iodo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-4-amine (4 g, 11.36 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl)carbamate (4.35 g, 13.63 mmol), Pd(dppf)Cl2 (994.16 mg, 1.36 mmol), K3PO4 (7.22
g, 34.08 mmol), DMF (50 mL), H2O (6.25 mL) and a stir bar before being evacuated and purged
with nitrogen three times. The mixture was stirred for 2 h at 90 °C. The reaction mixture was
diluted with H2O (300 mL), and the aqueous phase was extracted with ethyl acetate (300 mL)
three times. The combined organic layers were washed with brines, dried over sodium sulfate,
filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel
chromatography (eluting with MeOH/DCM = 1/40). Concentration in vacuo resulted in tert-butyl
(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate (3 g, 63.4%)
as a yellow solid.

6-(4-aminophenyl)-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A round bottomed flask was charged with tert-butyl (4-(4-amino-5-bromo-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate (3 g, 7.19 mmol), DCM (50 mL) and TFA (12.5mL) and a stirbar. The solution was stirred for 1 h at room temperature. The reaction mixture
was diluted with H2O (100 mL), and the aqueous phase was extracted with DCM (50 mL) three
times. The pH of aqueous phase was adjusted to 7~8, then the aqueous phase was extracted with
DCM (100 mL) three times. The combined organic layers were washed with saturated brines,
dried over sodium sulfate, filtered, and concentrated in vacuo resulted in 6-(4-aminophenyl)-5-
bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.1 g, 92.1%) as a yellow solid.

N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide

A resealable reaction vial was charged with 6-(4-aminophenyl)-5-bromo-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-4-amine (2.1 g, 6.62 mmol), pyridine (785 mg, 9.93 mmol), DCM (100
mL) and a stir bar before being evacuated and purged with nitrogen three times. Methacryloyl
chloride (757.3 mg, 7.28 mmol) was added slowly at 0 oC. Then the mixture was stirred for 2 h
at room temperature. The reaction mixture was diluted with H2O (100 mL), and the aqueous
phase was extracted with DCM (100 mL) three times. The combined organic layers were washed
with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude
material was purified by silica gel chromatography (eluting with MeOH/DCM=1/40).
Concentration in vacuo resulted in N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (1.8 g, 70.5%) as an off-white solid.

2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine

A round bottomed flask was charged with 4-bromo-2-fluorophenol (1.0 g, 5.24 mmol), 2-fluoro4-methylpyrimidine (704 mg, 6.28 mmol), Cs2CO3 (5.12 g, 15.7 mmol) and a stirbar. DMF (20
mL) was added, and the solution was stirred for 1 h at 100 oC. The reaction mixture was diluted
with H2O (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL) three
times. The combined organic layers were washed with saturated brines, dried over sodium
sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by HPLC.
Concentration in vacuo resulted in 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine (1.48 g,
99.8 %) as an off-white amorphous solid.

2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

A solution/mixture of 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine (500.00 mg, 1.77
mmol), bis(pinacolato)diboron (672.75 mg, 2.65 mmol), KOAc (520 mg, 5.3 mmol) and
Pd(dppf)Cl2 (129.4 mg, 0.177 mmol) in DMF (10 mL) was stirred for 2 h at 80 oC under nitrogen
atmosphere. The resulting mixture was diluted with water and extracted with EA. The combined
organic layers were washed with brines, dried over anhydrous Na2SO4. After filtration, the
filtrate was concentrated under reduced pressure. The residue was purified by HPLC.
Concentration in vacuo resulted in 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenoxy)-4-methylpyrimidine (430 mg, 73.7%) as a yellow solid.

2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine

A resealable reaction vial was charged with N-(4-(4-amino-5-bromo-7-methyl-7H-pyrrolo[2,3-
d]pyrimidin-6-yl)phenyl)methacrylamide (100 mg, 0.259 mmol), 2-(2-fluoro-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (102.6 mg, 0.310 mmol),
Pd(DtBPF)Cl2 (16.9 mg, 0.026 mmol), CsF (118 mg, 0.776 mmol), DMF (2 mL), H2O (0.25
mL) and a stir bar before being evacuated and purged with nitrogen three times. The mixture was
stirred for 1 h at 90 °C. The reaction mixture was diluted with H2O (10 mL), and the aqueousphase was extracted with DCM (10 mL) three times. The combined organic layers were washed
with brines, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude
material was purified by Pre-HPLC (Column: XBridge Prep C18 OBD Column, 19*150 mm,
5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25
mL/min; Gradient: 25% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min):
6.5). Concentration in vacuo resulted in N-(4-(4-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-
yl)oxy)phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)methacrylamide ( 27.2 mg,
20.6%) as an off-white solid. LC/MS(BAS1): [M+H]+= 510.20; tR =1.405 min. 1H NMR (400
MHz, DMSO-d6) δ 9.92 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.79 – 7.72 (m, 2H), 7.38
– 7.28 (m, 3H), 7.22 – 7.14 (m, 2H), 7.10 (dd, J = 8.1, 2.1 Hz, 1H), 5.98 (s, 2H), 5.80 (s, 1H),
5.54 (d, J = 1.7 Hz, 1H), 3.59 (s, 3H), 2.42 (s, 3H), 1.95 (d, J = 1.2 Hz, 3H).

PAT

WIPO Patent Publication: WO2020231990A1 (and related family filings)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020231990&_cid=P20-MUHRQT-01820-1

PAT

United States Patents: US11780845

PAT

US20230192709

https://patentscope.wipo.int/search/en/detail.jsf?docId=US399951539&_cid=P20-MUHRKD-96615-1

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References

[1]. Vivek Subbiah, et al. RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations. Cancer Discov. 2023 Sep 6;13(9):2012-2031. [Content Brief]

/////////lirafugratinib, anax labs, FDA 2026, APPROVALS 2026, Lyrfigtu, RLY-4008, RLY 4008, 23SEPT2026, CANCER

#lirafugratinib, #anax labs, #FDA 2026, #APPROVALS 2026, #Lyrfigtu, #RLY-4008, #RLY 4008, #23SEPT2026, #CANCER

Simedeutirom

September 20, 2026 2:33 am / Leave a comment

Simedeutirom

CAS 2403721-24-2

MF C18H92H3Cl2N6O4 MW 450.25

2-[3,5-Dichloro-4-[[(7R)-2,5,6,7-tetrahydro-7-(methyl-d3)-1-oxo-1H-cyclopenta[d]pyridazin-4-yl]oxy]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile

2-[3,5-dichloro-4-[[(7R)-1-oxo-7-(trideuteriomethyl)-2,5,6,7-tetrahydrocyclopenta[d]pyridazin-4-yl]oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile

2-(3,5-dichloro-4-{[(7R)-7-(2H3)methyl-1-oxo-2,5,6,7-tetrahydro-1Hcyclopenta[d]pyridazin-4-yl]oxy}phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
thyroid hormone beta receptor agonist, 4G7Z7KQ8GV

Simedeutirom is a selective, synthetic, deuterium-labeled thyroid hormone receptor beta (THR-β) agonist. It features a novel cyclopenta $d$ 𝑑pyridazine core and is primarily utilized as a specialized tool compound in the biochemical research of metabolic diseases, including obesity, type 2 diabetes mellitus, and related metabolic disorders.

Core Structural & Pharmacological Profile

Target Selectivity: It functions as a potent agonist specifically targeting the thyroid hormone receptor beta (THR-β), with an half-maximal effective concentration (EC₅₀) ranging between 0.1 to 1 μM. THR-β activation plays a foundational role in modulating hepatic lipid metabolism, lowering cholesterol, and regulating overall energy expenditure without heavily triggering the alpha receptor (THR-α), which is associated with adverse cardiac side effects.
Deuterium Labeling: The compound incorporates deuterium (a stable isotope of hydrogen) into its chemical architecture, specifically modified as a trideuteriomethyl group. Isotopic modification or “deuteration” is an established medicinal chemistry approach frequently evaluated to slow metabolic clearance and increase structural stability.
Chemical Identifiers:
- Molecular Formula: C₁₈H₁₂Cl₂N₆O₄
- Molecular Weight: 450.25 g/mol
- CAS Registry Number: 2403721-24-2
- FDA UNII Code: 4G7Z7KQ8GV

Research Context & Status

Simedeutirom is categorized under the International Nonproprietary Name (INN) database. However, it is fundamentally classified for in vitro and in vivo research use only. It has not been approved for clinical therapeutic use or direct distribution to patients.

PAT

WO 2019240938

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019240938&_cid=P11-MU978W-22170-1

PAT

US20250179050

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B04410250978C4E0B0F323AD027AC8B8.wapp1nB?docId=US457344867&_cid=P11-MU96YW-11754-1

Example 1 Preparation of crude free base of compound I

Step 1: preparation of compound b

N-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl)benzamid

4.62 kg of compound a was completely dissolved in 25.0 L of glacial acetic acid and added to a 100 L reaction kettle, 3300 g of benzoic anhydride was added, and the mixture was reacted at room temperature for about 4 hours with stirring turned on. The reaction was monitored by TLC (n-hexane/ethyl acetate=5/1) until compound a disappeared, then 2722 g of anhydrous sodium acetate was additionally added and the temperature was increased to 120° C. for a reaction under stirring for about 18 hours.

The reaction solution was cooled to 60-65° C., and concentrated under reduced pressure to remove most of the acetic acid. After the concentration was completed, 10 L of anhydrous ethanol was added to the residue and uniformly mixed. Then the mixed solution was slowly added to 250 L of water, while maintaining the rapid stirring, and a large amount of solid precipitated during the addition, and stirring was continued for about 0.5 hours after the addition, followed by centrifugation. The filter cake was washed with purified water (20 L×2) to give compound b in 100% yield, which went directly to the next step.

1H NMR (400 MHZ, DMSO) δ 12.07 (s, 1H), 10.55 (s, 1H), 8.04 (s, 2H), 7.98-7.95 (m, 2H), 7.63-7.50 (m, 3H), 3.29-3.25 (m, 1H), 3.02-2.90 (m, 2H), 2.39-2.36 (m, 1H), 1.75-1.72 (m, 1H).

LCMS m/z=433.1 [M+1]+

Step 2: preparation of compound c

4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-1-on

To a 100 L reaction kettle, 5.76 kg of the crude compound b from the previous step, a potassium hydroxide solution (2606 g KOH dissolved in 19.5 L of purified water) and 6.0 L of anhydrous ethanol were added under stirring. After the complete addition, the mixture was heated to reflux and reacted for about 16 hours, and the raw material was controlled for a complete reaction.

The temperature was reduced to 25° C., 30 L of water was added, the pH was adjusted to 8-9 with an ammonium chloride solid, and 35.0 L of ethyl acetate was added and stirred. The solution was phase-separated. The aqueous phase was extracted with ethyl acetate (15.0 L×2). The organic phases were combined and washed with a 5% aqueous sodium chloride solution (25 L×2). The organic phase was dried over 3.0 Kg of anhydrous sodium sulfate, filtered, and concentrated until no significant distillate flowed out, so as to obtain a crude product.

The crude product and 7.0 L of an aqueous 10% dioxane solution were heated for complete dissolution, cooled to room temperature, and crystallized with stirring for about 16 hours, followed by filtration to obtain a wet product, which was repeated purified twice and dried under vacuum at 50° C. for about 12 hours to give 1507 g of compound c.

1H NMR (400 MHZ, DMSO) δ 11.98 (s, 1H), 6.67 (m, 2H), 5.60 (s, 2H), 3.30-3.19 (m, 1H), 3.03-2.93 (m, 1H), 2.90-2.70 (m, 1H), 2.35 (m, 1H), 1.69 (m, 1H).

LCMS m/z=329.0 [M+1]+

Step 3: preparation of compound d

(R)-4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-1-one

3298 g of racemate c was subjected to chiral resolution to give, two optical isomers from separation:

Compound d (retention time: 1.583 min, 1230 g, off-white solid, ee %=99.60%, yield 37.3%); and compound d-1 (retention time: 1.926 min, 1255 g, off-white solid, ee %=99.76%, yield 38.1%).

Resolution conditions:

Instrument: MG III preparative SFC; column: Whelk 01 (S, S), 300× 50 mm I.D., 10 um; mobile phase: A: CO2, B: methanol; gradient: B 40%; flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38° C.; wavelength: 220 nm; period: 4.5 min; sample preparation: the racemate was dissolved in methanol/dichloromethane to achieve 50 mg/ml; and injection: 17 ml/injection.

Compound d

1H NMR (400 MHZ, DMSO) δ 11.98 (s, 1H), 6.67 (s, 2H), 5.60 (s, 2H), 3.30-3.19 (m, 1H), 3.03-2.93 (m, 1H), 2.90-2.70 (m, 1H), 2.35 (dtd,1H), 1.69 (ddt, 1H).

LCMS m/z=329.1 [M+1]+

Compound d-1

1H NMR (400 MHZ, DMSO) δ 11.98 (s, 1H), 6.68 (d, 2H), 5.60 (s, 2H), 3.29-3.18 (m, 1H), 2.97 (tdd, 1H), 2.90-2.72 (m, 1H), 2.35 (dtd, 1H), 1.69 (ddt, 1H).

LCMS m/z=329.0 [M+1]+

Step 4: preparation of compound e

Ethyl(R,Z)-(2-cyano-2-(2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl) hydrazineylidene) acetyl) carbamate

To a 100 L reaction kettle, 16.0 kg of acetic acid, 4.0 kg of purified water and 2.0 kg of compound d were added with stirring. The temperature was reduced to 0+5° C., then 2.36 kg of hydrochloric acid was added, and after the addition, the temperature was maintained at 0+5° C. with stirring for about 20 minutes. A sodium nitrite solution (0.5 kg of sodium nitrite dissolved in 1.0 kg of purified water) was dropwise added with the temperature being controlled at 0+5° C., and after the addition, the temperature was maintained at 0+5° C. for reaction for 2 hours. The temperature was controlled at 5+5° C. and a sodium acetate solution (1.5 kg of sodium acetate dissolved in 6.0 kg of purified water) was added dropwise, then 0.99 kg of N-cyanoacetourethane was added, and then the temperature was increased to 10+5° C. for a reaction for about 2 hours. Then a sample was taken for HPLC monitoring, after which time samples were taken at each about 2-hour interval, and the reaction was not stopped until the content of compound d was determined by HPLC to be≤1.0%.

After the completion of the reaction, the temperature was controlled to 10+5° C., and 30.0 kg of purified water was added to the reaction kettle. After the addition, the temperature was controlled at 10+5° C. with stirring continued for 1 hour, followed by filtration, and the cake was washed with 3.0 kg of purified water. The filter cake and 12.6 kg of anhydrous ethanol were added to a 100 L reaction kettle, heated to 50±5° C., and stirred for about 1 hour. The mixture was cooled to 20±5° C., stirred for 0.5 hours and filtered, and the filter cake was washed once with 1.26 kg of anhydrous ethanol.

The filter cake was dried at 55+5° C. with vacuum≤−0.07 MPa for about 17 hours, and compound e was obtained and collected, weighing 2.6327 kg.

1H NMR (400 MHZ, DMSO) δ 12.08 (d, 2H), 10.88 (s, 1H), 7.99 (s, 2H), 4.21 (q, 2H), 3.30-3.17 (m, 1H), 3.08-2.95 (m, 1H), 2.95-2.80 (m, 1H), 2.38 (ddd, 1H), 1.78-1.63 (m, 1H), 1.28 (t, 3H).

LCMS m/z=496.1 [M+1]+

Step 5: preparation of compound of formula I

(R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

To a 100 L reaction kettle, 12.40 kg of N,N-dimethylacetamide, 2.6269 kg of compound e and 0.54 kg of sodium acetate were added with stirring. After the addition, the temperature was increased and the internal temperature was maintained at 115+5° C. for a reaction for about 2 hours. Then a sample was taken for HPLC monitoring, after which time samples were taken at each about 2-hour interval, and the reaction was not stopped until the content of compound e was determined by HPLC to be≤1.0%.

After the completion of the reaction, the temperature was reduced to 60±5° C., 0.788 kg of purified water was added to the reaction solution, and after the addition, the reaction solution was filtered while still hot and quickly added to 13.66 kg of purified water, and the temperature was lowered to 10+5° C. After filtration, the filter cake was added to 20 L of dimethyl sulfoxide and warmed for complete dissolution. 800 L of acetone was added and stirred for 0.5 to 1 h, and then filtered. The filter cake was dried at 55+5° C. with vacuum≤−0.07 MPa for about 20 hours to give the amorphous form of the compound of formula (I), weighing 1.56 kg.

1H NMR (400 MHZ, DMSO) δ 13.26 (s, 1H), 12.09 (s, 1H), 7.79 (s, 2H), 3.32-3.24 (m, 1H), 3.10-2.99 (m, 1H), 2.96-2.88 (m, 1H), 2.45-2.31 (m, 1H), 1.77-1.69 (m, 1H).

LCMS m/z=450.0 [M+1]+.

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References

Method for preparing (r)-1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5h-cyclopenta[d]pyridazinePublication Number:WO-2025055949-A1Priority Date:2023-09-12
Polymorph as thyroid hormone receptor agonists and use thereofPublication Number:WO-2023147752-A1Priority Date:2022-02-07
Preparation method of pyridazinone derivative, and intermediate thereofPublication Number:TW-202342457-APriority Date:2022-02-07
Preparation method of pyridazinone derivative, and intermediate thereofPublication Number:WO-2023147779-A1Priority Date:2022-02-07
Polymorph as thyroid hormone receptor agonists and use thereofPublication Number:EP-4477652-A1Priority Date:2022-02-07

////////simedeutirom, anax labs, thyroid hormone beta receptor agonist, 4G7Z7KQ8GV

#simedeutirom, #anax labs, #thyroid hormone beta receptor agonist, #4G7Z7KQ8GV

Myself, NIPER-G and NDTL Collaborate to Synthesize ‘Methandienone LTM’ for Global Anti-Doping Efforts

September 6, 2025 5:43 am / Leave a comment

A proud moment for me [ ANTHONY MELVIN CRASTO ] as Scientific Advisor at Niper-G Dept Pharma Ministry of Chemicals and Fertilizers Govt of India

Congrats team Niper-G and team National Dope Testing Lab Govt of India Prof. (Dr.) P. L. Sahu and Myself being a part of it as Scientific Advisor Niper-G for few years in Medicinal chem dept. Launched by Union minister Mansukh Mandaviya on 4th sept 2025 in Delhi

will be distributed across the world via World Anti-Doping agency WADA

Methandienone LTM is high purity rare reference material

Hope my interactions and guidance has given fruitful results. Thanks to Dr Murty for appointing me as advisor. Methandienone LTM will make India proud across the World

A great achievement for India as nation and advanced capability demonstration

https://www.pib.gov.in/PressReleasePage.aspx?PRID=2163812

https://lnkd.in/d9KWWsJ9

India Develops Rare Reference Material for Enhanced Anti-Doping Testing in Sports

NIPER Guwahati and NDTL Collaborate to Synthesize ‘Methandienone Long-Term Metabolite’ for Global Anti-Doping Efforts

India Develops Rare Reference Material for Enhanced Anti-Doping Testing in Sports

NIPER Guwahati and NDTL Collaborate to Synthesize ‘Methandienone Long-Term Metabolite’ for Global Anti-Doping Effortshttps://t.co/qm3wI69rFx
— PIB_INDIA M/o Chemicals & Fertilizers (@PibMinistry) September 4, 2025

//////////NIPER-G, NDTL, Methandienone LTM, Global Anti-Doping, INDIA

Myself Anthony Crasto up for grabs as Advisor API & INT, Chem.

January 22, 2023 8:16 am / 1 Comment on Myself Anthony Crasto up for grabs as Advisor API & INT, Chem.

Admin note for myself . I am up for Grabs

I myself Dr Anthony Melvin Crasto Looking for a post retirement assignment as Advisor API & INT, Chem.
With 36 yrs rich experience, about dozen patents, 10000plus steps covered, 200 API targets, 30 plus products commercialization in plant in full career. Hands on knowledge of Synthesis, Process, scaleup, cost reduction, DOE , softwares etc

Kindly contact me
Dr Anthony Melvin Crasto
+919321316780
amcrasto@gmail.com

About myself
Dr Anthony Crasto
click on my website to know about me

Read http://amcrasto.weebly.com/
Also http://amcrasto.weebly.com/awards.html
Also
http://amcrasto.weebly.com/felicitations.html

1000 lakh google hits, 100lakh blog views, 10 lakh viewers in USA alone, all in 7 continents, 226 countries, 30 Indian and International awards, helping millions across the world

‘Top 10 Prominent & Great Personalities of the year 2022’ campaign by Fame Finders. ANTHONY CRASTO

January 17, 2023 3:13 am / 1 Comment on ‘Top 10 Prominent & Great Personalities of the year 2022’ campaign by Fame Finders. ANTHONY CRASTO

‘Top 10 Prominent & Great Personalities of the year 2022’ campaign by Fame Finders.
Feeling great to be selected in the ‘Top 10 Prominent & Great Personalities of the year 2022’ campaign by Fame Finders. It is an online campaign to honour inspiring personalities and feature them in the upcoming edition of the top news sites, including – Deccan Chronicle/Asian Age/Deccan Herald, ANI, Zee5, Latestly, Lokmat Times, DailyHunt, Google News, JioNews, MSN and 70+ sites.Jan 16 2023

LINK https://www.deccanherald.com/brandspot/pr-spot/top-10-prominent-and-great-personalities-of-the-year-2022-announced-by-fame-finders-media-1181964.html

[youtube https://www.youtube.com/watch?v=x98E01m9anw&w=560&h=315]

Chief Advisor Industry Advisory Board Amity University Noida, India. 26th Aug 2022

August 28, 2022 4:46 am / Leave a comment

DR ANTHONY MELVIN CRASTO is Chief Advisor Industry Advisory Board Amity Univ. Noida, INDIA

Journey begins with online meet. 26th aug 2022
Service to education is service to humanity
Brochure for First Industry Advisory Board meeting at Amity Institute of Pharmacy is attached. Date 26th Aug 2022
it as hybrid-Online/offline.

Thnx
Dr Sandeep Arora
#amity
@amity #education #pharmacy
Amity University
Amity University, Greater Noida Campus

DIFLUPREDNATE

June 13, 2022 2:58 am / 1 Comment on DIFLUPREDNATE

ChemSpider 2D Image | Difluprednate | C27H34F2O7

(1R,3aS,3bS,5S,9aS,9bR,10S,11aS)-1-[2-(acetyloxy)acetyl]-5,9b-difluoro-10-hydroxy-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl butanoate

(6a,11b)-21-(Acetyloxy)-6,9-difluoro-11-hydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione

(6α,11β)-21-(acetyloxy)-6,9-difluoro-11-hydroxy-3,20-dioxopregna-1,4-dien-17-yl butanoate

(6α,11β)-21-Acetoxy-6,9-difluor-11-hydroxy-3,20-dioxopregna-1,4-dien-17-ylbutyrat[German][ACD/IUPAC Name]

(6α,11β)-21-Acetoxy-6,9-difluoro-11-hydroxy-3,20-dioxopregna-1,4-dien-17-yl butyrate[ACD/IUPAC Name]

23674-86-4[RN]

245-815-4[EINECS]

2652

6a,9a-Difluoroprednisolone-21-acetate-17-butyrate

DIFLUPREDNATE

CAS# 23674-86-4

Molecular FormulaC₂₇H₃₄F₂O₇
Average mass508.552 Da

W 6309
W-6309

DFBA
Difluoroprednisolone butyrate acetate

S8A06QG2QE

TU3831500

дифлупреднат[Russian][INN]

ديفلوبريدنات[Arabic][INN]

二氟泼尼酯[Chinese][INN]

(1R,3aS,3bS,5S,9aS,9bR,10S,11aS)-1-[2-(acetyloxy)acetyl]-5,9b-difluoro-10-hydroxy-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl butanoate

(6a,11b)-21-(Acetyloxy)-6,9-difluoro-11-hydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione

(6α,11β)-21-(acetyloxy)-6,9-difluoro-11-hydroxy-3,20-dioxopregna-1,4-dien-17-yl butanoate

(6α,11β)-21-Acetoxy-6,9-difluoro-11-hydroxy-3,20-dioxopregna-1,4-dien-17-yl butyrate

23674-86-4[RN], 245-815-4[EINECS], 2652, 6a,9a-Difluoroprednisolone-21-acetate-17-butyrate

Difluprednate is a topical corticosteroid used for the symptomatic treatment of inflammation and pain associated with ocular surgery.

Difluprednate is a corticosteroid, It is chemically a butyrate ester of 6(alpha),9(alpha)-difluoro prednisolone acetate. Accordingly, difluprednate is sometimes abbreviated DFBA, for difluoroprednisolone butyrate acetate.

Difluprednate is a topical corticosteroid indicated for the treatment of infammation and pain associated with ocular surgery. It is a butyrate ester of 6(α), 9(α)-difluoro prednisolone acetate. Difluprednate is abbreviated DFBA, or difluoroprednisolone butyrate acetate. It is indicated for treatment of endogenous anterior uveiti.

Approval

On June 24, 2008, the US Food and Drug Administration (FDA) approved difluprednate for the treatment of post-operative ocular inflammation and pain.^[1] It is marketed by Alcon under the tradename Durezol.

Depositor-Supplied Patent Identifiers

Publication Number	Title	Priority Date	Grant Date
US-2020325543-A1	Diagnostic method	2017-11-20
WO-2012088044-A2	Compositions and methods for improving ocular surface health, corneal clarity, optical function and maintaining visual acuity	2010-12-20
US-7790905-B2	Pharmaceutical propylene glycol solvate compositions	2002-02-15	2010-09-07
US-7927613-B2	Pharmaceutical co-crystal compositions	2002-02-15	2011-04-19

PATENT

WO/2022/118271DIFLUPREDNATE FOR REDUCING THE ADVERSE EFFECTS OF OCULAR INFLAMMATION

SYN 1

Synthetic Reference

Process for preparation of Difluprednate from sterol fermentation product; Ding, Kai; Xu, Feifei; Assignee Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Peop. Rep. China; East China University of Science and Technology; 2014; Patent Information; Aug 06, 2014; CN; 103965277; A

SYN 2

Synthetic Reference

Preparation method of Difluprednate; Tian, Yuan; Zhou, Shengan; Guo, Bin; Xu, Zhiguo; Assignee Guangzhou Renheng Pharmaceutical Technology Co., Ltd., Peop. Rep. China 2017; Patent Information; May 10, 2017; CN; 106632561; A

SYN3

Synthetic Reference

Shailesh, Singh; Bharat, Suthar; Jain, Ashish; Gaikwad, Vinod; Kulkarni, Kuldip. Process for preparing difluprednate. Assignee Ajanta Pharma Ltd., India. IN 2013MU02535. (2015).

SYN4

Synthetic Reference

Sun, Hongbin; Chen, Bo. Method for preparation of Difluprednate. Assignee China Pharmaceutical University, Peop. Rep. China. CN 103509075. (2014).

PATENT

https://patents.google.com/patent/CN103509075A/en

Embodiment 1:4, pregnant steroid-17 α of 9 (11)-diene, 21-dihydroxyl-3,20-diketone-21-acetic ester (formula III compound)

10g hydrocortisone-21 acetic ester (formula II compound) is joined in 250mL eggplant type bottle, add 50mL N, dinethylformamide and 8.8mL pyridine, slowly heat up and make material dissolution complete, slowly cooling afterwards, slowly be added dropwise to 4.4mL methylsulfonyl chloride, add rear solution to be yellow completely.Be warming up to 85 ℃ of stirrings, the reaction solution thick one-tenth that can slowly become sticky is faint yellow, adds slightly some DMFs and makes reaction solution dilution, can normally stir, and keeps this thermotonus one hour, and reaction solution slowly becomes grey black during this period.TLC follows the tracks of (sherwood oil: ethyl acetate=1: 1) show that reaction finishes.Stop heating, treat that the backward reaction solution of slow cooling adds 200mL methyl alcohol, stir 1min, reaction flask is placed in to crystallization under ice-water bath.Suction filtration after 1h, makes water and methanol wash filter cake, crude product productive rate 100%.With methyl alcohol-methylene dichloride mixed solvent system recrystallization, obtain sterling, M.P.231-235 ℃, productive rate 90%. ¹H-NMR(300MHz，CDCl ₃)：δ(ppm)5.75(1H，s，4-H)，5.55(1H，s，11-H)，5.07(1H，d，J＝5Hz，21-H)，4.84(1H，d，J＝5Hz，21-H)，2.15(3H，s，H-21-OAc)，1.31(3H，s，19-CH ₃)，0.65(3H，s，18-CH ₃)，0.66-2.90(m，17H，backbone).

Embodiment 2:4,9 (11)-diene-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters (formula IV compound)

By 9.4g4, pregnant steroid-17 α of 9 (11)-diene, 21-dihydroxyl-3,20-diketone-21-acetic ester (formula III compound) and 10g4-Dimethylamino pyridine add in 1000mL eggplant-shape bottle, add again 50mL diethylene glycol dimethyl ether and 260mL methylene dichloride, heated and stirred makes dissolution of solid, slowly adds 32mL butyryl oxide slightly after cooling, is warming up to 80 ℃ of return stirrings.After 23h, TLC follows the tracks of, and raw material primitive reaction is complete, stops heating and stirs.Vacuum concentration is removed methylene dichloride.After being down to room temperature, add frozen water in reaction flask, white solid standing to be separated out.Suction filtration, saturated sodium bicarbonate aqueous solution washing leaching cake, dries under infrared lamp, obtain 4,9 (11)-diene-17 α, 21-dihydroxyl-3,20-ketone-21-acetic ester 17 iophenoxic acid esters (formula IV compound) sterling 10.65g, M.P220-224 ℃, productive rate 95.9%. ¹H-NMR(500MHz，CDCl ₃)：δ(ppm)5.75(1H，s，4-H)，5.54(1H，m，11-H)，4.87(1H，d，J＝4.8Hz，O＝C-CH ₂-O，21-H)，4.64-4.91(2H，ABq，J＝16.6Hz，21-H)，2.75(2H，m，2-H)，0.70(3H，s，18-CH ₃)，0.95(3H，t，J＝4.4Hz)，1.34(3H，s，18-CH ₃)，1.66(2H，m，-CH ₂CH ₃)，2.17(3H，s，O＝C-CH ₃)，2.32(2H，t，J＝4.3Hz，O＝C-CH ₂)，? ¹³C-NMR(75MHz，CDCl ₃)：δ(ppm)199.1，198.9，173.4，170.4，169.1，144.1，124.1，118.5，94.5，66.9，48.2，46.3，40.9，37.5，36.4，34.2，33.8，32.7，32.2，32.1，30.6，26.2，24.5，20.5，18.3，13.7，13.6；ESI-MS?m/z：457.2[M+H ⁺]，479.2[M+Na ⁺]；HRMS?for?C ₂₇H ₃₆O ₆+Na ⁺?calcd?479.2410，found479.2402.

Embodiment 3:3,5,9 (11) pregnant steroid-3 of triolefin, 17 α, 21 trihydroxy–3,20-diketone-3,21-diacetate esters 17 iophenoxic acid esters (formula V)

10g4, pregnant steroid-17 α of 9 (11)-diene, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters add in 250mL eggplant type bottle, then add 80mL methylvinyl acetate, slowly drip while stirring the 1mL vitriol oil.Be warming up to 80 ℃ of stirring reactions, solution is thin out yellow clarification slowly.(sherwood oil: ethyl acetate=3: 1), raw material reaction is complete produces new point to TLC after 30min.Stop heating, wait to be cooled to 50 ℃, add 1mL triethylamine, be stirred to and be down to room temperature.Add water in reaction solution, ethyl acetate aqueous layer extracted three times, saturated common salt water washing organic phase twice, anhydrous sodium sulfate drying.After 30min, steam organic solvent and obtain brown color oily matter.Column chromatography is purified and is obtained 3,5,9 (11) pregnant steroid-3 of triolefin, 17 α, 21 trihydroxy–3,20-diketone-3,21-diacetate esters 17 iophenoxic acid esters, productive rate 90%. ¹H-NMR(300MHz，CDCl ₃)：δ(ppm)5.74(1H，s，4-H)，5.53(1H，s，11-H)，5.45(1H，s，6-H)，4.64-4.91(2H，ABq，J＝16.6Hz，21-H)，2.17(3H，s，-COCH ₃)，1.17(3H，s，19-CH ₃)，0.96(3H，t，J＝7.5Hz)，0.70(3H，s，18-CH ₃).

Embodiment 4:4, fluoro-17 α of 9 (11)-diene-6-, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters

10g3,5,9 (11) pregnant steroid-3 of triolefin, 17 α, 21 trihydroxy–3,20-diketone-3,21-diacetate esters 17 iophenoxic acid esters are dissolved in 60mL acetonitrile, and under nitrogen protection ,-4 ℃ are stirred half an hour.Slowly drip the acetonitrile suspension 40mL of Selecfluor in reaction flask, under nitrogen protection, react 2 hours, TLC (sherwood oil: ethyl acetate=3: 1) monitoring reaction, raw material reaction is complete.Stopped reaction, adds water in reaction flask, ethyl acetate extraction three times, saturated common salt water washing twice, anhydrous sodium sulfate drying.Vacuum concentration is removed organic solvent, obtain faint yellow solid 4,9 (11)-diene-6 α-fluoro-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VII) and 9 (11)-diene-6 β-fluoro-17 α, 21-dihydroxyl-3, the mixture of 20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VI), productive rate 85%. ¹H-NMR(500MHz，CDC1 ₃)：δ(ppm)5.90(1H，d，J＝4.5Hz，4-H)，5.59(1H，s，11-H)，5.07(1H，m，6-H)，4.64-4.91(2H，ABq，J＝16.6Hz，21-H)，2.17(3H，s，-COCH ₃)，1.46(3H，s，18-CH ₃)，0.96(3H，t，J＝7.5Hz)，0.73(3H，s，19-CH ₃).

Embodiment 5:4,9 (11)-diene-6 α-fluoro-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VII)

14g4, 9 (11)-diene-6 α-fluoro-17 α, 21-dihydroxyl-3, 20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VII) and 9 (11)-diene-6 β-fluoro-17 α, 21-dihydroxyl-3, the mixture of 20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VI) adds in dry three-necked bottle, add while stirring 400mL acetum, under room temperature, slowly pass into anhydrous hydrogen chloride gas (98% vitriol oil is added dropwise in 37% concentrated hydrochloric acid solution and makes) until saturated, be stirred to raw material and be dissolved into yellow solution completely, continue to stir 2h, TLC monitoring reacts completely, stop stirring, in reaction solution, add the aqueous solution, after separating out solid, suction filtration, saturated sodium bicarbonate aqueous solution washing, dry, be weighed as 13g, productive rate is 93%. ¹H?NMR(300MHz，CDCl ₃)：δ(ppm)6.10(s，1H)，5.61(s，1H)，5.41-5.16(m，1H)，4.64-4.91(2H，ABq，J＝16.6Hz，21-H)，2.82(dd，J＝28.3，15.7Hz，3H)，2.50(s，2H)，2.32(t，J＝7.4Hz，2H)，2.17(s，3H)，1.96(s，5H)，1.66(d，J＝7.4Hz，2H)，1.46(s，2H)，1.33(s，3H)，0.96(s，3H)，0.71(s，3H).

Embodiment 6:6 α-fluoro-9 α-bromo-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester (formula VIII)

13g 6 α-fluoro-4; 9; (11)-diene-pregnant steroid-3,20-22 ketone-17-butyric ester-20-acetic ester is dissolved in and fills 300mL1, in the eggplant type bottle of 4 dioxane; add while stirring 40mL 0.46mol/L high chloro acid solution; under room temperature, stir after several minutes, add 14g N-succinimide in reaction system, under nitrogen protection, stir; raw material dissolves gradually, and it is faint yellow that reaction solution is.(the sherwood oil: ethyl acetate=12: 5) monitoring, raw material primitive reaction is complete, adds 10%Na of TLC after 2h ₂sO ₃unnecessary N-succinimide is fallen in aqueous solution cancellation, and checks (it is blue that test paper no longer becomes) with starch-kalium iodide test paper.Add water in reaction flask, ethyl acetate extraction three times, twice of saturated common salt water washing organic phase, anhydrous sodium sulfate drying organic phase, after 30min, be spin-dried for organic phase, obtain faint yellow oily matter, column chromatography purification (sherwood oil: ethyl acetate=12: 1) obtain white solid 6 α-fluoro-9 α-bromo-11 beta-hydroxies-4-alkene-pregnant steroid-3, the about 14g of 20-diketone-17-butyric ester-20-acetic ester, productive rate is 89%. ¹H-NMR(300MHz，CDCl ₃)：δ(ppm)5.93(1H，d，J＝4.5，4-H)，5.06(1H，m，6-H)，4.64-4.91(2H，ABq，J＝16.6Hz，21-H)，2.17(3H，s，-COCH ₃)，1.84(3H，s，18-CH ₃)，0.96(3H，t，J＝7.5Hz)，1.02(3H，s，19-CH ₃)，4.72(1H，s，11-H)；ESI-MS?m/z：593.3，595.3[M+Na ⁺].

Embodiment 7:6 α-fluoro-9 β, 11 beta epoxides-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester (formula IX)

14g 6 α-fluoro-9 α-bromo-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester drops in 500mL eggplant type bottle, adds 200mL acetone, stirs raw material is fully dissolved, and adds afterwards 3g Potassium ethanoate, is warming up to 60 ℃ of return stirring 13h.TLC (sherwood oil: ethyl acetate=2: 1) monitoring finds that new product occurs.Stop heating, in reaction solution, add water, ethyl acetate extraction, anhydrous sodium sulfate drying organic phase, after standing 30min, steams except organic solvent, obtains yellow oil, productive rate 96%.Column chromatography is purified, and obtains white solid powder, and nuclear-magnetism confirmation structure is 6 α-fluoro-9 β, 11 beta epoxides-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester. ¹H-NMR(300MHz，CDC1 ₃)：δ(ppm)6.11(1H，d，J＝4.5Hz，4-H)，5.31(1H，m，6-H)，4.64-4.91(2H，ABq，J＝16.6Hz，21-H)，2.17(3H，s，-COCH ₃)，0.94(3H，s，18-CH ₃)，0.97(3H，t，J＝7.5Hz)，1.55(3H，s，19-CH ₃)，3.52(1H，s，11-H)；ESI-MS?m/z：491.2[M+H ⁺]，513.2[M+Na ⁺].

Embodiment 8:6 α, 9 α-fluoro-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester (formula X)

100mg 6 α-fluoro-9 β, 11 beta epoxides-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester drops in the Plastic Bottle of tetrafluoroethylene, adds 2mL methylene dichloride to dissolve, and stirs at-20 ℃.1mL Olah reagent with under 1mL methylene dichloride low temperature, mix after, be slowly added dropwise in reaction system, maintain low temperature and stir 2 hours, TLC monitoring reaction finishes.Reaction flask shifts out low-temp reaction groove, is slowly added dropwise to the 1mol/L NaOH aqueous solution by excessive HF cancellation, is adjusted to pH7～8.Add chloroform in reaction system, extraction, organic layer is used respectively aqueous hydrochloric acid and the saturated common salt water washing of 3mol/L, anhydrous sodium sulfate drying, after standing 30min, steams except organic solvent, column chromatography is further purified and is obtained white solid powder 6 α, 9 α-fluoro-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester, productive rate 90%. ¹H-NMR(300MHz，CDCl ₃)：δ(ppm)?6.11(1H，d，J＝4.5Hz，4-H)，5.27(1H，m，6-H)，4.64-4.91(2H，ABq，J＝16.6Hz，21-H)，2.17(3H，s，-COCH ₃)，4.40(1H，d，J＝4.5Hz，11-H)，1.02(3H，s，18-CH ₃)，0.96(3H，t，J＝7.5Hz)，1.52(3H，s，19-CH ₃)；ESI-MS?m/z：533.3[M+Na ⁺]

Embodiment 9:6 α, 9 α-fluoro-11 beta-hydroxies-Isosorbide-5-Nitrae-diene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester (difluprednate) (formula I)

40mg 6 α, 9 α-fluoro-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester is dissolved in 3mL dioxane, adds 28mgDDQ, and 100 ℃ of return stirrings heat up.TLC monitoring reaction (sherwood oil: ethyl acetate=12: 8) after 13h, generate the larger product of polarity, steam except organic solvent dioxane, obtain brown color oily matter, add a small amount of methylene dichloride lysate, suction filtration, elimination solid residue, filtrate is washed with sodium bicarbonate aqueous solution after adding a small amount of methylene dichloride again, steams except organic phase rear pillar Chromatographic purification, obtain white solid powder 6 α, 9 α-fluoro-11 beta-hydroxies-Isosorbide-5-Nitrae-diene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester, be title molecule difluprednate, productive rate 70%. ¹h-NMR (300MHz, CDCl ₃): δ (ppm) 7.20 (1H, d, J=4.5Hz, 1-H), 6.43 (1H, s, 4-H), 6.38 (1H, d, J=6Hz, 2-H), 5.36 (1H, m, 6-H), 4.64-4.91 (2H, ABq, J=16.6Hz, 21-H), 4.43 (1H, d, J=4.5Hz, 11-H), 2.27 (2H, m ,-CH ₂-CH ₃), 2.17 (3H, s, O=C-CH ₃), 1.55 (3H, s, 19-CH ₃), 1.02 (3H, s, 18-CH ₃), 0.93 (3H, t, J=4.5Hz, 0=C-CH ₂cH ₂cH ₃); ESI-MS m/z:509.3[M+H ⁺]; HRMS for C ₂₇h ₃₅o ₇f ₂+ H ⁺calcd 509.2351, found 509.2356.M.P.188-190 ℃ (literature value M.P.190-194 ℃); [α] _d²²=+30.1 ° of (literature values [α] _d²²=+31.7 °).

Claims (6)

Hide Dependent

1. a method of preparing difluprednate, as following reaction formula:

Specifically comprise the following steps:

(1) by hydrocortisone-21-acetic ester (formula II compound):

Carry out dehydration reaction, generate formula III compound:

(2) formula III compound is carried out to butyric acid esterification, obtains formula IV compound:

(3) formula IV compound is carried out to the reaction of enolization esterifying reagent, obtains formula V compound:

(4) formula V compound is reacted with fluoro reagent and obtains formula VI and formula VII compound:

(5) by formula VI compound, through configuration reversal, reaction obtains formula VII compound;

(6) formula VII compound is reacted with N-bromo-succinimide and water, obtains formula VIII compound:

(7) formula VIII compound epoxidation under alkaline condition is obtained to formula IX compound:

(8) formula IX compound is reacted with fluorination reagent and obtains formula X compound:

(9) dehydrogenation of formula X compound oxidation is obtained to formula I compound (difluprednate).

2. method as claimed in claim 1, is characterized in that, in step (2), formula III compound is obtained to formula IV compound through fourth esterification, and the fourth esterifying reagent adopting is butyryl oxide or butyryl chloride; The alkaline catalysts adopting is pyridine, triethylamine or DMAP; The solvent adopting is methylene dichloride, diethylene glycol dimethyl ether, 1, the mixture of the optional solvents in 2-ethylene dichloride, dioxane, trichloromethane, DMF, methyl-sulphoxide, N,N-dimethylacetamide or above-mentioned solvent.

3. method as claimed in claim 1, is characterized in that, in step (3), formula IV compound is obtained to formula V compound through enolization esterification, and the enolization esterifying reagent adopting is diacetyl oxide, Acetyl Chloride 98Min., methylvinyl acetate or vinyl-acetic ester; The catalyzer adopting is the vitriol oil or tosic acid; The solvent adopting is the mixture of the optional solvents in methylene dichloride, chloroform, toluene, methylvinyl acetate, vinyl-acetic ester or above-mentioned solvent.

4. method as claimed in claim 1, is characterized in that, in step (4), formula V compound is obtained to formula VI compound and formula VII compound through fluoridizing, and the fluoro reagent adopting is Selectfluor or Accufluor; The solvent adopting is the mixture of the optional solvents in methylene dichloride, chloroform, toluene, acetonitrile or above-mentioned solvent.

5. method as claimed in claim 1, it is characterized in that, in step (8), formula IX compound is obtained to formula X compound through fluoridizing open loop, the fluorination reagent adopting is aqueous hydrogen fluoride solution, hydrogen fluoride pyridine solution (Olah reagent) or hydrogen fluoride triethylamine solution; The solvent adopting is methylene dichloride, chloroform, 1, the mixture of the optional solvents in 2-ethylene dichloride, tetrahydrofuran (THF), toluene or above-mentioned solvent; Range of reaction temperature is-50～50 ℃.

6. a key intermediate compound for synthetic difluprednate, shown in IV compound:

Patent

Publication numberPriority datePublication dateAssigneeTitle

US3780177A *1967-06-161973-12-18Warner Lambert Co17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use

US4525303A *1982-06-211985-06-25Dainippon Ink And Chemicals Inc.Process for preparation of steroids

CN101397321A *2007-09-292009-04-01天津药业研究院有限公司Preparation of hydrocortisone and derivatives thereof

CN102076344A *2008-05-282011-05-25瓦利杜斯生物医药有限公司Non-hormonal steroid modulators of nf-kb for treatment of disease

CN102134266A *2010-12-302011-07-27北京市科益丰生物技术发展有限公司Preparation method of melengestrol acetate

Publication numberPriority datePublication dateAssigneeTitle

CN102964412A *2012-11-272013-03-13山东省医药工业研究所Novel crystal form and preparation method of difluprednate

CN103965277A *2014-05-192014-08-06中国科学院上海有机化学研究所Method for synthesizing difluprednate from sterol fermentation product

CN106632561A *2016-12-162017-05-10广州仁恒医药科技股份有限公司Method for preparing difluprednate

CN106749464A *2016-12-292017-05-31奥锐特药业有限公司Steroidal epoxide carries out open loop, the method for fluorination reaction and its device

CN107915766A *2016-10-112018-04-17江苏福锌雨医药科技有限公司A kind of preparation method of fludrocortison acetate

CN108503679A *2018-04-032018-09-07广州仁恒医药科技股份有限公司A kind of purification process of Difluprednate intermediate

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Clinical trials

Difluprednate ophthalmic emulsion 0.05% is also being studied in other ocular inflammatory diseases, including a phase 3 study evaluating difluprednate for the treatment of anterior uveitis^[2][3]

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References

^ “Sirion Therapeutics Announces FDA Approval of Durezol for Treatment of Postoperative Ocular Inflammation and Pain” (Press release). Sirion Therapeutics, Inc. 2008-06-24. Retrieved 2008-06-30.
^ Clinical trial number NCT00501579 for “Study of Difluprednate in the Treatment of Uveitis” at ClinicalTrials.gov
^ Sheppard JD, Toyos MM, Kempen JH, Kaur P, Foster CS (May 2014). “Difluprednate 0.05% versus prednisolone acetate 1% for endogenous anterior uveitis: a phase III, multicenter, randomized study”. Investigative Ophthalmology & Visual Science. 55 (5): 2993–3002. doi:10.1167/iovs.13-12660. PMC 4581692. PMID 24677110.

Clinical data


AHFS/Drugs.com	Monograph
MedlinePlus	a609025
License data	US FDA: Difluprednate
Routes of administration	eye drops
ATC code	D07AC19 (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
show IUPAC name
CAS Number	23674-86-4
PubChem CID	32037
DrugBank	DB06781
ChemSpider	391990
UNII	S8A06QG2QE
KEGG	D01266
ChEBI	CHEBI:31485
ChEMBL	ChEMBL1201749
CompTox Dashboard (EPA)	DTXSID0046773
ECHA InfoCard	100.041.636
Chemical and physical data
Formula	C₂₇H₃₄F₂O₇
Molar mass	508.559 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
(what is this?) (verify)

///////////////DIFLUPREDNATE, W 6309, W-6309, DFBA, Difluoroprednisolone butyrate acetate, S8A06QG2QE, TU3831500, дифлупреднат , ديفلوبريدنات , 二氟泼尼酯 , OCCULAR, PAIN

CCCC(=O)OC1(CCC2C1(CC(C3(C2CC(C4=CC(=O)C=CC43C)F)F)O)C)C(=O)COC(=O)C

Anthony crasto is now Consultant Glenmark Lifesciences at Glenmark Life Sciences!

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I’m happy to share that I’m starting a new position as Consultant Glenmark Lifesciences at Glenmark Life Sciences!
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I retired 16th Jan 2022 at 58 yrs from Glenmark . completed 16 yrs 2 months

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References

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Step 1: preparation of compound b

N-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl)benzamid

Step 2: preparation of compound c

4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-1-on

Step 3: preparation of compound d

(R)-4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-1-one

Compound d

Compound d-1

Step 4: preparation of compound e

Ethyl(R,Z)-(2-cyano-2-(2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl) hydrazineylidene) acetyl) carbamate

Step 5: preparation of compound of formula I

(R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta [d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

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