PROUD Indian WORLD RECORD VIEWS holder on THIS BLOG, ………live, by DR ANTHONY MELVIN CRASTO, Worldpeaceambassador, Worlddrugtracker, Helping millions, 100 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 45 lakh plus VIEWS on this blog in 227 countries, 7 CONTINENTS ……A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, [THIS BLOG HOLDS WORLD RECORD VIEWS ] A PROUD INDIAN
DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was
with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc
He has total of 32 International and Indian awards
To treat estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy
On May 1, 2026, the FDA approved vepdegestrant (Veppanu), a first-in-class oral PROTAC estrogen receptor (ER) degrader developed by Arvinas and Pfizer, for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer who have progressed on endocrine therapy. It demonstrated significant progression-free survival (PFS) improvements compared to fulvestrant.
Key Details About Vepdegestrant (Veppanu):
Mechanism of Action: As an oral PROTAC (Proteolysis-Targeting Chimera), vepdegestrant targets the estrogen receptor for degradation, designed to be more effective than traditional endocrine therapies, particularly in ESR1-mutated tumors.
Approved Indication: For treating adults with ER+/HER2-, ESR1-mutated advanced/metastatic breast cancer (detected by Guardant360 CDx) after at least one line of endocrine therapy.
Dosage: The recommended dose is 200 mg taken orally once daily with food.
Clinical Efficacy (VERITAC-2): In trials, vepdegestrant showed a significantly longer PFS compared to intramuscular fulvestrant.
Side Effects & Risks: Common side effects include decreased white blood cell counts, increased liver function tests, muscle/bone pain, fatigue, and nausea. Warnings include embryo-fetal toxicity and QTc interval prolongation (heart rhythm issues).
Companion Diagnostic:Guardant360 CDx was approved alongside the drug to identify patients with ESR1 mutations
Vepdegestrant is designed as a PROTAC that recruits the ubiquitin-proteasome system to target the estrogen receptor for degradation.[4] The compound contains both an E3 ubiquitin ligase-binding moiety and an estrogen receptor-binding domain, intended to bring these proteins into proximity to trigger ubiquitination and subsequent proteasomal degradation of the ER protein.[5] In laboratory studies, vepdegestrant demonstrated ER degradation in ER-positive breast cancer cell lines with reported DC50 values of approximately 1-2 nM.[6]
Vepdegestrant is an orally available hetero-bifunctional molecule and selective estrogen receptor (ER) alpha-targeted protein degrader, using the proteolysis targeting chimera (PROTAC) technology, with potential antineoplastic activity. Vepdegestrant is composed of an ER alpha ligand attached to an E3 ligase recognition moiety. Upon oral administration,vepdegestrant targets and binds to the ER ligand binding domain on ER alpha. E3 ligase is recruited to the ER by the E3 ligase recognition moiety and ER alpha is tagged by ubiquitin. This causes ubiquitination and degradation of ER alpha by the proteasome. This decreases ER alpha protein levels, decreases the expression of ER alpha-target genes and halts ER-mediated signaling. This results in an inhibition of proliferation in ER alpha-overexpressing tumor cells. In addition, the degradation of the ER alpha protein releases the ARV-471 and can bind to additional ER alpha target proteins. ER alpha is overexpressed in a variety of cancers and plays a key role in cancer cell proliferation.
Step 11: Preparation of 3-[5-[4-[[1-[4-[(1R, 2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound (I-b))
To a solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione hydrochloride (319 mg, 0.87 mmol, prepared in Step 17 described for Exemplary Compound 62) in methanol (4 mL) and dichloromethane (4 mL) was added sodium acetate (120 mg, 1.46 mmol, 2 eq). The mixture was stirred at 20° C. for 0.5 h, then to the mixture was added 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (300 mg, 0.73 mmol, 1 eq) and sodium cyanoborohydride (137 mg, 2.19 mmol, 3 eq). The mixture was stirred at 20° C. for 12 h. LC-MS showed the starting material was consumed completely and one main peak with desired MW was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex luna C 18 column, 250×50 mm, 10 um; mobile phase: [water (0.05% HCl)-acetonitrile]; B %: acetonitrile 10%-40% in 30 min). The desired compound 3-[5-[4-[[1-[4-[(1R, 2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (288.4 mg, 0.37 mmol, 51% yield) was obtained as a white solid of hydrochloride salt. LC-MS (ESI) m/z: 724.4 [M+1] +; 1H NMR (400 MHz, DMSO-d 6) δ 10.97 (s, 1H), 10.83 (s, 0.9H, HCl), 7.60 (d, J=8.5 Hz, 1H), 7.40 (br s, 2H), 7.22-7.11 (m, 5H), 6.83 (d, J=6.0 Hz, 2H), 6.69-6.63 (m, 2H), 6.58-6.47 (m, 3H), 5.07 (dd, J=5.2, 13.2 Hz, 1H), 4.41-4.30 (m, 2H), 4.28-4.21 (m, 1H), 4.00 (d, J=12.7 Hz, 2H), 3.61 (d, J=11.0 Hz, 2H), 3.54-3.36 (m, 6H), 3.16 (br s, 4H), 3.06-2.84 (m, 3H), 2.76-2.53 (m, 1H), 2.43-2.33 (m, 1H), 2.27 (br s, 1H), 2.16-2.04 (m, 3H), 2.02-1.69 (m, 5H).
Synthesis of (3S)-3-[5-[4-[[1-[4-[(1R, 2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound (I-c))
To a mixture of (3 S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (1.30 g, 3.47 mmol, 1 eq, benzene sulfonate) in dichloromethane (8 mL) and methanol (32 mL) was added sodium acetate (854 mg, 10.41 mmol, 3 eq) in one portion at 20° C. The mixture was stirred at 20° C. for 10 minutes. Then 1-[4-[(1R, 2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl] piperidine-4-carbaldehyde (1 g, 2.43 mmol, 0.7 eq, prepared as described above in the synthesis of Compound (I-b)) was added. The mixture was stirred at 20° C. for 10 minutes. After that, acetic acid (0.2 mL) and sodium cyanoborohydride (436 mg, 6.94 mmol, 2 eq) was added in one portion. The mixture was stirred at 20° C. for 40 minutes. The mixture was concentrated in vacuum, and 50 mL of tetrahydrofuran and 20 mL of water were added. The mixture was stirred for 20 minutes. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8-9. The aqueous phase was extracted with ethyl acetate and tetrahydrofuran (v:v=2:1, 60 mL×3). The combined organic phase was washed with brine (60 mL×1), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative reverse phase HPLC (column: Phenomenex luna C18 250×50 mm, 10 micron; mobile phase: [water (0.225% formic acid)-acetonitrile]; B %: 20%-50% in 30 min). The product (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl] piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (964 mg, 1.23 mmol, 35% yield, 98% purity, formate) was obtained as a white solid of formic acid salt after lyophilization. Chiral purity was analyzed by chiral SFC (Chiralcel OJ-3 50×4.6 mm, 3 micron; mobile phase: 50% ethanol (0.05% DEA) in CO 2; flow rate: 3 mL/min, wavelength: 220 nm) and observed t p=2.89 min with de over 95%. [α D=−267.5 (c=0.2 in DMF, 25° C.). LC-MS (ESI) m/z: 724.2 [M+1] +. 1H NMR (400 MHz, DMSO-d 6) δ 10.94 (s, 1H), 8.16 (s, 1H, formate), 7.51 (d, J=8.8 Hz, 1H), 7.21-6.98 (m, 5H), 6.83 (d, J=6.4 Hz, 2H), 6.68-6.57 (m, 2H), 6.56-6.44 (m, 3H), 6.20 (d, J=8.8 Hz, 2H), 5.04 (dd, J=5.2, 13.2 Hz, 1H), 4.32 (d, J=16.8 Hz, 1H), 4.19 (d, J=17.2 Hz, 1H), 4.12 (d, J=4.8 Hz, 1H), 3.51 (br d, J=10.0 Hz, 4H), 3.27 (br s, 8H), 3.03-2.82 (m, 3H), 2.63-2.54 (m, 1H), 2.43-2.28 (m, 2H), 2.19 (d, J=6.8 Hz, 2H), 2.15-2.02 (m, 1H), 2.01-1.89 (m, 1H), 1.83-1.51 (m, 4H), 1.28-1.04 (m, 2H).
Iwata, H.; Naito, Y.; Hattori, M.; Yoshimura, A.; Yonemori, K.; Aizawa, M.; et al. (November 2023). “58P Safety and pharmacokinetics (PK) of vepdegestrant in Japanese patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Results from a Japanese phase I study”. Annals of Oncology. 34: S1488–S1489. doi:10.1016/j.annonc.2023.10.193. S2CID265657144.
MOLECULAR FORMULA C231H386N64O67S5 + (C2H4O)4n MOLECULAR WEIGHT approx. 45 kDa
The structure of navepegritide (YUVIWEL®) is built using a “prodrug” design. It is not a simple small molecule, but rather a complex conjugate consisting of three distinct components designed to release the active drug slowly over time.
1. The Active Part: C-Type Natriuretic Peptide (CNP)
The core of the molecule is a synthetic 38-amino acid peptide (CNP-38).
Sequence: This peptide mimics the natural human C-type natriuretic peptide, which is essential for bone growth.
Function: Once released, this peptide binds to the natriuretic peptide receptor B (NPR-B) on the surface of chondrocytes (cartilage cells) in the growth plates, stimulating bone formation.
2. The Carrier: Polyethylene Glycol (PEG)
To prevent the body from clearing the small peptide too quickly, it is attached to a large, inert carrier.
Type: It uses a multi-arm, branched 40 kDa Polyethylene Glycol (PEG) molecule.
Purpose: The PEG carrier acts as a shield and a “weight,” making the molecule too large to be filtered out rapidly by the kidneys. This is what allows for once-weekly dosing instead of daily injections.
3. The Linker: TransCon™ Technology
This is the most critical part of the structure. The peptide is attached to the PEG carrier via a cleavable linker.
Mechanism: This linker is designed to break down spontaneously at a predictable rate under physiological conditions (neutral pH and body temperature).
The Result: As the linker slowly breaks, it releases the unmodified, active CNP-38 into the bloodstream. Because the peptide is released in its natural state, it retains its full biological activity.
Summary Table: Structural Components
Component
Description
Role
Peptide
CNP-38 (38 amino acids)
The “payload” that stimulates bone growth.
Linker
pH-sensitive cleavable bond
Controls the slow release of the peptide.
Carrier
40 kDa PEG
Increases the half-life and prevents rapid clearance.
Note: This structure is technically a prodrug because the large PEG-bound version is inactive; only the released CNP-38 peptide performs the therapeutic work.
C-Type natriuretic peptide (CNP), human, (89-126)-fragment (1-38) (CNP-38), conjugated at N6 of Lys26 with four O-methylpoly(ethylene glycol) chains (approx. 10 kDa each) via a cleavable tetra-antennary linker; L-leucyl-L-glutaminyl-L-?-glutamyl-L-histid
Poly(oxy-1,2-ethanediyl), ?-hydro-?-methoxy-, 26,26,26,26-tetraether with L-leucyl-L-glutaminyl-L-?-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-sery
FDA 2026, APPROVALS 2026, 2/27/2026, Yuviwel, Y3BH8M899D, MN-266, TRANSCON CNP, PA (224-233), Influenza, DA-66438, ACP-015, WHO 11981,
To increase linear growth in pediatric patients 2 years and older with achondroplasia with open epiphyses
Navepegritide is a prodrug consisting of a 38-amino acid C-type natriuretic peptide (CNP) moiety conjugated to a multi-arm polyethylene glycol (PEG) carrier via a cleavable linker. This structure allows for the once-weekly dosing approved by the FDA for children with achondroplasia.
Key Details
Purpose: It is designed to increase linear growth by providing continuous exposure to C-type natriuretic peptide (CNP), a protein that helps regulate bone growth.
Mechanism: As a prodrug, it uses Ascendis Pharma’s TransCon technology to release active CNP slowly into the body over a week, maintaining steady levels and avoiding high peaks.
Clinical Benefits: In the pivotal ApproaCH trial, patients treated with navepegritide showed a significant improvement in annualized growth velocity (AGV) compared to those on a placebo. It also showed potential improvements in body proportionality and lower-limb alignment.
Administration: It is administered via a once-weekly subcutaneous injection, offering a less frequent alternative to daily treatments like vosoritide.
Safety: Most common side effects include injection site reactions (redness, itching, or swelling) and a risk of low blood pressure (hypotension).
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethane-1-sulfonamide orexin type 2 receptor agonist, TAK-861, TAK 861, 59MF6P2ATF
Oveporexton is a small molecule drug. The usage of the INN stem ‘-orexton’ in the name indicates that Oveporexton is a orexin receptor agonist. Oveporexton has a monoisotopic molecular weight of 520.15 Da.
Oveporexton is being developed by Takeda.[1] As of July 2025, it has completed phase 3 clinical trials for treatment of narcolepsy, whereas no recent development has been reported for treatment of idiopathic hypersomnia.[1][5][10] Takeda plans to submit a New Drug Application (NDA) of oveporexton for the treatment of narcolepsy to the United StatesFood and Drug Administration (FDA) in 2025.[5] Oveporexton is a follow-on and replacement compound for Takeda’s earlier lead drug danavorexton (TAK-925), which is administered intravenously and stopped being developed due to unexpected liver toxicity findings.[10]
A Trial of TAK-861 for the Treatment of Narcolepsy With CataplexyCTID: NCT07363720Phase: Phase 3Status: Not yet recruitingDate: 2026-01-23Conditions: Narcolepsy Type 1 (NT1); Narcolepsy With CataplexyInterventions: PlaceboLinked Compound CID: 154617563
A Study of TAK-861 for the Treatment of Selected Central Hypersomnia ConditionsCTID: NCT05816382Phase: Phase 2/Phase 3Status: RecruitingDate: 2025-12-01Conditions: Narcolepsy Type 1Interventions: TAK-861Linked Compound CID: 154617563
A Study of TAK-861 in People With Narcolepsy Type 1CTID: NCT06505031Phase: Phase 3Status: CompletedDate: 2025-09-15Conditions: Narcolepsy Type 1Interventions: PlaceboLinked Compound CID: 154617563
A Study of TAK-861 for the Treatment of Narcolepsy Type 1CTID: NCT06470828Phase: Phase 3Status: CompletedDate: 2025-07-01Conditions: Narcolepsy Type 1Interventions: PlaceboLinked Compound CID: 154617563
A Study of TAK-861 in Participants With Narcolepsy Type 1CTID: NCT05687903Phase: Phase 2Status: CompletedDate: 2025-01-09Conditions: Narcolepsy Type 1Interventions: PlaceboLinked Compound CID: 154617563
A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of Narcolepsy With Cataplexy (Narcolepsy Type 1)EudraCT: 2022-001654-38Phase: Phase 2Status: CompletedDate: 2023-05-26Linked Compound CID: 154617563
A Long-term Extension Study to Evaluate the Safety and Tolerability of TAK-861 in Participants With Selected Central Hypersomnia ConditionsEudraCT: 2022-002965-13Phase: Phase 2, Phase 3Status: Trial now transitionedDate: 2023-04-11Linked Compound CID: 154617563
A Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-861 for the Treatment of Narcolepsy Without Cataplexy (Narcolepsy Type 2)EudraCT: 2022-002966-34Phase: Phase 2Status: CompletedDate: 2023-03-20Linked Compound CID: 154617563
A) tert-butyl (2S,3R)-3-(ethylsulfonamido)-4,4-difluoro-2-((2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-1-carboxylate
To a mixture of tert-butyl (2S,3R)-2-(3-chloro-2-fluorobenzyl)-3-(ethylsulfonamido)-4,4-difluoropyrrolidine-1-carboxylate (3.70 g), (3,5-difluorophenyl)boronic acid (2.56 g) and 1 M aqueous potassium phosphate solution (24.3 mL) in DME (50 mL) was added XPhos Pd G3 (0.343 g) at room temperature. The mixture was stirred at 90° C. under nitrogen atmosphere for 15 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EOAc/hexane) to give the title compound (3.30 g).
MS: [M−H] − 533.2.
B) N-((2S,3R)-4,4-difluoro-2-((2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride
A mixture of tert-butyl (2S,3R)-3-(ethylsulfonamido)-4,4-difluoro-2-((2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidine-1-carboxylate (3.30 g) and 4 M HCl/CPME solution (30 mL) was stirred overnight at room temperature. By filtration, the title compound (2.86 g) was obtained.
MS: [M+H] + 435.1.
C) N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
To a mixture of N-((2S,3R)-4,4-difluoro-2-((2,3′,5′-trifluoro-[1,1′-biphenyl]-3-yl)methyl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (200 mg) and DIPEA (0.367 ml) in THF (3 mL) was added alpha-acetoxy-isobutyryl chloride (0.074 ml) at 0° C., and the mixture was stirred at same temperature for 10 min. To the mixture were added water (1 ml) and 4 M lithium hydroxide solution (1.06 ml), and the mixture was stirred overnight at room temperature. The mixture was diluted with saturated brine and extracted with EtOAc. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane) and recrystallized from EtOAc/hexane to give the title compound (154 mg).
1H NMR (400 MHz, CDCl 3) δ 1.32-1.40 (9H, m), 2.27-2.54 (1H, m), 2.88-3.16 (4H, m), 4.02-4.49 (3H, m), 4.86-5.20 (2H, m), 6.78-6.86 (1H, m), 7.02-7.10 (2H, m), 7.16-7.22 (1H, m), 7.27-7.31 (1H, m), 7.35-7.43 (1H, m).
N-{(2S,3R)-4,4-difluoro-l-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[l,l’-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide, (hereafter referred as to “Compound A”) is described in U.S. Patent No. 11,028,048.
Dauvilliers Y, Plazzi G, Mignot E, Lammers GJ, Del Río Villegas R, Khatami R, et al. (May 2025). “Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1”. The New England Journal of Medicine. 392 (19): 1905–1916. doi:10.1056/NEJMoa2405847. PMID40367374.
25 Feb 2026Vanda Pharmaceuticals has patent protection for an improved method of treatment with milsaperidone in USA
25 Feb 2026Vanda Pharmaceuticals has patents pending for an improved method of treatment with milsaperidone in China, Australia, Israel, Mexico and worldwide
56.36 g of boran complex of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1 ,3,2]oxazaborole (1 equivalent) is dissolved under nitrogen in methylenchloride, and the solution is cooled to 0°C. A 1M solution of 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone (iloperidone; 1 equivalent) in methylenchloride is added via a dropping funnel over 90 minutes while the internal temperature is maintained at 0°C ± 2°C. After the addition is complete, the mixture is stirred at 0°C for 20 hours. The reaction mixture is then poured into precooled methanol (0-5°C) during 1 hour. The solution is warmed to room temperature and stirred until the H2 evolution ceases. The solution is concentrated by distillation and the residue dried in vacuum, treated with methanol and stirred for about 1 hour at 50°C and an additional hour at 0CC. The product is isolated by filtration and dried under reduced pressure for 3 hours at 50°C. The title compound is obtained (white crystals).
[α]D20– 19.3° (c=1 in chloroform) Mp: 138.2 – 138.8°C
The boran complex used as starting material can be obtained as follows:
200 ml of a solution of (3aR, 7R)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole (1M in toluene) is stirred at room temperature under nitrogen. 1.2 equivalent borane-dimethylsulfide complex is added with a syringe. The solution is stirred for 2 further hours at room temperature. The borane complex is then crystallised by addition of 4 vol dry hexane and cooling to -12°C for 1.5 hour. The product is isolated by filtration in a sintered glass funnel and dried in vacuum at 40°C. The boran complex is obtained /white crystals).
Copper histidinate, sold under the brand name Zycubo, is a medication used for the treatment of Menkes disease.[1] Copper histidinate is a copper replacement therapy given by subcutaneous injection.[1][2]
The most common side effects include infections, respiratory problems, seizures, vomiting, fever, anemia and injection site reactions.[2]
Copper histidinate was approved for medical use in the United States in January 2026.[2]
Menkes disease is a neurodegenerative disorder caused by a genetic defect that impairs a child’s ability to absorb copper.[2] The disease is characterized by seizures, failure to gain weight and grow, developmental delays, and intellectual disability.[2] It leads to abnormalities of the vascular system, bladder, bowel, bones, muscles, and nervous system.[2]
SYN
A275388 — Flores-Pulido AA, Jimenez-Perez VM, Garcia-Chong NR: Sintesis y uso de histidinato de cobre en ninos con enfermedad de Menkes en Mexico. Gac Med Mex. 2019;155(2):191-195. doi: 10.24875/GMM.18004310. [PubMed:31056589]
World Health Organization (2025). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 94”. WHO Drug Information. 39 (3). hdl:10665/383022.
Clinical trial number NCT00811785 for “Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency” at ClinicalTrials.gov
Baxdrostat is under investigation in clinical trial NCT06344104 (A Phase III Study to Investigate the Efficacy and Safety of Baxdrostat in Asian Participants With Uncontrolled Hypertension on Two or More Medications Including Participants With Resistant Hypertension).
In analogy to the procedures described for the preparation of intermediate A-2 [E] and for the preparation of intermediate B-1, Suzuki reaction of (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-3b) with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one and after subsequent reaction with propionyl chloride the title compound as colorless solid. MS: 364.2 (M+H +).
Dissolve 4-bromo-6,7-dihydroisoquinolin-8(5H)-one (1.56 g, 6.9 mmol) and (S)-tert-butylsulfenamide (2.51 g, 20.7 mmol) in 20 mL of tetrahydrofuran. Add ethyl titanate (10.08 mL, 48.28 mmol). Heat to 65°C and stir for 48 hours. Cool to room temperature, add ethyl acetate and water, stir for 15 minutes, and remove the resulting solid by filtration. Separate the liquids, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain the crude product (S,Z)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H)-tert-butylsulfenimide), which is used directly in the next step.
Step B
Compound (S,Z)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfonyl imide) (1.98 g, 6 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to -45°C. Sodium borohydride (0.34 g, 9.0 mmol) was added, and the mixture was allowed to return to room temperature and stirred for 18 hours. The mixture was quenched with ice water and extracted with dichloromethane. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to obtain compound (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonyl imide (755 mg, 38% yield). LC/MS (ESI): m/z = 331.2 [M+H] + .
Step C
To a mixture of (S)-N-(4-bromo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonimide (0.66 g, 2 mmol), pinacol diboronate (1.05 g, 2.1 mmol), and AcOK (0.578 g, 6 mmol) in toluene (10 mL) was added Pd(dppf)Cl 2 (0.144 g, 0.2 mmol). The mixture was degassed and stirred at 130 ° C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. EtOAc (15 mL) and water (10 mL) were added to the residue. The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 ) and eluted with 30-40% ethyl acetate in petroleum ether to afford (S)-N-tert-butylsulfonamido-6,7-dihydroisoquinolin-8(5H)-4-boronic acid pinacol ester (0.45 g, 60% yield). LC/MS (ESI): m/z = 378.3 [M+H] + .
Step D
To a reaction flask, add 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.29 g, 1.2 mmol), (S)-N-tert-butylsulfonamido-6,7-dihydroisoquinolin-8(5H)-4-boronic acid pinacol ester (0.42 g, 1.26 mmol), bistriphenylphosphine palladium dichloride (84 mg, 0.12 mmol), cuprous iodide (38 mg, 0.2 mmol), triethylamine (1.01 g, 10.0 mmol), and 15 mL of N,N-dimethylformamide. The atmosphere was purged with nitrogen three times and the reaction was stirred at 90°C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The resulting organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to afford (S)-2-methyl-N-((R)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)tert-butylsulfonimide (0.37 g, 74% yield) as a yellow solid. LC/MS (ESI): m/z = 411.5 [M+H] + .
Step E
Compound (S)-2-methyl-N-((R)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)tert-butylsulfonimide (0.33 g, 0.80 mmol) was dissolved in 1 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred and reacted for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by reverse preparative column chromatography to obtain compound (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.24 g, 97% yield). LC/MS (ESI): m/z = 307.1 [M+H] + .
Step F
To a reaction flask, add (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.33 mmol), triethylamine (51 mg, 0.5 mmol), and 4 ml of tetrahydrofuran. After cooling in an ice-water bath, slowly add a solution of propionyl chloride (46.25 mg, 0.5 mmol) in 0.5 ml of tetrahydrofuran dropwise. Stirring is continued for 4 hours after addition. The reaction mixture is quenched with methanol and evaporated to dryness under reduced pressure. The residue is purified by column chromatography to obtain the target compound, Baxdrostat (46 mg, 38% yield). LC/MS(ESI):m/z＝363.1[M+H]+.H NMR(400MHz, CDCl3)ppm 1.22(t,3H)1.79(s,3H)2.07(s,1H)2.28(q,2H)2.43-2.68(m,2H)2.71(t,2H)2.82-3.12(m,2H) 3.40(s,3H)5.34(d,1H)5.78(d,1H)7.05(d,1H)7.09(s,1H)7.17(d,1H)8.28(s,1H)8.49(s,1H)
Example 2
Step A
Compound (S)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H))-tert-butylsulfonylimide (1.65 g, 5 mmol) was dissolved in 20 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added. The mixture was stirred and reacted for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by reverse-phase preparative column chromatography to obtain compound (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (1.07 g, 94% yield). LC/MS (ESI): m/z = 226.0 [M+H] + .
Step B
To a mixture of (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (0.86 g, 3.8 mmol), pinacol diboron (2 g, 4 mmol), AcOK (1.10 g, 11.4 mmol) in toluene (10 mL) was added Pd(dppf)Cl 2 (0.27 g, 0.38 mmol). The mixture was degassed and stirred at 130 ° C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. EtOAc (10 mL) and water (10 mL) were added to the residue. The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 ) and eluted with 30-40% ethyl acetate in petroleum ether to afford (R)-8-amino-5,6,7,8-tetrahydroisoquinoline-4-boronic acid pinacol ester (0.68 g, 65% yield). LC/MS (ESI): m/z = 274.1 [M+H] + .
Step C
To a reaction flask, add 6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.72 g, 3.0 mmol), (R)-8-amino-5,6,7,8-tetrahydroisoquinolin-4-boronic acid pinacol ester (0.99 g, 3.6 mmol), bistriphenylphosphine palladium dichloride (210 mg, 0.3 mmol), and potassium phosphate monohydrate (204 mg, 0.9 mmol). Dissolve the mixture in dioxane and water (9:1, 30 mL). Replace the atmosphere with nitrogen three times and allow the mixture to react overnight at 90°C with stirring. Cool to room temperature, dilute the reaction solution with ethyl acetate and water, and extract with ethyl acetate. The resulting organic phase is then washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to obtain (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.81 g, 88% yield). LC/MS (ESI): m/z = 307.1 [M+H] + . The target compound, Baxdrostat, was then prepared using a method similar to the last step in Example 1.
Example 3
Step A
4-Bromo-6,7-dihydroisoquinolin-8(5H)-one (1.88 g, 6.9 mmol) and (S)-tert-butylsulfenamide (2.51 g, 20.7 mmol) were dissolved in 20 mL of tetrahydrofuran. Ethyl titanate (10.08 mL, 48.28 mmol) was added and the mixture was heated to 65°C with stirring for 48 hours. After cooling to room temperature, ethyl acetate and water were added and stirred for 15 minutes. The resulting solid was removed by filtration. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product (S,Z)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H)-tert-butylsulfenimide), which was used directly in the next step. LC/MS (ESI): m/z = 376.2 [M+H] + .
Step B
Compound (S,Z)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H)-tert-butylsulfonyl imide) (2.26 g, 6 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to -45°C. Sodium borohydride (0.36 g, 9.0 mmol) was added, and the mixture was allowed to return to room temperature and stirred for 18 hours. The mixture was quenched with ice water and extracted with dichloromethane. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to obtain compound (S)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonyl imide (1.04 g, 46% yield). LC/MS (ESI): m/z = 378.0 [M+H] + .
Step C
To a mixture of (S)-N-(4-iodo-6,7-dihydroisoquinoline-8(5H))-tert-butylsulfonimide (0.76 g, 2 mmol), pinacol diboronate (1.05 g, 2.1 mmol), and AcOK (0.578 g, 6 mmol) in toluene (10 mL) was added Pd(dppf)Cl 2 (0.144 g, 0.2 mmol). The mixture was degassed and stirred at 130 ° C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. EtOAc (15 mL) and water (10 mL) were added to the residue. The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 ) and eluted with 30-40% ethyl acetate in petroleum ether to afford (S)-N-tert-butylsulfonamido-6,7-dihydroisoquinolin-8(5H)-4-boronic acid pinacol ester (0.51 g, 68% yield). LC/MS (ESI): m/z = 378.2 [M+H] + .
The next three steps were carried out in the same manner as in Example 1 to prepare the target compound Baxdrostat.
A new treatment has been shown to significantly lower blood pressure in people whose levels stay dangerously high, despite taking several existing medicines, according to the results of a Phase III clinical trial led by a UCL Professor. Globally, around 1.3 billion people have high blood pressure (hypertension), and in around half of cases the condition is uncontrolled or treatment resistant. These individuals face a much greater risk of heart attack, stroke, kidney disease, and early death. In the UK the number of people with hypertension is around 14 million.
The international BaxHTN trial, led by Professor Bryan Williams (UCL Institute of Cardiovascular Science), assessed the new drug baxdrostat—which is taken as a tablet—with participation from nearly 800 patients across 214 clinics worldwide.
The trial results showed that, after 12 weeks, patients taking baxdrostat (1 mg or 2 mg once daily in pill form) saw their blood pressure fall by around 9-10 mmHg more than placebo—a reduction large enough to cut cardiovascular risk. About four in 10 patients reached healthy blood pressure levels, compared with fewer than two in 10 on placebo.
Principal Investigator, Professor Williams, who is presenting the results at ESC, said, “Achieving a nearly 10 mmHg reduction in systolic blood pressure with baxdrostat in the BaxHTN Phase III trial is exciting, as this level of reduction is linked to substantially lower risk of heart attack, stroke, heart failure and kidney disease.”
How baxdrostat works
Blood pressure is strongly influenced by a hormone called aldosterone, which helps the kidneys regulate salt and water balance.
Some people produce too much aldosterone, causing the body to hold onto salt and water. This aldosterone dysregulation pushes blood pressure up and makes it very difficult to control.
Addressing aldosterone dysregulation has been a key effort in research over many decades, but it has been so far difficult to achieve.
Baxdrostat works by blocking aldosterone production, directly addressing this driver of high blood pressure (hypertension).
Professor Williams, Chair of Medicine at UCL, said, “These findings are an important advance in treatment and in our understanding of the cause of difficult-to-control blood pressure.
“Around half of people treated for hypertension do not have it controlled, however this is a conservative estimate and the number is likely higher, especially as the target blood pressure we try to reach is now much lower than it was previously.
“In patients with uncontrolled or resistant hypertension, the addition of baxdrostat 1mg or 2mg once daily to background antihypertensive therapy led to clinically meaningful reductions in systolic blood pressure, which persisted for up to 32 weeks with no unanticipated safety findings.
“This suggests that aldosterone is playing an important role in causing difficult to control blood pressure in millions of patients and offers hope for more effective treatment in the future.”
Historically, higher-income Western countries were reported to have far higher levels of hypertension. However, largely due to changing diets (adding less salt to food), the numbers of people living with the condition is now far higher in Eastern and lower-income countries. More than half of those affected live in Asia, including 226 million people in China and 199 million in India.
Professor Williams added, “The results suggest that this drug could potentially help up to half a billion people globally—and as many as 10 million people in the UK alone, especially at the new target level for optimal blood pressure control.”
AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
Dogra S, Shah S, Gitzel L, Pusukur B, Sood A, Vyas AV, Gupta R (July 2023). “Baxdrostat: A Novel Aldosterone Synthase Inhibitor for Treatment Resistant Hypertension”. Current Problems in Cardiology. 48 (11): 101918. doi:10.1016/j.cpcardiol.2023.101918. PMID37399857. S2CID259320969.
Awosika A, Cho Y, Bose U, Omole AE, Adabanya U (October 2023). “Evaluating phase II results of Baxdrostat, an aldosterone synthase inhibitor for hypertension”. Expert Opinion on Investigational Drugs. 32 (11): 985–995. doi:10.1080/13543784.2023.2276755. PMID37883217. S2CID264517675.
Orforglipron has a half-life of 29 to 49 hours across the doses tested and is taken once per day by mouth without food or water restrictions.[3]
Safety and dosing trials showed that the incidence of adverse events in orforglipron-treated participants was 62–89%, mostly from gastrointestinal discomfort (44–70% with orforglipron, 18% with placebo) having mild to moderate severity.[6] The most common side effects of orforglipon are diarrhea, nausea, upset stomach, and constipation.[1][6]
The ability of orforglipron to reduce blood sugar levels and body weight was judged favorable compared to dulaglutide.[6]
Phase III ACHIEVE-1 trial
In April 2025, results from a Phase III clinical trial involving 559 people with type 2 diabetes who took an oral orforglipron pill, injectabledulaglutide or a placebo daily for 40 weeks showed that orforglipron produced a reduction in blood glucose levels by 1.3 to 1.6 percentage points from a starting level of 8%.[1][7]
More than 65% of participants taking the highest dose of orforglipron achieved a reduction of hemoglobin A1C level by more than or equal to 1.5 percentage points, bringing them into the non-diabetic range as defined by the American Diabetes Association.[1] People taking the highest dose of the pill lost 8% of their weight, or around 16 lb (7.3 kg), on average after 40 weeks.[1][8]
Side effects were similar to those seen with other GLP-1 agonists, and no significant liver problems were observed.[1]
^ Wharton S, Blevins T, Connery L, et al. (June 2023). “Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity”. The New England Journal of Medicine. 389 (10): 877–888. doi:10.1056/NEJMoa2302392. PMID37351564.
To treat platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer after one to three prior systemic treatment regimens, at least one of which included bevacizumab
Mechanism of ActionGlucocorticoid receptor antagonists
Orphan Drug StatusYes – Pancreatic cancer; Cushing syndrome
Phase IIICushing syndrome; Ovarian cancer; Pancreatic cancer
Phase IIFallopian tube cancer; Peritoneal cancer; Prostate cancer
Phase I/IISolid tumours
Phase IAdrenocortical carcinoma
Most Recent Events
09 Sep 2022Subgroup analysis efficacy data from a phase-II trial in Ovarian cancer presented at the 47th European Society for Medical Oncology Congress (ESMO-2022)
29 Jun 2022Phase-III clinical trials in Ovarian cancer (Combination therapy, Recurrent, Second-line therapy or greater) in USA (PO)
06 Jun 2022Corcept Therapeutics announces intentions to submit a NDA for Ovarian cancer
The drug was approved by the USFDA in 2026 for the treatment of platinum-resistant ovarian cancer.[3]
Relacorilant is an orally available antagonist of the glucocorticoid receptor (GR), with potential antineoplastic activity. Upon administration, relacorilant competitively binds to and blocks GRs. This inhibits the activity of GRs, and prevents both the translocation of the ligand-GR complexes to the nucleus and gene expression of GR-associated genes. This decreases the negative effects that result from excess levels of endogenous glucocorticoids, like those seen when tumors overproduce glucocorticoids. In addition, by binding to GRs and preventing their activity, inhibition with CORT125134 also inhibits the proliferation of GR-overexpressing cancer cells. GRs are overexpressed in certain tumor cell types and promote tumor cell proliferation.
OriginatorCorcept Therapeutics
DeveloperCorcept Therapeutics; University of Chicago
Mechanism of ActionGlucocorticoid receptor antagonists
Orphan Drug StatusYes – Pancreatic cancer; Ovarian cancer; Cushing syndrome
RegisteredFallopian tube cancer; Ovarian cancer; Peritoneal cancer
PreregistrationCushing syndrome
Phase IIIAdenocarcinoma
Phase IIProstate cancer
DiscontinuedAdrenocortical carcinoma
27 Mar 2026Discontinued – Phase-I for Adrenocortical carcinoma (Inoperable/Unresectable, Late-stage disease, Metastatic disease, Combination therapy) in USA (PO), before March 2026 (Corcept Therapeutics pipeline, March 2026)
27 Mar 2026Corcept Therapeutics plans the phase II STELLA trial for Cervical cancer (Combination therapy, Second-line therapy or greater) in first quarter of 2026
25 Mar 2026Registered for Fallopian tube cancer (Combination therapy, Second-line therapy or greater) in USA (PO) – First global approval
Relacorilant (CORT125134)118) is being developed by Corcept Therapeutics, Inc. It is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that may benefit from the modulation of cortisol activity. In structural optimization, the introduction of a trifluoromethyl group to the 4-position on the pyridyl moiety was found to increase HepG2 tyrosine amino transferase assay potency by a factor of four. Relacorilant is currently being evaluated in a phase II clinical study in patients with Cushing’s syndrome.119)
2-Bromo-4-(trifluoromethyl)pyridine (17) prepared from (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one is employed as a key intermediate for the preparation of relacorilant as shown in Scheme 31.120)
118) H. Hunt, T. Johnson, N. Ray and I. Walters (Corcept Therapeutics, Inc.): PCT Int. Appl. WO2013/177559 (2013).
119) H. J. Hunt, J. K. Belanoff, I. Walters, B. Gourdet, J. Thomas, N. Barton, J. Unitt, T. Phillips, D. Swift and E. Eaton: Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist. J. Med. Chem. 60, 3405–3421 (2017). [Abstract] [Google Scholar]
120) B. Lehnemann, J. Jung and A. Meudt (Archimica GmbH): PCT Int. Appl. WO 2007/000249 (2007).
The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushing’s syndrome. While this drug is highly effective, lack of selectivity for GR leads to unwanted side effects in some patients. Optimization of the previously described fused azadecalin series of selective GR antagonists led to the identification of CORT125134, which is currently being evaluated in a phase 2 clinical study in patients with Cushing’s syndrome.
Cushing’s syndrome (CS) is a metabolic disorder caused by chronic hypercortisolism. CS is associated with cardiovascular, metabolic, skeletal and psychological dysfunctions and can be fatal if left untreated. The first-line treatment for all forms of CS is a surgery. However, medical therapy has to be chosen if surgical resection is not an option or is deemed ineffective. Currently available therapeutics are either not selective and have side effects or are only available as an injection (pasireotide).
To treat hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer upon detection of ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy
ClassAmines; Antineoplastics; Azetidines; Fluorinated hydrocarbons; Isoquinolines; Pyrazolones; Pyridines; Small molecules
Mechanism of ActionSelective estrogen receptor degraders
Phase IIIBreast cancer, APPROVED FDA 2026
13 Jun 2022AstraZeneca initiates a phase I drug-drug interaction trial of AZD 9833 Healthy postmenopausal female volunteers, in USA (NCT05438303)
10 Jun 2022AstraZeneca and Quotient Sciences complete the phase I QSC205863 trial in Breast cancer (In volunteers) in United Kingdom (PO, Liquid) (NCT05364255)
03 Jun 2022Safety, efficacy and pharmacokinetics data from the phase I SERENA 1 trial for Breast cancer presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022)
Mechanism:selective estrogen receptor degrader
Area under investigation:estrogen receptor +ve breast cancer
Date commenced phase:Q1 2019
Estimated Filing Acceptance:
CountryDateUS: EU: Japan: China:
AZD9833 is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon administration, SERD AZD9833 binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This prevents ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells
Camizestrant is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon administration, camizestrant binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This prevents ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells
Camizestrant is an oral selective estrogen receptor degrader (ngSERD) and complete estrogen receptor (ER) antagonist.[2] It blocks the activity of estrogen receptor alpha encoded by both wild-type and mutated ESR1 and induces proteasome-dependent degradation of estrogen receptor alpha, without agonizing estrogen receptor alpha.[2]
Camizestrant was authorized for medical use in the European Union in July 2026,[2] and in the United States in September 2026.[1][5]
Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist J. Med. Chem. 2020, 63, 14530–14559, DOI: 10.1021/acs.jmedchem.0c01163.
SYN
doi: 10.1021/acs.jmedchem.0c01163.
aReagents and Conditions: (a) n-BuLi, THF, −78 oC to 0 oC, 1 h, then 4 N HCl/dioxane, RT, 1 h, 60%; (b) alkyl triflate, DIPEA, 1,4-dioxane, 90 oC, 63-74% or isobutyrylaldehyde, Na(OAc)3BH, THF, 0 oC, 56%; (c) benzophenone imine, Pd2dba3, Rac-BINAP, NaOtBu, toluene, 90 oC, then 1 N aq. HCl, 71-85%; (d) nBuLi, THF, −78 oC to 0 oC, 1 h, then 4 N HCl/dioxane, RT, 4 h; e) NH2OH, NH2OH.HCl, EtOH, reflux. 84% over 2 steps; (f) alkyl triflate, DIPEA, 1,4-dioxane, 90 oC, 44-100% or 1-fluorocyclopropane-1- carboxylic acid, HATU, Et3N, DMF, RT, 61%, then BH3.THF, THF, 65 oC, 82%.
AZD9833 is selective oestrogen receptor degrader (SERD). It works by breaking down the site where oestrogen attaches to the cancer cell. This can help stop or slow the growth of hormone receptor breast cancer. Researchers think that AZD9833 with palbociclib might work better than anastrozole and palbociclib.
AZD9833 + palbociclib
The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125 mg for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (1 mg, PO, once daily)
Camizestrant (AZD-9833) is a potent and orally active estrogen receptor (ER) antagonist. Camizestrant is used for the study of ER+ HER2-advanced breast cancer[1].
Camizestrant is extracted from patent US20180111931A1, example 17[1].MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
Camizestrant (oral administration; 0.2-50 mg/kg; 20 days) exhibits anti-tumour efficacy as a dose-dependent manner in human parental MCF7 mice xenograft[1]. Camizestrant (oral administration; 0.8-40 mg/kg; 30 days) decreases tumor growth as a dose-dependent manner. It gives almost complete tumour growth inhibition at the doses >10 mg/kg in mice[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Model:Human ESR1 mutant breast cancer patient derived xenograft with CTC174 cells in female NSG mice[1]Dosage:0.8 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kgAdministration:Oral administration; 30 days; once dailyResult:Inhibited tumor growth in a dose-dependent manner.
Clinical Trial
NCT NumberSponsorConditionStart DatePhaseNCT04711252AstraZenecaER-Positive HER2-Negative Breast CancerJanuary 28, 2021Phase 3NCT04964934AstraZenecaER-Positive HER2-Negative Breast CancerJune 30, 2021Phase 3NCT04214288AstraZenecaAdvanced ER-Positive HER2-Negative Breast CancerApril 22, 2020Phase 2NCT04588298AstraZenecaHER2-negative Breast CancerNovember 2, 2020Phase 2NCT04541433AstraZenecaER&addition; HER2- Advanced Breast CancerSeptember 29, 2020Phase 1NCT03616587AstraZenecaER&addition; HER2- Advanced Breast CancerOctober 11, 2018Phase 1NCT04546347AstraZeneca|Quotient SciencesHealthy VolunteersSeptember 17, 2020Phase 1NCT04818632AstraZenecaER&addition;, HER2-, Metastatic Breast CancerOctober 11, 2021Phase 1
“Etcamah EPAR”. European Medicines Agency (EMA). 22 May 2026. Retrieved 30 May 2026. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
“Etcamah PI”. Union Register of medicinal products. 22 July 2026. Retrieved 8 September 2026.
Scott JS, Moss TA, Balazs A, Barlaam B, Breed J, Carbajo RJ, et al. (December 2020). “Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist”. Journal of Medicinal Chemistry. 63 (23): 14530–14559. doi:10.1021/acs.jmedchem.0c01163. PMID32910656.
World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.
////////////Camizestrant, AZD 9833, AZ 14066724, UNII-JUP57A8EPZ, WHO 11592, PHASE 2, ASTRA ZENECA, CANCER, FDA 2026, APPROVALS 2026, Etcamah
Mechanism of ActionType 4 cyclic nucleotide phosphodiesterase inhibitors
RegisteredAtopic dermatitis
27 Sep 2021Registered for Atopic dermatitis (In adolescents, In children, In adults) in Japan (Topical)
11 Nov 2020Otsuka Pharmaceutical completes a phase III trial in Atopic dermatitis (In children, In adolescents, In adults) in Japan (Topical) (NCT03961529)
28 Sep 2020Preregistration for Atopic dermatitis in Japan (In children, In adolescents, In adults) (Topical)
Difamilast is under investigation in clinical trial NCT01702181 (A Safety Study to Evaluate the Use and Effectiveness of a Topical Ointment to Treat Adults With Atopic Dermatitis).
Synthesis of Oxazole Compound (Type A Crystal)
Compound (5) (white powder) was prepared in accordance with the method disclosed in Example 352 of PTL 1 (WO2007/058338).
Synthesis of difamilast commenced with the monobenzylated protocatechuic acid ethyl ester 15.1. Phenol 15.1 was first converted into the corresponding isopropyl ether, which was subsequently debenzylated under palladium-catalyzed hydrogenation conditions to generate the phenolic intermediate 15.3. Difluoromethylation of 15.3 was accomplished by introducing sodium chlorodifluoroacetate 15.4 in the presence of potassium carbonate at an elevated temperature. The decarboxylative C− O bond-forming reaction presumably proceeded via a difluorocarbene species. The difluoromethylated product was treated with acid followed by ester hydrolysis under a basic medium to furnish benzoic acid derivative 15.5. Benzoic acid 15.5 was subsequently transformed into benzamide 15.6 via a benzoyl imidazole intermediate. Condensation of benzamide 15.6 with 1-acetoxy-3-chloroacetone 15.7 produced an oxazole derivative, which was subsequently saponified and recrystallized from 50% aqueous MeOH to generate alcohol 15.8.
First, an activation−displacement process transformed alcohol 15.8 into bromide 15.9 via a mesylate intermediate. Alkyl bromide 15.9 was then treated with potassium phthalimide to incorporate the nitrogen center via an SN2-type displacement. Methylamine-mediated phthalimide deprotection and subsequent salt formation produced amine 15.11 as a hydrochloride salt in 69% yield over 3 steps. Finally, hydrochloride salt 15.11 was treated with aqueous sodium bicarbonate to generate a free amine, which was subjected to amide bond formation with 2-ethoxybenzoic acid 15.12 to deliver difamilast after recrystallization from aqueous EtOH.
Patent Documents 1 and 2 report an oxazole compound having a specific inhibitory action on phosphodiesterase 4 (PDE4) and a method for producing the same. PDE4 is the predominant PDE in inflammatory cells, inhibition of PDE4 increases intracellular cAMP concentration, and the increase in this concentration downregulates the inflammatory response through regulation of the expression of TNF-α, IL-23, and other inflammatory cytokines. .. Elevated cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, it is considered that the oxazole compound is suitable for use as an anti-inflammatory agent. For example, it may be useful for controlling skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound having a specific inhibitory effect on PDE4 and can be efficiently absorbed into the skin. The contents of Patent Documents 1 to 3 are incorporated in the present specification by reference.
[Synthesis of Oxazole Compound (Type A Crystal)]
Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007/088383).
[Preparation of B-type crystal 2]
Using the obtained B-type crystal as a seed crystal, it was examined to further prepare a B-type crystal. Specifically,
B-type crystals were prepared as follows according to the method described in Patent Document 3 (International Publication No. 2017/115780).
[0072]
[Chem. 6]
[0073]
Compound (1) 20.00 g (66.8 mmol) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate to cool the mixture, and 11.48 g (100 mmol) of methanesulfonyl chloride was introduced into the compound (1) at 10 to 30 ° C. Stir for hours. Subsequently, 17.41 g (200 mmol) of lithium bromide was added, and the mixture was stirred at 20 to 35 ° C. for 1 hour. 100 mL of water was added to the reaction solution to separate the layers, and the organic layer was concentrated under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve it, and the mixture was concentrated again under reduced pressure. 200 mL of N, N-dimethylformamide and 17.33 g (93.6 mmol) of phthalimide potassium were added to the concentrated residue, and the mixture was reacted at 75 to 85 ° C. for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals, and the precipitated crystals were collected by filtration and dried at 80 ° C. to obtain 27.20 g (yield 95.01%) of compound (3).
[0074]
[Chem. 7]
[0075]
Compound (3) 20.00 g (46.7 mmol), 40 mL of a 40% aqueous methylamine solution, 40 mL of methanol, and 100 mL of water were mixed and reacted under reflux for 30 minutes. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75 ° C. to separate the liquids. A mixed solution of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted again to 65 to 75 ° C. to separate the liquids. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. Precipitated crystals were collected by filtration to obtain 27.58 g of wet crystals of compound (4).
[0076]
Wet crystals (46.7 mmol) of compound (4) were mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and the mixture was stirred at 20 to 30 ° C. for 1 hour. To the reaction solution, 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) were added, and 20 to 30 were added. The reaction was carried out at ° C. for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50 ° C. to separate the solutions. 60 mL of water and 6 mL of a 25%
aqueous sodium hydroxide solution were added to the organic layer, the temperature was adjusted again to 40 to 50 ° C., the liquid was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. Activated carbon was removed by filtration, washed with 12 mL of ethanol, the filtrate was cooled, and 10 mg of B-type crystals (seed crystals) were added to precipitate crystals. Precipitated crystals were collected by filtration and dried at 60 ° C. to obtain 18.38 g (yield 88.18%) of crystals of compound (5).
Using the compound obtained in Example 347 and 2-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Production Example 1: Production 1 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.
[0146]
[Chem. 11]
[0147]
10.00 g (55.5 mmol) of compound (1a) and 9.20 g (66.6 mmol) of potassium carbonate were added to 40 ml of N,N-dimethylformamide and 6 ml of water, and the mixture was stirred until exotherm subsided. 16.92 g (111 mmol) of sodium chlorodifluoroacetate was added thereto, and the mixture was reacted at 95 to 110°C for 3 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the solution was partitioned. 80 ml of water was added again to the organic layer, followed by partitioning. 3 ml of concentrated hydrochloric acid was added to the organic layer, and the mixture was stirred at 60 to 70°C for 30 minutes. 40 ml of water and 10 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the mixture was partitioned. 5.93 g (61.1 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 22.08 g (61.0 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at a temperature of 20°C or below. The mixture was reacted at 20°C or below for 15 minutes, and 10 ml of a 25% sodium hydroxide aqueous solution was added dropwise thereto at a temperature of 20°C or below, followed by pouring in 83.95 g (66.6 mmol) of a 10% sodium sulfite aqueous solution. Additionally, 2 ml of concentrated hydrochloric acid was added and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue to dissolve the residue, and 5 ml of concentrated hydrochloric acid was added dropwise thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 11.81 g (yield: 86.4%) of compound (3) as a white powder.
Production Example 2: Production 2 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.
[0149]
[Chem. 12]
[0150]
10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of potassium carbonate, and 8.50 g (69.1 mmol) of isopropyl bromide were added to 40 ml of N,N-dimethylformamide, and the mixture was reacted at 75 to 85°C for 2 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the mixture was partitioned. 5.68 g (58.5 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 21.15 g (58.5 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at 20°C or below, followed by reaction for 15 minutes. 10 ml of a 25% sodium hydroxide aqueous solution was added thereto at 20°C or below, and subsequently 80.41 g (63.8 mmol) of a 10% sodium sulfite aqueous solution was poured in. Additionally, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue, and the residue was dissolved, followed by dropwise addition of 5 ml of concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 12.09 g (yield: 92.4%) of compound (3) as a white powder.
[0151]
Production Example 3: Production of Compound (7)
Compound (7) was produced in accordance with the following reaction scheme.
[0152]
[Chem. 13]
Production Example 4: Production of Compound (11)
Compound (11) was produced in accordance with the following reaction scheme.
[0160]
[Chem. 14]
[0161]
Synthesis of Compound (9)
20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white powder.
Synthesis of Compound (10)
15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, and reacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by partitioning. A mixture of 150 ml of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder.
Synthesis of Compound (11)
13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder.
Type B Crystal Preparation 2
Analysis was conducted to further prepare the type B crystal using the obtained type B crystal as a seed crystal. More specifically, the type B crystal was prepared as follows, in accordance with the method disclosed in PTL 3 (WO2017/115780).
[0072]
[0073]
20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto, and the mixture was stirred at 20 to 35°C for 1 hour. 100 mL of water was added to the reaction solution, and the mixture was separated, followed by concentration of the organic layer under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue, and reacted at 75 to 85°C for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 27.20 g (yield: 95.01%) of compound (3).
[0074]
[0075]
20.00 g (46.7 mmol) of compound (3), 40 mL of a 40% methylamine aqueous solution, 40 mL of methanol, and 100 mL of water were mixed and reacted for 30 minutes under reflux. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by separation. A mixture of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by separation. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, thereby obtaining 27.58 g of compound (4) as a wet crystal.
[0076]
The wet crystal (46.7 mmol) of compound (4) was mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and stirred at 20 to 30°C for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by separation. 60 mL of water and 6 mL of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% sodium hydroxide aqueous solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 12 mL of ethanol. The filtrate was cooled, and 10 mg of the type B crystal (a seed crystal) was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 18.38 g (88.18%) of compound (5).
PATENT
WO2014034958A1
WO2007058338A2
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WO2007058338A3
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US2017216260A1
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