Home » 2025 » May

Monthly Archives: May 2025

Lotilaner

May 31, 2025 2:58 am / Leave a comment

Lotilaner

CAS 1369852-71-0
Credelio
XDEMVY
lotilanerum
596.8 g/mol, C₂₀H₁₄Cl₃F₆N₃O₃S
TP 03
TP-03
TP03

3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]thiophene-2-carboxamide

FDA Xdemvy, 7/25/2023, To treat Demodex blepharitis
Drug Trials Snapshot

Lotilaner, sold under the brand name Xdemvy, is an ectoparasiticide (anti-parasitic) medication used for the treatment of blepharitis (inflammation of the eyelid) caused by infestation by Demodex (tiny mites).^[1]^[7] It is used as an eye drop.^[1]

It was approved for medical use in the United States in July 2023.^[1]^[7]^[8]^[9] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[10]

SYN

https://patents.google.com/patent/WO2022016490A1/en

Scheme 1

Scheme 1 depicts coupling the compound of formula (5) with an appropriate amine to give lotilaner. An appropriate amine refers to either 2-amino-2′, 2′, 2′-trifluoroethyl-acetamide or the sequential reaction of glycine optionally carboxyl protected, followed by coupling with 2, 2, 2-trifluorethylamine. Such coupling reactions of carboxylic acids or activated carboxylic acid derivatives such as acid halides with amines to form amides are well known in the art. The use of carboxyl protected glycine, deprotection, and an amide coupling with 2, 2, 2-trifluorethylamine is likewise readily accomplished. See WO 2010/070068 and WO 2014/090918.

Example 1

(5S) -3- (5-Bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H- isoxazole

Combined (Z/E) 1- (5-bromo-4-methyl-2-thienyl) -4, 4, 4-trifluoro-3- (3, 4, 5-trichlorophenyl) but-2-en-1-one (50.0 g, 104.5 mmol) and (R) – [ (2S) -1- [ [3, 5-bis (tert-butyl) phenyl] methyl] -5-vinyl-quinuclidin-1-ium-2-yl] – (6-methoxy-4-quinolyl) methanol bromide (0.11 eq. ) in dichloromethane (100 mL) and ethyl t-butyl ether (400 mL) . The reaction mixture was stirred at 30℃ for 30 minutes and then cooled to the range of-20℃ then slowly added a solution of hydroxylamine in water (50%, 40 mL, 313 mmol, 3.0 eq. ) and sodium hydroxide (34.5 mL, 345 mmol, 10 M, 3.3 eq. ) maintaining an internal temperature in the range of-15℃ to-20℃. After stirring 18 hours at-15℃ to-20℃ aqueous hydrochloric acid (1N, 500 mL) was added and the reaction mixture was stirred at 15℃ to 20℃ then the stirring was stopped and after 30 minutes the phases were separated. The organic layer was extracted with aqueous hydrochloric acid (1N, 75 mL) , the layers separated and the organic layer again extracted with aqueous hydrochloric acid (1N, 100 mL) . The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (75 mL) and the layers were separated and again the organic layer was extracted with saturated aqueous sodium bicarbonate (100 mL) . The layers were separated and the organic layer was dried over sodium sulfate (10 g) . The organic layer was filtered, the cake washed with ethyl t-butyl ether (50 mL) and then montmorillonite clay (50 g) was added and the mixture was stirred at 10℃ to 20℃. After 2 hours the reaction mixture was filtered, the cake rinsed with ethyl t-butyl ether (50 mL) and the filtrate was concentrated to about 100 mL, twice added THF and concentrated again to about 100 mL, and then added THF (150 mL) to obtain the title compound as a solution in THF. The solution was evaluated by chiral HPLC which indicated 96.5%S-isomer and 3.5%R-isomer.

Example 2

3-Methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3- yl] thiophene-2-carboxylic acid

A 22%solution of (5S) -3- (5-bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazole (185.0 g, 374.8 mmol) in THF was cooled to 0℃ to 5℃. A solution of ethyl magnesium chloride in THF (2 M, 300 mL, 1.6 eq) was added dropwise maintaining an internal temperature below 10℃. The reaction mixture was stirred at 15℃ to 20℃ for 2 to 4 hours. Then carbon dioxide gas (58 g, 3.5 eq) was introduced subsurface at 0℃ to 5℃ after passing through concentrated sulfuric acid (50 mL) . The reaction mixture was stirred at 0℃ to 5℃ for 2 hours and an 8%aqueous sodium chloride solution (601 g) was added dropwise at below 10℃, followed by addition of 37%aqueous HCl solution (92.5 g) at below 0℃. The reaction mixture was stirred at 10℃ to 15℃ for 30 minutes then the stirring was stopped and after 30 minutes the phases were separated. The organic layer was concentrated to about 370 mL under vacuum, followed by three iterations of THF (1850 mL) addition and concentration under vacuum to about 370 mL to 555 mL. After confirming the reaction mixture was dry, three cycles of acetonitrile (925 mL) addition followed by vacuum concentration to about 555 mL to 740 mL were performed. The reaction mixture was heated to 75℃ and gradually cooled to 50℃ over one hour. Product seeds (1.85 g) were added at 50℃ and the reaction mixture was stirred at 50℃ for 30 minutes. The batch was gradually cooled to-10℃ over three hours and kept at-10℃ for two hours. The batch was filtered and the cake was washed with cold acetonitrile (93 to 185 mL) . 110 g of the title compound was obtained after drying the wet cake at 50℃ under vacuum for 12 hours. The product was evaluated by chiral HPLC which indicated>99.9%S-isomer.

Above-referenced product seeds were prepared as follows. A solution of (5S) -3- (5-bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazole (48.93 g, 99.1 mmol) in 300mL of THF was cooled to 0℃ to 5℃. A solution of ethyl magnesium chloride in THF (2 M, 80 mL) was added dropwise maintaining an internal temperature below 10℃. The reaction mixture was stirred at 15℃ to 20℃ for 2 to 4 hours. Then carbon dioxide gas (25 g, 3.5 eq) was introduced subsurface at 0℃ to 5℃ after passing through concentrated sulfuric acid (50 mL) . The reaction mixture was stirred at 0℃ to 5℃ for 6 hours and an 5%aqueous sodium chloride solution (157 g) was added dropwise at below 10℃, followed by addition of 37%aqueous HCl solution (25 g) at below 0℃. The reaction mixture was stirred at 10℃ to 15℃ for 30 minutes then the stirring was stopped and after 30 minutes the phases were separated. The organic layer was concentrated to remove the solvent. 50ml of heptane was added into the mixture then removed the solvent. The crude product was dissolved in 50mL of EA and 100mL of heptane at 40℃. Additional 1000mL of heptane was charged dropwise into the mixture slowly. Then the mixture was stirred at 40℃ for 15h. The mixture was filtered and the wet cake was obtained. The wet cake was slurried by acetone at 20℃. The mixture was filter and the wet cake was dried at 50℃ under vacuum for 3h to afford 9.7g of product. The product was evaluated by chiral HPLC which indicated>99.9%S-isomer.

Example 3

3-Methyl-N- [2-oxo-2- (2, 2, 2-trifluoroethylamino) ethyl] -5- [ (5S) -5- (3, 4, 5-trichlorophenyl) – 5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxamide

A solution of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid (101.5 g, 221.3 mmol) in DCM (1000 mL) was heated to 40℃. Thionyl chloride (50 g, 1.9 eq) was added dropwise and the reaction mixture was stirred at reflux for 2 to 4 hours. The reaction mixture was concentrated to 100 to 200 mL and DCM (500 mL) was added. Two more cycles of concentration followed by DCM addition were performed. In a separate vessel, a suspension of 2-amino-trifluoroethyl-acetamide HCl (50.26 g, 1.2 eq) in DCM (500 mL) was cooled to 0℃ to 5℃, triethylamine (70.15 g, 3.1 eq) was added, and the reaction mixture was stirred at 0℃ to 5℃ for 30 minutes. The acid chloride solution in DCM was then transferred to the reaction mixture containing 2-amino-trifluoroethyl-acetamide maintaining the internal temperature below 5℃. The reaction mixture was stirred at 0℃ to 5℃ for 2 to 4 hours. 1 N HCl (500 mL) was added dropwise and the reaction mixture was stirred at 15 to 25℃ for 30 minutes. The stirring was stopped and after 30 minutes the phases were separated. The organic layer was extracted with saturated sodium bicarbonate solution (1N, 1000 mL) , the layers separated and the organic layer extracted with water (1000 mL) . The layers were separated and the organic layer was concentrated under vacuum to 200 to 300 mL. Twice ethyl acetate (500 mL) was added and the batch was concentrated to 200 mL. The reaction mixture was heated to 55℃ and n-heptane (700 mL) was added dropwise at 55℃. Product seeds (1.0 g) was added and the reaction mixture was stirred at 55℃ for one hour. n-Heptane (1000 mL) was added dropwise and the mixture was stirred at 55℃ for three hours. The batch was gradually cooled to 35℃ over three hours, then to 20℃ over three hours. The batch was filtered and the cake was washed with n-heptane (200 mL) . 113 g of the title compound was obtained after drying at 50℃ under vacuum for 12 hours.

Above-referenced product seeds are prepared as follows. The crude product was dissolved in 7.9 wt-parts of cumene to obtain a solution at<150℃. Then 2.3 wt-parts of heptanes was added to the hot solution until slight haze was observed. The heating was turned off and the mixture was cooled to ambient temperature and stirred overnight. The desired polymorph G was obtained as powder after filtration and drying under vacuum, which was used as seeds to induce crystallization of polymorph G in future batches.

PATENT

https://patents.google.com/patent/WO2017176948A1/en

PATENT

CN112457267

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN320823634&_cid=P10-MBBMZO-15915-1

REFSatish Kumar RangarajuSatish Kumar Rangaraju •

The first FDA-approved treatment for Demodex Blepharitis, a common eyelid disease caused by microscopic mites living in the eyelashes’ hair follicles. hashtag#Lotilaner
For more information blog:
https://lnkd.in/gFTeKEtv

Research

Tarsus Pharmaceuticals has conducted phase II studies of lotilaner as a remedy to prevent tick bites in humans.^[16]^[11]

References

^ Jump up to:^a ^b ^c ^d ^e “Xdemvy- lotilaner ophthalmic solution solution/ drops”. DailyMed. 26 July 2023. Retrieved 23 August 2023.
^ Jump up to:^a ^b ^c “Credelio- lotilaner tablet, chewable”. DailyMed. Archived from the original on 5 August 2021. Retrieved 4 August 2021.
^ Jump up to:^a ^b ^c “Credelio- lotilaner tablet, chewable”. DailyMed. Archived from the original on 5 August 2021. Retrieved 4 August 2021.
^ Jump up to:^a ^b “Credelio EPAR”. European Medicines Agency (EMA). 17 September 2018. Archived from the original on 27 January 2022. Retrieved 4 August 2021.
^ Jump up to:^a ^b ^c “Lotimax EPAR”. European Medicines Agency. 13 March 2024. Retrieved 20 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Lotimax Product information”. Union Register of veterinary medicinal products. 29 April 2024. Retrieved 29 August 2024.
^ Jump up to:^a ^b “Novel Drug Approvals for 2023”. U.S. Food and Drug Administration (FDA). 25 July 2023. Archived from the original on 21 January 2023. Retrieved 5 August 2023.
^ “Xdemvy: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Archived from the original on 27 July 2023. Retrieved 5 August 2023.
^ “FDA Approves Xdemvy (lotilaner ophthalmic solution) 0.25% for the treatment of Demodex blepharitis” (Press release). Tarsus Pharmaceuticals. 25 July 2023. Retrieved 5 August 2023 – via GlobeNewswire.
^ New Drug Therapy Approvals 2023. U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original (PDF) on 10 January 2024. Retrieved 9 January 2024.
^ Jump up to:^a ^b ^c “A Pill That Kills Ticks Is a Promising New Weapon Against Lyme Disease”. Wired. 15 March 2024. Retrieved 17 March 2024.
^ Jump up to:^a ^b “Lotimax PI”. Union Register of medicinal products. 29 April 2024. Retrieved 17 June 2024.
^ Kuntz EA, Kammanadiminti S (November 2017). “Safety evaluation of lotilaner in dogs after oral administration as flavoured chewable tablets (Credelio)”. Parasites & Vectors. 10 (1): 538. doi:10.1186/s13071-017-2468-y. PMC 5664904. PMID 29089043.
^ “Freedom Of Information Summary, Supplemental New Animal Drug Application, NADA 141-494, Credelio, Lotilaner, Chewable Tablets, Dogs”. 3 September 2019. Archived from the original on 18 May 2022. Retrieved 1 December 2019.
^ Jump up to:^a ^b “Credelio Plus EPAR”. European Medicines Agency. 19 February 2021. Archived from the original on 7 December 2022. Retrieved 4 August 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Tarsus Announces Positive Topline Results from Carpo, a Phase 2a Proof-of-Concept “Tick-Kill” Trial Evaluating TP-05 (lotilaner) for the Prevention of Lyme Disease (press release)”. Tarsus Pharmaceuticals. 22 February 2024. Archived from the original on 17 March 2024. Retrieved 17 March 2024.

Clinical data

Trade names	Credelio, Xdemvy, others
Other names	TP-03
AHFS/Drugs.com	Monograph
License data	US DailyMed: Lotilaner
Routes of administration	By mouth, eye drops
Drug class	Antiparasitic
ATC code	S01AX25 (WHO) QP53BE04 (WHO)
Legal status
Legal status	US: ℞-only^[1]^[2]^[3]EU: Rx-only^[4]^[5]^[6]
Identifiers
showIUPAC name
CAS Number	1369852-71-0
PubChem CID	76959255
DrugBank	DB17992
ChemSpider	32699771
UNII	HEH4938D7K
KEGG	D11212
ChEBI	CHEBI:229657
ChEMBL	ChEMBL3707310
CompTox Dashboard (EPA)	DTXSID701027551
Chemical and physical data
Formula	C₂₀H₁₄Cl₃F₆N₃O₃S
Molar mass	596.75 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

Toutain CE, Seewald W, Jung M: Pharmacokinetics of lotilaner following a single oral or intravenous administration in cats. Parasit Vectors. 2018 Jul 13;11(1):412. doi: 10.1186/s13071-018-2966-6. [Article]
Rufener L, Danelli V, Bertrand D, Sager H: The novel isoxazoline ectoparasiticide lotilaner (Credelio): a non-competitive antagonist specific to invertebrates gamma-aminobutyric acid-gated chloride channels (GABACls). Parasit Vectors. 2017 Nov 1;10(1):530. doi: 10.1186/s13071-017-2470-4. [Article]
Lamassiaude N, Toubate B, Neveu C, Charnet P, Dupuy C, Debierre-Grockiego F, Dimier-Poisson I, Charvet CL: The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis. PLoS Pathog. 2021 Feb 18;17(2):e1008863. doi: 10.1371/journal.ppat.1008863. eCollection 2021 Feb. [Article]
FDA Approved Drug Products: XDEMVY (lotilaner) 0.25%, Ophthalmic Solution (July 2023) [Link]
Business Wire: FDA Approves XDEMVY™ (lotilaner ophthalmic solution) 0.25% for the treatment of Demodex blepharitis [Link]
EMA Medicines Overview: Credelio [Link]

///////////Lotilaner, Xdemvy, FDA 2023, APPROVALS 2023, Credelio, XDEMVY, lotilanerum

Fexagratinib

May 30, 2025 2:58 am / Leave a comment

Fexagratinib

AZD 4547; ADSK091 cas 1035270-39-3

WeightAverage: 463.582
Monoisotopic: 463.258339943

Chemical FormulaC₂₆H₃₃N₅O₃

N-(5-(2-(3,5-DIMETHOXYPHENYL)ETHYL)-1H-PYRAZOL-3-YL)-4-((3R,5S)-3,5-DIMETHYLPIPERAZIN-1-YL)BENZAMIDE

N-{5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl}-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide

OriginatorAstraZeneca
DeveloperAbbisko Therapeutics; AstraZeneca; Dust Diseases Authority; Institute of Respiratory Health; National Cancer Institute (USA); University of Glasgow; University of Leeds; University of Wisconsin-Madison
ClassAntineoplastics; Benzamides; Phenyl ethers; Piperazines; Pyrazoles; Small molecules
Mechanism of ActionType 1 fibroblast growth factor receptor antagonists; Type 3 fibroblast growth factor receptor antagonists; Type-2 fibroblast growth factor receptor antagonists

Phase IIGastric cancer; Lymphoma; Multiple myeloma; Solid tumours; Urogenital cancer
PreclinicalSkin cancer
No development reportedLiver cancer
DiscontinuedBladder cancer; Breast cancer; Glioblastoma; Head and neck cancer; Lung cancer; Mesothelioma; Non-small cell lung cancer; Oesophageal cancer

13 Sep 2024Pharmacodynamics data from the preclinical studies in Solid tumours presented at the 49^th European Society for Medical Oncology Congress (ESMO-2024)
28 Feb 2024No recent reports of development identified for preclinical development in Liver-cancer in China (PO)
23 Jan 2024Preclinical trials in Solid tumours (Monotherapy) in China (PO) (Abbisko Therapeutics pipeline, January 2024)

Fexagratinib (AZD4547) is an experimental drug which acts as an inhibitor of the fibroblast growth factor receptors, having high affinity for FGFR1, FGFR2 and FGFR3 and weaker activity at FGFR4. It has reached clinical trials in humans against several forms of cancer, but has had only limited use as a medicine due to an unfavorable side effect profile, though it may have some applications in combination with other drugs. However it is still widely used in cancer research.^{[1][2][3][4][5]}

SCHEME

SIDECHAIN

MAIN

SYN

At present, the preparation of AZD4547 mainly includes the following methods:

(1) Patent application WO2008075068A1 discloses a preparation method comprising the following steps:

In the preparation method, AZD4547 is prepared by three-step reactions using ethyl 3-(3,5-dimethoxyphenyl)propionate as a raw material, wherein the first step reaction needs to be purified by column chromatography, and the yield is only 42%; the second step reaction requires reflux reaction for 24 hours, hydrazine hydrate is prone to explosion in high-temperature reactions, and hydrazine hydrate is a highly toxic and genotoxic reagent, and direct high-temperature reaction is not friendly to humans and the environment; the third step reaction also requires column chromatography purification, and the total yield of the three-step reaction for preparing AZD4547 is only 21.08%; therefore, the multi-step reactions of the preparation method require column chromatography operations, have poor safety, low yield, are not suitable for industrialization, and cannot solve the problem of drug accessibility.

(2) Patent application CN111072638A discloses another preparation method, comprising the following steps:

In this preparation method, 3-(3,5-dimethoxyphenyl)propionic acid is used as the starting material, and AZD4547 is prepared through a five-step reaction with a total yield of 42.5%. In this preparation method, highly toxic reagent ethyl cyanoacetate and expensive reagents palladium carbon, stannous chloride, and Raney nickel are required, and it is not suitable for industrial production.

(3) In addition, patent application WO2016137506A1 discloses a method for preparing AZD4547 key intermediate 3-(3,5-dimethoxyphenethyl)-1H-pyrazole-5-amine, as follows:

In this preparation method, the first step of the reaction uses ethanol reflux reaction, the second step of the reaction uses a large amount of solvent, and needs to be reacted at an ultra-low temperature of -78°C. After the reaction is completed, column chromatography purification is required, which is not suitable for industrial application.

CN115819239

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN394502634&_cid=P11-MBA7JR-97597-1

Example 1

Add isopropanol (300 mL) and 3-(3,5-dimethoxyphenyl)propionic acid (60.0 g, 0.285 mol) to a 1L three-necked reaction bottle, raise the temperature to 40±5°C, and stir for 5 to 10 minutes to dissolve. Add SOCl dropwise at 40±5°C.₂(37.3g, 0.314mol), the dropping time is ≥0.5 hours (the dropping process is obviously exothermic), after the dropping is completed, the temperature is raised to 60±5℃, the reaction is stirred for 1 hour, and the reaction of the raw materials is complete when HPLC is detected. The reaction solution is cooled to 35±5℃, the temperature is controlled below 50℃ and the solution is concentrated under reduced pressure until there is no obvious fraction, methyl tert-butyl ether (300mL) is added to dissolve, 5% potassium carbonate aqueous solution is added under ice bath to adjust the pH value of the reaction solution to 8-9, the temperature is controlled at 25±5℃ and stirred for 0.5 hours, the solution is allowed to stand and the organic phase is separated, washed with saturated brine, and the solution is concentrated under reduced pressure at 45℃ to dryness to obtain 72.1g of light yellow oily 3-(3,5-dimethoxyphenyl) propionic acid isopropyl ester, purity: 94%, yield: 94.3%.

¹HNMR(DMSO-d₆,400MHz)δ6.384-6.378(d,2H),6.318-6.306(t,1H),4.925-4.831(m,1H),3.706(s,6H),2.787-2.749(t,2H),2.571-2.533(t,2H),1.164-1.148(d,6H)。

Example 2

Under nitrogen protection, add isopropyl 3-(3,5-dimethoxyphenyl)propionate (20.0 g, 0.079 mol), anhydrous acetonitrile (80 ml), and anhydrous tetrahydrofuran (100 ml) to a 500 ml three-necked reaction bottle, cool the reaction solution to an internal temperature of about -20 ° C, slowly add lithium diisopropylamide (83 ml, 0.166 mol, 2M THF solution), and add the solution dropwise for about 25 minutes. Continue stirring for 5-10 minutes, and detect the reaction of the raw materials by HPLC. After the reaction mixture was completely dried, acetic acid solution (15 ml) was added to quench the reaction, the mixture was concentrated under reduced pressure, water (100 ml) was added, the pH was adjusted to neutral with 25% aqueous sodium carbonate solution, ethyl acetate (200 ml) was added for extraction (HPLC chart see Figure 2), the organic layer was concentrated under reduced pressure until there was no fraction, ethanol (200 ml) was added, stirred and slurried, filtered, and the filter cake was dried in vacuum at 45°C to obtain 14.8 g of 5-(3,5-dimethoxyphenyl)-3-oxopentanonitrile with a purity of 98% and a yield of 76%.

¹HNMR(DMSO-d₆,400MHz)δ6.370-6.364(s,2H),6.320-6.309(s,1H),4.038(s,2H),3.709(s,6H),2.851-2.815(t,2H),2.739-2.702(t,2H)。

After preliminary separation, the HPLC, LCMS and ¹ HNMR spectra of the impurity-containing mother liquor are shown in Figures 3-5. After analysis, the main impurity is generated by the self-polymerization of 5-(3,5-dimethoxyphenyl)-3-oxopentanonitrile, and the structure of the impurity compound [compound of formula (B’)] is as follows:

Example 3

Under nitrogen protection, 3-(3,5-dimethoxyphenyl)propionic acid isopropyl ester (11.29 g, 0.045 mol), anhydrous acetonitrile (40 ml) and anhydrous tetrahydrofuran (50 ml) were added to a 500 ml three-necked reaction bottle, the reaction solution was cooled to -20°C, diisopropylamide lithium tetrahydrofuran solution (47 ml, 0.094 mol) was slowly added dropwise, and the addition was completed in about 25 minutes. The reaction was continued with stirring for 5-10 minutes. HPLC detected that the raw material reaction was complete, anhydrous ethanol (20 ml) was added to quench the reaction, and 2-methyltetrahydrofuran (50 g) was added for extraction. The pH of the aqueous layer was adjusted to neutral with hydrochloric acid, filtered, and the filter cake was dried in vacuo at 45°C to obtain 9.28 g of 5-(3,5-dimethoxyphenyl)-3-oxopentanonitrile, purity: 99.5%, yield: 88.0%.

Example 4

Under nitrogen protection, a tetrahydrofuran solution containing isopropyl 3-(3,5-dimethoxyphenyl)propionate (120.0 g, 0.4756 mol), anhydrous acetonitrile (380 g, 9.25 mol), and anhydrous tetrahydrofuran (270 g) were added to a 3L three-necked reaction flask. The mixture was stirred until the internal temperature dropped to about -20°C. At this temperature, a tetrahydrofuran solution of lithium diisopropylamide (500 ml, 1 mol) was slowly added dropwise. After the addition was completed, the mixture was stirred at about -20°C for 1 minute. -2 hours, HPLC detected that the raw material was completely converted, ethanol (474g) was added to the reaction to quench the reaction, and the reaction was concentrated under reduced pressure. Purified water was added, the internal temperature was controlled at 0-15°C, HCl was slowly added, the pH was adjusted to 7.0, and a large amount of solid was precipitated. The reaction was stirred for 30 minutes and filtered, and the mixture was rinsed with purified water and ethanol in turn. The mixture was dried in vacuo at 45°C to obtain 98.7g of 5-(3,5-dimethoxyphenyl)-3-oxopentanonitrile with a purity of 99.6% and a yield of 89.0%.

In addition, the inventors investigated the effects of the reaction raw materials, anhydrous acetonitrile, alkaline reagent, and reaction temperature on the reaction. The purity and reaction phenomena in the HPLC test were as follows:

From the above experimental investigation factors and experimental phenomena, it can be seen that the types of ester groups of different reaction raw materials, the amount of acetonitrile and the alkaline reagent have the following effects on the reaction:

(1) Effect of the type of ester group in the reaction raw materials on the reaction

When the reaction raw material is a compound of formula (A’) having a methyl ester group, a sticky mass will be formed during the reaction, affecting stirring, and the purity of the reaction is not high. Specifically, at the beginning of the reaction, a sticky mass appears in the reaction liquid, affecting stirring. As the reaction proceeds, the reaction liquid gradually becomes sticky, and even sticks to the wall, making it impossible to stir.

When the reaction raw material is a compound of formula (A”) having an ethyl ester group, the reaction purity is increased to 87%, but sticky lumps are still formed during the reaction, affecting stirring. The specific situation is similar to that when the reaction raw material is a compound of formula (A’) having a methyl ester group.

The appearance of viscous clumps during process scale-up can easily lead to incomplete reactions, and may even cause dangerous situations such as entanglement of stirring blades and burning of motors. Therefore, the above two preparation processes are not suitable for industrial scale-up production.

When the ester structure of the reaction raw material is changed to isopropyl ester, the reaction liquid is homogeneously clear without sticky micelles, and the reaction control purity is increased to more than 97%, which is suitable for industrial scale-up production. The inventors analyzed that the above experimental phenomenon may be due to the higher stability of the isopropyl ester structure, which reduces the formation of side reactions.

(2) Effect of acetonitrile dosage on the reaction

In Experiment 6 and Experiment 3 of the present invention, when the molar ratio of acetonitrile to the reaction raw material increased from 10eq to 20eq, the reaction control purity increased from 90.4% to 97.2%.

Comparing Experiment 2 and Experiment 3 in Experiment 1, when the molar ratio of acetonitrile to the reaction raw material increased from 1.2eq to 25eq, the reaction control purity increased from 60.8% to 92.8%.

(3) Effect of the selection and dosage of alkaline reagents on the reaction

From the above experimental results, it can be seen that the reaction control purity of NaHMDS, LDA and n-BuLi is relatively high.

The optimal molar ratio of alkaline reagent to reaction raw materials is 2.1eq. A molar ratio lower than 2eq may result in incomplete reaction.

Example 5

Step 1: Synthesis of 5-(3,5-dimethoxyphenyl)-3-oxopentanonitrile (compound of formula (B))

Under nitrogen protection, add isopropyl 3-(3,5-dimethoxyphenyl)propionate (20.0 g, 0.079 mol), anhydrous acetonitrile (80 ml), and anhydrous tetrahydrofuran (100 ml) into a 500 ml three-necked reaction bottle, cool the reaction solution to -20°C, slowly add lithium diisopropylamide (83 ml, 0.166 mol, 2M THF solution) dropwise, add for about 25 min, stir and react for 5-10 minutes, HPLC detection shows that the raw material reaction is complete, add anhydrous ethanol (40 ml), concentrate under reduced pressure to a viscous state, add anhydrous ethanol (60 ml) to prepare an ethanol solution, and directly put into the next step reaction.

Step 2: Preparation of 3-(3,5-dimethoxyphenethyl)-1H-pyrazole-5-amine (compound of formula (C))

Add acetic acid (26.0 g, 0.436 mol), ethanol (100 ml), and 80% hydrazine hydrate (15.0 g, 0.238 mol) to a 500 ml three-necked reaction bottle, heat to an internal temperature of about 68°C, slowly add the product ethanol solution (18.5 g, 0.079 mol) obtained in step 1 to the mixed solution of acetic acid and hydrazine hydrate at this temperature, add for about 40 minutes, stir and react at an internal temperature of about 68°C for 1 hour, and HPLC detection shows that 5-(3,5-dimethoxyphenyl)-3-oxopentanonitrile is completely converted; the reaction solution is concentrated under reduced pressure, water (100 ml), ethyl acetate (200 ml), and about 25% Na₂CO₃(40ml) adjust the pH value of the water layer to 7-8; separate the water layer, wash the layers with saturated brine (20ml), concentrate the organic layer under reduced pressure until there is no fraction, add isopropyl acetate (100ml) and reduce the pressure to bring it to a viscous state, add isopropyl acetate (120ml) and heat to dissolve, cool and crystallize, filter at about 10°C, and dry under vacuum at 50°C to obtain 16.3g of 3-(3,5-dimethoxyphenethyl)-1H-pyrazole-5-amine with a purity of 99.6% and a total yield of 83% in two steps.

¹HNMR(DMSO-d₆,400MHz)δ6.370-6.364(s,2H),6.320-6.309(s,1H),4.038(s,2H),3.709(s,6H),2.851-2.815(t,2H),2.739-2.702(t,2H)。

In addition, the inventors investigated the effect of the amount of acetic acid used in this step of the reaction on the reaction, and the purity was controlled by HPLC as follows:

In addition, the inventors also investigated that the solid compound of formula (B) obtained after purification of the product in step 1 was reacted with hydrazine hydrate in the presence of acetic acid, and the compound of formula (B) was also completely converted to obtain a high-purity compound of formula (C).

Example 6

3-(3,5-dimethoxyphenethyl)-1H-pyrazole-5-amine (100.0 g, 0.4044 mol), ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (132.5 g, 0.5050 mol), and 2-methyltetrahydrofuran (1300 ml) were added to the reaction kettle, heated to 50-55°C and stirred for 1 hour, filtered through diatomaceous earth, and the filtrate was added to a clean reaction kettle, heated to atmospheric distillation with water, and the reaction temperature was controlled at 78°C-88°C, and 25% KO-tAm toluene solution (490.0 g) was slowly added dropwise for about 2 hours. After the addition was completed, the reaction temperature was adjusted to 83-88°C and stirred for 3-6 hours. Sampling was performed to detect whether the reaction of the raw materials was complete. The reaction system was cooled to 30-60°C, water (8 ml) was slowly added to quench the reaction, and the mixture was stirred at 30-60°C for 0.5 hour, then cooled to about 25°C, water (400 ml) was added, stirred and allowed to stand for stratification, the organic phase was separated, water (200 ml) was added, the mixture was heated to about 50°C and stirred for 0.5 hour, the water layer was separated, and this was repeated 2-3 times until the pH of the water layer was 7.0-9.5; the organic layer was concentrated under reduced pressure to remove part of the solvent, the residue was heated to 80-90°C and stirred for 1 hour, slowly cooled to 20-30°C, stirred for 2-5 hours, filtered, rinsed twice with ethyl acetate, and dried in vacuo at 45°C to obtain 155.6 g of a white amorphous solid product (AZD4547) with a purity of 98.5% and a yield of 83%.

¹HNMR(DMSO-d₆,400MHz)δ12.067(s,1H),10.275(s,1H),7.888-7.867(d,2H),6.943-6.922(d,2H),6.437-6.409(m,3H),6.317(s,1H),3.712-3.692(m,8H),2.861-2.803(m,6H),2.230-2.174(m,3H),1.036-1.020(d,6H)。

Example 7

3-(3,5-dimethoxyphenethyl)-1H-pyrazole-5-amine (10.0 g, 0.040 mol), ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (12.1 g, 0.047 mol), anhydrous tetrahydrofuran (170 ml) were added to the reaction bottle, heated and distilled at atmospheric pressure until about 100 ml remained, cooled to -30°C to -20°C, and NaHMDS (0.125 mol, 63 ml, 2M THF solution) was slowly added dropwise. The temperature of the reaction system was controlled at about -25°C and stirred for 20 minutes. HPLC detected that the raw materials were basically reacted. Water (30 ml) was slowly added under temperature control to quench, and glacial acetic acid (about 10 ml) was added to neutralize. The temperature was raised to about 0°C and stirred, and 20% Na₂CO₃(10ml), concentrated under reduced pressure until there is no fraction, added ethyl acetate (120ml) to the residue, heated to about 45°C, stirred and separated, the organic phase was separated, added with saturated brine (30ml), washed once, concentrated under reduced pressure to leave about (30ml), then added ethyl acetate (30ml), concentrated under reduced pressure again, repeated twice, a large amount of solid precipitated, added ethyl acetate to a material volume of about 50ml, stirred at 0-10°C for 1 hour, filtered, and dried in vacuo at 45°C to obtain 16.87g of white amorphous solid product (AZD4547) with a purity of 99.8% and a yield of 91%.

Heterocycles (2020), 100(2), 276-282 ,

CN111072638

PATENT

CN115819239

Nature Catalysis (2021), 4(5), 385-394

Shandong Huagong (2021), 50(7), 19-21

CN111072638

Heterocycles (2020), 100(2), 276-282

Physical Chemistry Chemical Physics (2020), 22(17), 9656-9663

Journal of Chemical Theory and Computation (2019), 15(2), 1265-1277

Journal of Medicinal Chemistry (2017), 60(14), 6018-6035

Bioorganic & Medicinal Chemistry Letters (2016), 26(20), 5082-5086

WO2016089208

WO2008075068

References

^ Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, et al. (April 2012). “AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family”. Cancer Research. 72 (8): 2045–2056. doi:10.1158/0008-5472.CAN-11-3034. PMID 22369928.
^ Katoh M, Nakagama H (March 2014). “FGF receptors: cancer biology and therapeutics”. Medicinal Research Reviews. 34 (2): 280–300. doi:10.1002/med.21288. PMID 23696246.
^ Katoh M (July 2016). “FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review)”. International Journal of Molecular Medicine. 38 (1): 3–15. doi:10.3892/ijmm.2016.2620. PMC 4899036. PMID 27245147.
^ Zengin ZB, Chehrazi-Raffle A, Salgia NJ, Muddasani R, Ali S, Meza L, et al. (February 2022). “Targeted therapies: Expanding the role of FGFR3 inhibition in urothelial carcinoma”. Urologic Oncology. 40 (2): 25–36. doi:10.1016/j.urolonc.2021.10.003. PMID 34840077.
^ Zarei P, Ghasemi F (2024). “The Application of Artificial Intelligence and Drug Repositioning for the Identification of Fibroblast Growth Factor Receptor Inhibitors: A Review”. Advanced Biomedical Research. 13: 9. doi:10.4103/abr.abr_170_23. PMC 10958741. PMID 38525398.

Identifiers

showIUPAC name
CAS Number	1035270-39-3
PubChem CID	51039095
IUPHAR/BPS	7707
DrugBank	DB12247
ChemSpider	26333104
UNII	2167OG1EKJ
ChEBI	CHEBI:63453
ChEMBL	ChEMBL3348846
PDB ligand	66T (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID80145887
ECHA InfoCard	100.206.232
Chemical and physical data
Formula	C₂₆H₃₃N₅O₃
Molar mass	463.582 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

////////////Fexagratinib, AZD 4547, ADSK091

GDC 0853, Fenebrutinib

May 29, 2025 11:14 am / Leave a comment

GDC 0853, Fenebrutinib

Ritlecitinib, PF 06651600

May 29, 2025 3:02 am / Leave a comment

Ritlecitinib, PF 06651600

ETRIPAMIL

May 28, 2025 2:57 am / Leave a comment

ETRIPAMIL

CAS 1593673-23-4

AS ACETATE 512.64 CAS 2891832-59-8

HCL SALT 2560549-35-9

WeightAverage: 452.595
Monoisotopic: 452.267507647

Chemical FormulaC₂₇H₃₆N₂O₄

Benzoic acid, 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-, methyl ester

methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-methylamino]ethyl]benzoate

Methyl 3-[2-[[(4S)-4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]benzoate
(-)-MSP 2017
MSP 2017

OriginatorMilestone Pharmaceuticals
DeveloperCorxel Pharmaceuticals; Milestone Pharmaceuticals
ClassAmines; Antiarrhythmics; Benzoates; Esters; Ischaemic heart disorder therapies; Small molecules
Mechanism of ActionCalcium channel antagonists

PreregistrationParoxysmal supraventricular tachycardia
Phase IIAtrial fibrillation
Phase IUnspecified
No development reportedAngina pectoris

14 May 2025Milestone Pharmaceuticals has patent protection for etripamil in the USA
28 Mar 2025Milestone pharmaceuticals plans to request a Type A meeting with USFDA to discuss the issues raised in the complete response letter
28 Mar 2025USFDA has issued a Complete Response Letter (CRL) regarding New Drug Application (NDA) for Etripamil for Paroxysmal supraventricular tachycardia

Etripamil has been used in trials studying the treatment of Paroxysmal Supraventricular Tachycardia (PSVT).

Etripamil (MSP-2017) is a short-acting, L-type calcium-channel antagonist. Etripamil inhibits calcium influx through slow calcium channels, thereby slowing AV node conduction and prolonging the AV node refractory period. Etripamil increases heart rate and decreases systolic blood pressure. Etripamil can be used in the study of paroxysmal supraventricular tachycardia (PSVT).

SCHEME

SIDE CHAIN

MAIN

SYN

US20180110752/ U.S. Patent No. 10,117,848,

EXAMPLES

Example 1: Synthesis methyl 3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate

Part I: Synthesis of 5-Bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile

(MOL) (CDX)

Method A, Step 1:

To a solution of 9.99 g (56.4 mmol) of (3,4-Dimethoxyphenyl)acetonitrile in 141 mL of tetrahydrofuran (THF) at −30° C., was slowly added 56.4 mL (56.4 mmol) of sodium bis(trimethylsilyl)amide ( NaHMDS, 1.0 M in THF). The mixture was stirred at −30° C. for 10 minutes and 10.6 mL (113.0 mmol) of 2-bromopropane was added. The mixture was heated to reflux for 2 hours (h) then left at 22° C. for about 16 h. A saturated aqueous solution of NH₄Cl was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried ( Na₂SO₄), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile as an oil.

Method A, Step 2:

To a solution of 11.21 g (51.1 mmol) of 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile in 126 mL of tetrahydrofuran (THF) at −30° C., was slowly added 46.0 mL (46.0 mmol) of sodium bis(trimethylsilyl)amide ( NaHMDS, 1.0 M in THF). The mixture was stirred at −30° C. for 10 minutes and 9.40 mL (256 mmol) of 1,3-dibromopropane was added dropwise. The mixture was warmed to 22° C. and stirred for about 16 h. A saturated aqueous solution of NH₄Cl was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried ( Na₂SO₄), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give 5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile as an oil.

Part II: Synthesis of methyl 3-(2-(methylamino)ethyl)benzoate

(MOL) (CDX)

To a solution of 5.71 g (24.9 mmol) of methyl 3-bromomethylbenzoate in 36 mL of methanol was added 2.11 g (32.4 mmol) of potassium cyanide. The mixture was refluxed for about 16 h, cooled to 22° C. and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 15% ethyl acetate/hexane to give methyl 3-(cyanomethyl)benzoate.

To a solution of 1.31 g (7.48 mmol) of methyl 3-(cyanomethyl)benzoate in 31 mL of THF stirred at −10° C. was slowly added 710 mg (18.7 mmol) of sodium borohydride followed by 1.44 mL (18.7 mmol) of trifluoroacetic acid. The mixture was warmed to 22° C. and stirred for about 16 h. About 100 mL of water was carefully added to the mixture (gas evolution). The mixture was extracted with ethyl acetate (5×50 mL). The organic phase was washed with brine, dried ( Na₂SO₄), filtered and evaporated to give methyl 3-(2-aminoethyl)benzoate which was used in the next step without purification.

Method B:

To 5.12 g (28.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 71 mL tetrahydrofuran (THF) was added 7.48 g (34.3 mmol) of BOC ₂O. The mixture was stirred for about 16 h at 22° C. and 100 mL of water was added. The mixture was extracted with ethyl acetate (2×100 mL) and the organic phase was washed with brine, dried ( Na₂SO₄) and evaporated. The residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 20% ethyl acetate/hexane to give methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate which was further converted to III by Method C (described below).

Method C, Step 1:

To a solution of methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate in dry THF under a nitrogen atmosphere was added dropwise NaHMDS (1.0 M in THF) at 0° C. After stirring for 10 min, dimethyl sulfate was added and the reaction was warmed to 22° C. and stirred for about 16 h. The reaction was quenched by adding 25 mL of saturated NaHCO₃ and the mixture was extracted with DCM (2×25 mL). The combined organic extracts were dried ( Na₂SO₄) and evaporated and the residue was purified by flash chromatography on silica gel, eluting first with hexane and then gradually increasing to 10% ethyl acetate/hexane to give methyl 3-(2-(tert-butoxycarbonyl(methyl)amino) ethyl)benzoate.

Method C, Step 2:

To a solution of methyl 3-(2-(tert-butoxycarbonyl(methyl)amino) ethyl)benzoate in DCM at 0° C. was added trifluoroacetic acid (TFA). The reaction was warmed to 22° C., stirred for 3 h and the solvents were then evaporated. The residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1 N NaOH which had been saturated with NaCl. The aqueous layer was back-extracted with ethyl acetate (6×50 mL) and the combined organics were dried ( Na₂SO₄) and evaporated to give 2c as a colorless oil.

Part III: Reaction of Compound II with Compound III Produced Compound I

Analysis of the product by mass spectrometry revealed a peak with a mass-to-charge ratio (m/z) of 453, corresponding to the M+H molecular ion of compound I.

Example 2: Concentrated Solution of Acetate Salt of Compound I

A concentrated aqueous solution of the acetate salt of compound I is formed according to the following protocol:

An aqueous solution of 7.5 M sulfuric acid is first made by diluting concentrated sulfuric acid in water and manually mixing in a sealed bottle, periodically venting the pressure by releasing the bottle cap. Separately, 175±1.0 g of compound I is dispensed from a pre-heated container into a glass bottle and maintained at a temperature of 50±2° C. in a water bath. Next, 96.7±0.2 mL of a 4.0 M acetic acid solution is added to compound I, followed by 83.3 mL±0.2 mL of a 31.8 mM solution of EDTA. The mixture containing the (−) enantiomer (S-enantiomer) of compound I is maintained at 50±2° C. and stirred using a magnetic stir bar during both additions. Heating and stirring is continued until the compound appears to be fully dispersed throughout the mixture.

Upon complete dispersion of compound I, the solution of 7.5 M sulfuric acid is added drop-wise to the compound I mixture until a pH of 5.0±0.1 is reached. At this point, heating is discontinued and the mixture continues to stir. The mixture is then allowed to cool to within 2° C. of ambient temperature. A solution of 0.9 M sulfuric acid is then added drop-wise to the mixture until a pH of 4.5±0.1 is reached. The mixture containing compound I is then diluted to 90% of the final target volume by the addition of water to the mixture, and the pH is monitored after this dilution. If necessary, the pH is lowered back to 4.5±0.1 by drop-wise addition of 0.9 M sulfuric acid. The mixture is then diluted to the final target volume by the addition of water.

This protocol readily can be adapted to provide a concentrated solution of the methanesulfonate salt of compound I.

PATENT

PRED BY CHIRAL SEPERATION

US20230065401

WO2016165014

EP4119137 chiral sepn done

[0034] In one embodiment the present invention is a kit for treating a cardiac arrhythmia (e.g., PSVT or atrial fibrillation), angina, or a migraine in a subject in need thereof wherein the kit comprises a nasal delivery system comprising two doses of a therapeutically effective amount of compound I having a structure according to the formula:

and instructions for nasally administering to the subject (i) a first dose, and, optionally, (ii) a second dose of an aqueous composition comprising a pharmaceutically acceptable acetate or methanesulfonate salt of compound I, or a racemate or enantiomer thereof, wherein the acetate or methanesulfonate salt of compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of 350 mg/mL± 50 mg/mL, and wherein the second dose of the compound is to be administered between 5 minutes and 60 minutes after the first dose.

Cross ref U.S. Patent No. 10,117,848,

[0336]

1. A method of treating a cardiac arrhythmia in a subject in need thereof with a therapeutically effective amount of compound I having a structure according to the formula:

the method comprising nasally administering to the subject (i) a first dose, and (ii) a second dose of an aqueous composition comprising a pharmaceutically acceptable acetate or methanesulfonate salt of compound I, or a racemate or enantiomer thereof, wherein the acetate or methanesulfonate salt of compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of 350 mg/mL ± 50 mg/mL, and wherein the second dose of the compound is administered between 5 minutes and 25 minutes after the first dose.

PATENT

Journal of the American College of Cardiology (2018), 72(5), 489-497

American Heart Journal (2022), 253, 20-29

Expert Opinion on Investigational Drugs (2020), 29(1), 1-4

EP4119137 WO2016165014

WO2023108146

EP-2170050-B1

US-9737503-B2

US-4968717-A

EP-0231003-A2

[1]. Stambler BS, et al. Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm. J Am Coll Cardiol. 2018 Jul 31;72(5):489-497. [Content Brief][2]. Milestone Pharmaceuticals Announces USAN Approval of Generic Name “Etripamil” for its Phase 2 Clinical Development Product for the Treatment of Paroxysmal Supraventricular Tachycardia.[3]. Ascah A, et al. Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys. Int J Toxicol. 2025 Apr 1:10915818251327963. [Content Brief][4]. Pion J, et al. Preclinical Safety Evaluation of Etripamil Nasal Spray in Cynomolgus Macaques (Macaca fascicularis) to Assess for Safety in Patients With Paroxysmal Supraventricular Tachycardia. Int J Toxicol. 2024 Sep-Oct;43(5):503-510. [Content Brief]

//////////ETRIPAMIL, (-)-MSP 2017, MSP 2017

Ervogastat

May 27, 2025 3:04 am / Leave a comment

Ervogastat

CAS 2186700-33-2

Non-alcoholic Steatohepatitis (NASH) with Liver Fibrosis (FAST TRACK – U.S.)

2-[5-[(3-Ethoxy-2-pyridinyl)oxy]-3-pyridinyl]-N-[(3S)-tetrahydro-3-furanyl]-5-pyrimidinecarboxamide
(S)-2-(5-((3-Ethoxypyridin-2-yl]oxy]pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide
PF 06865571
BSOIY5AKQW
407.4 g/mol, C₂₁H₂₁N₅O₄

2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-[(3S)-oxolan-3-yl]pyrimidine-5-carboxamide

OriginatorPfizer
ClassAmides; Ethers; Furans; Hepatoprotectants; Pyridines; Pyrimidines; Small molecules
Mechanism of ActionDiacylglycerol O-acyltransferase inhibitors

Phase IINon-alcoholic fatty liver disease; Non-alcoholic steatohepatitis

08 Jan 2025Chemical structure information added.
21 Feb 2024Pfizer completes a phase II trial in Non-alcoholic steatohepatitis (Combination therapy) in Slovakia, Japan, Bulgaria, Canada, China, Hong Kong, India, Poland, Puerto Rico, South Korea, Taiwan (PO) (NCT04321031) (EudraCT2019-004775-39)
21 Feb 2024Pfizer completes a phase II trial in Non-alcoholic steatohepatitis (Monotherapy) in Slovakia, Japan, Bulgaria, Canada, China, Hong Kong, India, Poland, Puerto Rico, South Korea, Taiwan (PO) (NCT04321031) (EudraCT2019-004775-39)

Ervogastat is an experimental small-molecule drug and selective diacylglycerol O-acyltransferase 2 inhibitor developed by Pfizer for non-alcoholic steatohepatitis.^[1] Its development was previously halted by the company but resumed in 2022.^[2]

Scheme

SIDE CHAIN

MAIN

https://doi.org/10.1021/acs.jmedchem.2c01200

SYN

WO2023026180

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023026180&_cid=P11-MB5XF4-40032-1

Preparation of Intermediates and Examples

Preparation of Intermediate 1 and Example 1 (Forms 1 and 2) were described in WO2018/033832 and are reproduced below.

Intermediate 1 : 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid

Step 1 : 3-Ethoxypyridine

Cesium carbonate (12 mol, 1.5 equiv) and ethyl iodide (9.7 mol, 1.2 equiv) were added to a solution of 3-hydroxypyrdine (8.10 mol, 1.0 equiv) in acetone (12 L) at 15 °C. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the organic layer was concentrated to give crude product. Ethyl acetate (20 L) was added and washed with water (3×5 L). The organic layer was dried over sodium sulfate, filtered and concentrated to give 3-ethoxypyridine (620 g, 62%) as an oil. ¹H NMR (400 MHz, CDCh) 5 1.44 (t, 3H), 4.07 (q, 2H), 7.15-7.23 (m, 2H), 8.20 (dd, 1 H), 8.30 (d, 1 H).

Step 2: 3-Ethoxypyridine-1 -oxide

m-Chloroperoxybenzoic acid (6.5 mol, 1.3 equiv) was added to a solution of 3-ethoxypyridine (5.0 mol, 1.0 equiv) in dichloromethane (12 L) at 10 °C. The reaction mixture was stirred at room temperature for 24 hours. Sodium thiosulfate (4 kg, in 5 L of water) was added. The reaction mixture was stirred at 15 °C for 2 hours. Another portion of sodium thiosulfate (1.5 kg, in 5 L of water) was added. The reaction mixture was stirred at 15 °C for 1 hour. The mixture was extracted with dichloromethane (16×10 L). The combined organic layers were concentrated to give crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol; 100:1-10:1) to give the title compound (680 g, 97%) as brown oil. This was further purified by trituration with petroleum ether (4 L) at room temperature for 24 hours to give 3-ethoxypyridine-1 -oxide (580 g, 83%) as yellow solid. ¹H NMR (400 MHz, CDCh) 5 1.41 (t, 3H), 4.02 (q, 2H), 6.84 (dd, 1 H), 7.12 (dd, 1 H), 7.85 (d, 1 H), 7.91-7.95 (m, 1 H).

Step 3: 2-((5-Bromopyridin-3-yl)oxy)-3-ethoxypyridine

This reaction was carried out in five parallel batches.

Diisopropylethylamine (2.69 mol, 3.7 equiv) and bromotripyrrolidinophosphonium hexafluorophosphate (0.93 mol, 1.3 equiv) were added to a stirred solution of 3-ethoxypyridine-1-oxide (0.72 mol, 1.0 equiv) and 3-bromo-5-hydroxypyridine (0.72 mol, 1.0 equiv) in tetrahydrofuran (2500 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 days then the separate batches were combined to a single batch. The resulting suspension was concentrated to dryness and dissolved in dichloromethane (25 L). The organic layer was washed with 1 N sodium hydroxide (15 L), water (3×20 L), and brine (20 L). The organic layer was dried over sodium sulfate, filtered and concentrated to give an oil. The crude oil was purified by silica gel column chromatography (petroleum ether : ethyl acetate; 10:1-1 :1) to give crude product as brown solid. This solid was triturated with methyl tert-butyl ether: petroleum ether (1 :10; 11 L) to afford 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (730 g, 69%) as off yellow solid. ¹H NMR (400 MHz, CDCh) 5 1.49 (t, 3H), 4.16 (q, 2H), 7.04 (dd, 1 H), 7.25 (dd, 1 H), 7.68-7.73 (m, 2H), 8.44 (d, 1 H), 8.49 (d, 1 H). MS (ES+) 297.1 (M+H).

Step 4: Ethyl 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate

A solution of 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (300 mmol, 1.0 equiv) in tetrahydrofuran (1.3 L) was degassed with nitrogen for 30 minutes. Turbo Grignard

(390 mmol, 1.3 equiv, 1.3 M in tetrahydrofuran) was added at room temperature at a rate to maintain the internal temperature below 30 °C. The reaction mixture was allowed to cool to room temperature and stirred for 3 hours. The reaction was cooled to 10 °C and zinc chloride (390 mmol, 1.3 equiv, 1.9 M in 2-methyltetrahydrofuran) was added at a rate to maintain the temperature below 15 °C. The resulting suspension was warmed to room temperature until all the precipitate was dissolved and then cooled back to 10 °C. Ethyl 2-chloropyrimidine-5-carboxylate (360 mmol, 1.2 equiv) and dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(ll) (6.00 mmol, 0.02 equiv) were added as solids. The resulting suspension was degassed with nitrogen for 30 minutes then heated to 50 °C for 16 hours. The reaction was worked up under aqueous conditions then treated sequentially with ethylenediaminetetraacetic acid disodium salt, thiosilica, and charcoal to remove metal impurities. The crude compound was recrystallized from methanol (450 mL) to yield ethyl 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate (77 g, 70%) as a pale, yellow solid. ¹H NMR (400 MHz, CDCI3) 5 1.44 (t, 3H), 1.50 (t, 3H), 4.19 (q, 2H), 4.46 (q, 2H), 7.00-7.04 (m, 1 H), 7.25 (s, 1 H), 7.71 (d, 1 H), 8.59 (s, 1 H), 8.66 (d, 1 H), 9.32 (s, 2H), 9.55 (s, 1 H).

Step 5: 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid

Sodium hydroxide (307 mmol, 1.5 equiv, 4M aqueous) and methanol (50 mL) were added to a suspension of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate (205 mmol, 1.0 equiv) in tetrahydrofuran (300 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (400 mL) and extracted with 2:1 diethyl ether: heptanes (2x 300 mL). The aqueous layer was acidified to pH of 4 with 4M hydrochloric acid. The resulting suspension was stirred at room temperature for 1 hour. The solid was filtered, washed with water, and dried to yield 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid (69 g, 100%) as a pale, yellow solid. ¹H NMR (400 MHz, DMSO-de) 51.37 (t, 3H), 4.18 (q, 2H), 7.19 (dd, 1 H), 7.58 (dd, 1 H), 7.70 (dd, 1 H), 8.35-8.40 (m, 1 H), 8.66 (d, 1 H), 9.33 (s, 2H), 9.41 (d, 1 H), 13.9 (br. s, 1 H).

Example 1 : (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-/V-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide

Preparation of Form 1 of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-/\/- (tetrahydrofuran-3-yl)pyrimidine-5-carboxamide

Oxalyl chloride (13.8 mL, 160 mmol, 1.2 equiv) and dimethylformamide (0.510 mL, 6.65 mmol, 0.05 equiv) were added to a suspension of 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid (45.0 g, 133 mmol, 1.0 equiv) in dichloromethane (500 mL). The suspension was stirred for 2 hours when a solution was achieved. The reaction mixture was concentrated to yield crude acid chloride as a red solid. A solution of (S)-tetrahydrofuran-3-amine (12.2 g, 140 mmol, 1.05 equiv) and diisopropylethylamine (51.0 mL, 293 mmol, 2.2 equiv) in tetrahydrofuran (100 mL) was added dropwise to a solution of the crude acid chloride in dichloromethane (200 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 hours. Water (1.0 L) and ethyl acetate (600 mL) were added and the organic layer was separated, washed with saturated sodium bicarbonate, dried over magnesium sulfate, and filtered. The filtrate was treated with activated charcoal (20 g) was stirred at 65 °C for 20 minutes. The suspension was filtered warm and filtrate was concentrated to a pale, yellow solid which was recrystallized from methanol in ethyl acetate (1 :4, 1 L) to yield (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-/\/-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide (43.5 g, 81%) as a colorless solid. The title compound was combined with previous batches (108.7 g, 266.8 mmol) prepared in the same manner and slurried with ethyl acetate (1 .0 L) at 80 °C for 4 hours. The suspension was allowed to cool to room temperature and stirred for 4 days. The solid was filtered, washed with ethyl acetate (3×200 mL) and dried under high vacuum at 50 °C for 24 hours to yield (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-/\/-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide (100.5 g, 92%) as a colorless solid. ¹H NMR (300 MHz, DMSO-de) 5 1.38 (t, 3H), 1.89-1.98 (m, 1 H), 2.15-2.26 (m, 1 H), 3.65 (dd, 1 H), 3.70-3.78 (m, 1 H), 3.85-3.92 (m, 2H), 4.18 (q, 2H), 4.46-4.55 (m, 1 H), 7.18 (dd, 1 H), 7.58 (dd, 1 H), 7.69 (dd, 1 H), 8.37 (dd, 1 H), 8.64 (d, 1 H), 8.95 (d, 1 H), 9.28 (s, 2H), 9.39 (d, 1 H). MS (ES+) 408.4 (M+H). Melting point 177.5 °C. Elemental analysis for C21H21N5O4: calculated C, 61.91 ; H, 5.20; N, 17.19; found C, 61.86; H, 5.18; N, 17.30.

PATENT

WO2020234726

WO2020044266

WO2018033832

WO2021171164

compound 6 [PMID: 34635855]

US10071992, Example 1

US10071992, Example 3.4

WO2016036636 EG 1

References

^ Futatsugi, Kentaro; Cabral, Shawn; Kung, Daniel W.; Huard, Kim; Lee, Esther; Boehm, Markus; Bauman, Jonathan; Clark, Ronald W.; Coffey, Steven B.; Crowley, Collin; Dechert-Schmitt, Anne-Marie; Dowling, Matthew S.; Dullea, Robert; Gosset, James R.; Kalgutkar, Amit S.; Kou, Kou; Li, Qifang; Lian, Yajing; Loria, Paula M.; Londregan, Allyn T.; Niosi, Mark; Orozco, Christine; Pettersen, John C.; Pfefferkorn, Jeffrey A.; Polivkova, Jana; Ross, Trenton T.; Sharma, Raman; Stock, Ingrid A.; Tesz, Gregory; Wisniewska, Hanna; Goodwin, Bryan; Price, David A. (24 November 2022). “Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis”. Journal of Medicinal Chemistry. 65 (22): 15000–15013. doi:10.1021/acs.jmedchem.2c01200. PMID 36322383. S2CID 253257260.
^ “With the right partner, Pfizer gains fast-track tag for previously shelved NASH drug”. Retrieved 20 November 2023.

Clinical data

Other names	PF-06865571
Legal status
Legal status	Investigational
Identifiers
showIUPAC name
CAS Number	2186700-33-2
PubChem CID	134262752
ChemSpider	114929473
UNII	BSOIY5AKQW
ChEMBL	ChEMBL4760665
Chemical and physical data
Formula	C₂₁H₂₁N₅O₄
Molar mass	407.430 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

////////////Ervogastat, PF 06865571, fast track, BSOIY5AKQW, PFIZER, PHASE 2,

Flotufolastat F 18

May 26, 2025 1:30 pm / Leave a comment

Flotufolastat F 18

Flotufolastat F-18 Gallium
POSLUMA
CAS 2305081-64-3
18FrhPSMA-7.3
18F-rhPSMA-7.3
1537.3 g/mol
C₆₃H₉₆FGaN₁₂O₂₅Si

gallium;2-[7-[(1S)-1-carboxy-4-[[(2R)-1-[[(1R)-1-carboxy-5-[[4-[[(4R)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(1S)-1,3-dicarboxypropyl]carbamoylamino]butanoyl]amino]butyl]amino]-4-oxobutanoyl]amino]pentyl]amino]-3-[[4-[ditert-butyl(fluoranyl)silyl]benzoyl]amino]-1-oxopropan-2-yl]amino]-4-oxobutyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate

WeightAverage: 1470.63
Monoisotopic: 1469.662295938

Chemical FormulaC₆₃H₉₉FN₁₂O₂₅Si

2639294-14-5 CAS

FDA 2023, Posluma, 5/25/2023, To use with positron emission tomography imaging in certain patients with prostate cancer
Drug Trials Snapshot

Flotufolastat (¹⁸F), sold under the brand name Posluma, is a radioactive diagnostic agent for use with positron emission tomography (PET) imaging for prostate cancer.^[1] The active ingredient is flotufolastat (¹⁸F).^[1]

Flotufolastat (¹⁸F) was approved for medical use in the United States in May 2023.^[1]^[2]

SYNTHESIS

Bejot, R., et al. (2022). Methods of preparation of 18F labelled silyl-fluoride compounds (WO 2023047138 A1). World Intellectual Property Organization. https://patents.google.com/patent/WO2023047138A1/en?oq=WO2023047138A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023047138&_cid=P12-MB54HA-36492-1

EXAMPLES

rhPMSA-7, rhPMSA-10 & 2C013

Synthesis protocols for the ¹⁹F compounds ¹⁹F-rhPSMA-7.1 , ¹⁹F-rhPSMA-7.2, ¹⁹F-rhPSMA-7.3, ¹⁹F-rhPSMA-7.4, ¹⁹F-rhPSMA-10.1 , ¹⁹F-rhPSMA-10.2 and ¹⁹F-2C013 (shown below) are provided in WO2019/020831 , W02020/157177, WO2020/157184 and EP21157154.2.

rhPMSA-7.1

rhPMSA-7.2

rhPMSA-7.4

2C013

¹⁸F-Fluorination of rhPSMA-7.3

Aqueous ¹⁸F’ was passed through a quaternary methyl ammonium carbonate anion exchange cartridge (Sep-Pak Accell Plus QMA Carbonate), which was preconditioned with 5 mL of water. ¹⁸F’ was eluted with a 15 mg/mL cryptand 222 and 2.0 mg/mL potassium carbonate solution in acetonitrile/water (9/1 v/v). The resulting [¹⁸F]fluoride, cryptand and potassium carbonate solution was then azeotropically dried by heating at approx. 100 °C. Before radiolabelling, a 160 mM solution of acetic acid in DMSO was used to dissolve 0.27 pmol of rhPSMA-7.3. The resulting rhPSMA-7.3 solution was added to azeotropically-dried [¹⁸F]fluoride and the reaction mixture was incubated for 5 minutes at room temperature. For purification, a solid-phase extraction cartridge containing a hydrophobic resin (Sep-Pak Plus Short tC18 cartridge), preconditioned with 5 mL EtOH, followed by 10 mL of H2O was used. The labelling mixture was diluted with 5 mL citrate buffer (pH 5) and passed through the cartridge followed by 24 mL of citrate buffer. The ¹⁸F-rhPSMA-7.3 was eluted with 3 mL of a 1 :1 mixture (v/v) of EtOH in water.

Previously the process made use of oxalic acid and the impact of oxalic acid content, with on-cartridge drying of alkaline [¹⁸F]fluoride/K222, on radionuclide incorporation with rhPSMA-7.3 and similar silicon-fluorine acceptors (Kostikov, A. P. et al. Bioconjugate Chem. 2012, 23, 106-114) was evaluated. Maximum ¹⁸F-radiolabelling was reached when using approx.

30 pmol oxalic acid for 90 pmol of potassium hydroxide (acid-base molar ratio -0.6:1) (Wurzer, A. et al. EJNMMI radiopharm. chem. 6, 4 (2021)).

Although used in a limited quantity, oxalic acid may be toxic. Hence further development was conducted to replace oxalic acid with acetic acid, a common excipient for parenteral administration. Therefore, oxalic acid (dicarboxylic acid, 30 pmol) was replaced with 2 molar equivalents of acetic acid (monocarboxylic acid 60 pmol) and was shown to yield ¹⁸F-rhPSMA- 7.3 successfully using the Scintomics GRP synthesis module.

Implementation of the process with azeotropic drying of [¹⁸F]fluoride requires inverse addition, i.e., addition of acidified precursor solution to alkaline [¹⁸F]fluoride/K222 instead of addition of alkaline [¹⁸F]fluoride/K222 to the acidic precursor solution. As shown in Figure 1 , a higher amount of acid was required to prevent isomerisation of ¹⁸F-rhPSMA-7.3 or ¹⁹F-rhPSMA-7.3 in the presence of carbonate to related Compound A shown below. A decrease of radiolabelling conversion was also observed with increasing acid content. The optimised acetic acid amount for each process is provided in Table 1.

Compound A

Table 1 : Nominal acetic acid amounts for ¹⁸F-radiolabelling

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 : Impact of acetic acid content on isomerisation (formation of Related Compound A) and yield.

Medical uses

Flotufolastat (¹⁸F) is indicated for positron emission tomography of prostate-specific membrane antigen positive lesions in men with prostate cancer.^[1]^[3]

References

^ Jump up to:^a ^b ^c ^d ^e “Posluma- flotufolastat f-18 injection”. DailyMed. 2 June 2023. Retrieved 25 June 2023.
^ “U.S. FDA Approves Blue Earth Diagnostics’ Posluma (Flotufolastat F 18) Injection, First Radiohybrid PSMA-targeted PET Imaging Agent for Prostate Cancer” (Press release). Blue Earth Therapeutics. 30 May 2023. Retrieved 25 June 2023 – via Business Wire.
^ Heo YA (September 2023). “Flotufolastat F 18: Diagnostic First Approval”. Molecular Diagnosis & Therapy. 27 (5): 631–636. doi:10.1007/s40291-023-00665-y. PMID 37439946. S2CID 259843992.

External links

Clinical trial number NCT04186819 for “Imaging Study to Investigate the Safety and Diagnostic Performance of rhPSMA 7.3 (18F) in Newly Diagnosed Prostate Cancer (LIGHTHOUSE)” at ClinicalTrials.gov
Clinical trial number NCT04186845 for “Imaging Study to Investigate Safety and Diagnostic Performance of rhPSMA 7.3 (18F) PET Ligand in Suspected Prostate Cancer Recurrence (SPOTLIGHT)” at ClinicalTrials.gov

Clinical data
Flotufolastat F-18 gallium
Trade names	Posluma
Other names	18F-rhPSMA-7.3, flotufolastat F18 (USAN US)
License data	US DailyMed: Flotufolastat f-18
Routes of administration	Intravenous
ATC code	V09IX18 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	2639294-14-5
PubChem CID	166177191
DrugBank	DB17851
UNII	811W19E3OL
KEGG	D12606
Chemical and physical data
Formula	C₆₃H₉₉¹⁸FN₁₂O₂₅Si
Molar mass	1537.3 g·mol⁻¹
3D model (JSmol)	Interactive image Interactive image
showSMILES
showInChI

/////////Flotufolastat F 18, Posluma, FDA 2023, APPROVALS 2023, Flotufolastat F-18 Gallium, 18FrhPSMA-7.3, 18F-rhPSMA-7.3

ELUBIOL

May 25, 2025 2:56 am / Leave a comment

ELUBIOL

Dichlorophenyl imidazoldioxolan

CAS 67914-69-6

Elubiol
67914-69-6
OristaR DCI
Dichlorophenyl imidazoldioxolan
(+/-)-Dichlorophenyl imidazoldioxolan

AMY 925
C₂₇H₃₀Cl₂N₄O₅, 561.5 g/mol

ethyl 4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine-1-carboxylate

Elubiol (Dichlorophenyl imidazoldioxolan) has moderate sebum-inhibiting activity and can be used in the treatment of oily skin or dandruff.

SCHEME

PATENT

DE2804096

https://patentscope.wipo.int/search/en/detail.jsf?docId=DE102084041&_cid=P20-MB323Q-91006-1

PATENT

US4358449

https://patentscope.wipo.int/search/en/detail.jsf?docId=US37288536&_cid=P20-MB3265-92366-1

PATENT

CN102070620

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN84648943&_cid=P20-MB329Q-94515-1

Example 1

According to the method of the present invention, bacteriostatic ester (±) cis-4-[4-[[2-(2,4-dichlorophenyl)-2-(1-H-imidazolemethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinecarboxylic acid ethyl ester is prepared, comprising the following steps:

1. Condensation reaction

In a dry 500ml three-necked flask, add 473g of dimethyl sulfoxide, 130g of active lipid, 50g of N-(4-hydroxyphenyl)piperazine, and 21g of potassium hydroxide. Control the temperature at 30℃ and keep the reaction for 24 hours. After the reaction, add 520g of purified water. After the addition is completed, cool to 5℃, stir and keep warm for 2h, and filter to obtain the antibacterial ester condensate. The condensation yield is about 85%.

2. Esterification reaction

In a three-necked flask, 322g of dichloromethane, 50g of antibacterial ester condensate, and 52g of potassium carbonate were added, and then 11.9g of ethyl chloroformate was slowly added. After the addition was completed, the temperature was controlled at 25°C and the reaction was kept warm for 4 hours. After the reaction was completed, 108g of purified water was slowly added. After the addition was completed, stirring was continued for 2h. The organic layer was washed three times with purified water until the pH reached 7. After washing, dichloromethane was evaporated under reduced pressure. After evaporation, 60ml of methyl isobutyl ketone was added and the temperature was kept at 0-5°C for 2-4h. The antibacterial ester was obtained by suction filtration, and the esterification yield was about 80%.

Heat the antibacterial ester and dissolve it in 8 times the amount of acetone, add 0.5 times the amount of activated carbon, reflux and keep warm for 0.5 hours, cool down to no reflux, filter and remove the activated carbon, concentrate the filtrate to 5 times the weight of the antibacterial ester, add water and cool down to 0-5°C after concentration, keep warm for 1-3 hours under stirring, and filter to obtain an off-white crystalline powder. After analysis, the antibacterial ester content is greater than 97%.

PATENT

CN101665490

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN83857361&_cid=P20-MB32BE-95479-1

Synthesis of 4-(4-hydroxyphenyl)piperazine:

Example 1

In a 1000ml reaction bottle, under nitrogen protection, add 500g of water, 178.5g of dichloroethylamine hydrochloride and 109g of p-hydroxyaniline, heat to 100°C, add 160g of 50% sodium hydroxide solution (80g of sodium hydroxide dissolved in 80g of water), reflux for 10 hours. Then cool to 35°C, add 400g of methanol, adjust the pH value to 8 with ammonia water, filter, and dry the filter cake in vacuum at 40°C to obtain 128g of 4-(4-hydroxyphenyl)piperazine (HPLC content greater than 98%), with a yield of 71.9%.

Example 2

In a 1000ml reaction bottle, under nitrogen protection, add 500g of water, 178.5g of dichloroethylamine hydrochloride and 218g of p-hydroxyaniline, heat to 70°C, add 112g of 50% potassium hydroxide solution (56g of potassium hydroxide dissolved in 56g of water), and react for 5 hours. Then cool to 35°C, add 400g of methanol, adjust the pH value to 8 with ammonia water, filter, and dry the filter cake in vacuum at 40°C to obtain 112g of 4-(4-hydroxyphenyl)piperazine (HPLC content greater than 98%), with a yield of 62.9%.

Example 3

In a 1000ml reaction bottle, under nitrogen protection, add 500g of water, 312g of dichloroethylamine hydrobromide and 150g of p-hydroxyaniline, stir at room temperature (25°C), add 200g of 50% potassium bicarbonate solution (100g of potassium bicarbonate dissolved in 100g of water), react for 1 hour, then cool to 35°C, add 400g of methanol, adjust the pH value to 8 with ammonia water, filter, and dry the filter cake in vacuum at 40°C to obtain 87g of 4-(4-hydroxyphenyl)piperazine (HPLC content greater than 98%), with a yield of 48.8%.

Example 4

In a 1000ml reaction bottle, under nitrogen protection, add 500g of water, 452g of dichloroethylamine hydroiodide and 327g of p-hydroxyaniline, heat to 100°C, add 480g of 50% sodium hydroxide solution (240g of sodium hydroxide dissolved in 240g of water), reflux for 10 hours. Then cool to 35°C, add 600g of methanol, adjust the pH value to 8 with ammonia water, filter, and dry the filter cake in vacuum at 40°C to obtain 154g of 4-(4-hydroxyphenyl)piperazine (HPLC content greater than 98%), with a yield of 86.5%.

Synthesis of Ethyl [4-(4-Hydroxyphenyl)]-1-piperazinecarboxylate

Example 5

In a 2000 ml reaction bottle, add 178 g of 4-(4-hydroxyphenyl)piperazine, 150 g of sodium bicarbonate and 500 g of acetone, cool to -20°C with ice brine, add 110 g of ethyl chloroformate dropwise, and keep the temperature in the bottle not higher than zero degrees. After the addition is complete, heat to room temperature and react for 5 hours;

Add 700g of water, stir for 1 hour and filter. Add the filter cake obtained by filtration to a 1000ml reaction bottle, add 300g of 75% ethanol solution by volume, heat to dissolve, cool to zero degrees with ice brine, filter, and dry the filter cake in vacuum at 40°C to obtain 146g of [4-(4-hydroxyphenyl)]-1-piperazinecarboxylic acid ethyl ester (HPLC content greater than 99%), 58.4%.

Example 6

In a 2000ml reaction bottle, add 178g of 4-(4-hydroxyphenyl)piperazine, 180g of sodium carbonate and 500g of acetone, cool to -10°C with ice brine, add 165g of ethyl chloroformate dropwise, and keep the temperature in the bottle not higher than zero degrees. After the addition is complete, heat to 50 degrees and react for 1 hour;

Add 700g of water, stir for 1 hour and filter. Add the filter cake obtained by filtration to a 1000ml reaction bottle, add 300g of 75% ethanol solution by volume, heat to dissolve, cool to zero degrees with ice brine, filter, and dry the filter cake in vacuum at 40°C to obtain 156g of [4-(4-hydroxyphenyl)]-1-piperazinecarboxylic acid ethyl ester (HPLC content greater than 99%), 62.4%.

Example 7

In a 2000ml reaction bottle, add 178g of 4-(4-hydroxyphenyl)piperazine, 400g of potassium bicarbonate and 1000g of acetone, cool to 0°C with ice brine, add 440g of ethyl chloroformate dropwise, and keep the temperature in the bottle not higher than zero degrees. After the addition is completed, react at about 0°C for 10 hours;

Add 1000g of water, stir for 1 hour and filter. Add the filter cake obtained by filtration to a 1000ml reaction bottle, add 500g of 75% ethanol solution by volume, heat to dissolve, cool to zero degrees with ice brine, filter, and dry the filter cake in vacuum at 40°C to obtain 216g of [4-(4-hydroxyphenyl)]-1-piperazinecarboxylic acid ethyl ester (HPLC content greater than 99%), 86.4%.

Example 8

In a 2000ml reaction bottle, add 178g of 4-(4-hydroxyphenyl)piperazine, 140g of triethylamine, and 500g of acetone; cool to -10°C with ice brine, add 110g of ethyl chloroformate dropwise, and keep the temperature in the bottle not higher than zero degrees. After the addition is complete, react at -10°C for 10 hours;

Add 700g of water, stir for 1 hour and filter. Add the filter cake obtained by filtration to a 1000ml reaction bottle, add 300g of 75% ethanol solution by volume, heat to dissolve, cool to zero degrees with ice brine, filter, and dry the filter cake in vacuum at 40°C to obtain 126g of [4-(4-hydroxyphenyl)]-1-piperazinecarboxylic acid ethyl ester (HPLC content greater than 99%), 50.4%.

Synthesis of Ketoconazole Derivatives:

Example 9

In a 1000ml reaction bottle, add 45g of cis-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-yl-methyl)-1,3-dioxopentyl]-4-methyl-p-toluenesulfonate, 25g of ethyl [4-(4-hydroxyphenyl)]-1-piperazinecarboxylate, 5.6g of potassium hydroxide and 180g of dimethyl sulfoxide; react at 25°C for 20 hours. After the reaction, add 450g of ice water to the reaction bottle to reduce the temperature in the reaction bottle to 10°C, and filter; wash the filter cake with water until it is neutral and dry; obtain 42g of crude ketoconazole derivative (HPLC content is 94%).

In a 1000ml reaction bottle, add 42g of crude ketoconazole derivative and 350g of ethyl acetate, heat to dissolve, add 0.5g of activated carbon, reflux for half an hour, filter, wash the filter cake with hot ethyl acetate, combine the ethyl acetate, and concentrate to 230g; cool naturally to room temperature, then continue to cool to 0°C with ice water, and keep warm for 1 hour, filter, and vacuum dry to obtain 39g of white powder (HPLC content greater than 99%), with a yield of 73.6%.

Example 10

In a 1000 ml reaction bottle, add 45 g of cis-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-yl-methyl)-1,3-dioxolane]-4-methyl-p-toluenesulfonate, 50 g of ethyl [4-(4-hydroxyphenyl)]-1-piperazinecarboxylate, 11.2 g of sodium hydroxide and 200 g of dioxane; react at 50° C. for 10 hours. After the reaction, add 450 g of ice water to the reaction bottle to reduce the temperature in the reaction bottle to 10° C. and filter; wash the filter cake with water until it is neutral and dry; obtain 41 g of crude ketoconazole derivative (HPLC content is 94%).

In a 1000ml reaction bottle, add 41g of crude ketoconazole derivative and 340g of ethyl acetate, heat to dissolve, add 0.5g of activated carbon, reflux for half an hour; filter, wash the filter cake with hot ethyl acetate, combine ethyl acetate, and concentrate to 230g; cool naturally to room temperature, then continue to cool to 0°C with ice water, and keep warm for 1 hour, filter, and vacuum dry to obtain 37g of white powder (HPLC content greater than 99%), with a yield of 69.8%.

Embodiment 11

In a 1000ml reaction bottle, add 45g of cis-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-yl-methyl)-1,3-dioxopentyl]-4-methyl-p-toluenesulfonate, 100g of ethyl [4-(4-hydroxyphenyl)]-1-piperazinecarboxylate, 22.4g of sodium methoxide and 300g of tetrahydrofuran; react at 0°C for 50 hours. After the reaction, add 500g of ice water to the reaction bottle to reduce the temperature in the reaction bottle to 10°C, filter; wash the filter cake with water until neutral and dry; obtain 49g of crude ketoconazole derivative (HPLC content is 94%).

In a 1000ml reaction bottle, add 49g of crude ketoconazole derivative and 350g of ethyl acetate, heat to dissolve, add 0.5g of activated carbon, reflux for half an hour; filter, wash the filter cake with hot ethyl acetate, combine ethyl acetate, and concentrate to 250g; cool naturally to room temperature, then continue to cool to 0°C with ice water, and keep warm for 1 hour, filter, and vacuum dry to obtain 43.9g of white powder (HPLC content greater than 99%), with a yield of 82.8%.

Example 12

In a 1000ml reaction bottle, add 45g of cis-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-yl-methyl)-1,3-dioxopentyl]-4-methyl-p-toluenesulfonate, 42g of ethyl [4-(4-hydroxyphenyl)]-1-piperazinecarboxylate, 15g of sodium ethoxide and 300g of N,N-dimethylformamide; react at 10°C for 30 hours. After the reaction, add 500g of ice water to the reaction bottle to reduce the temperature in the reaction bottle to 10°C, and filter; wash the filter cake with water until it is neutral and dry; obtain 51.2g of crude ketoconazole derivative (HPLC content is 94%).

In a 1000ml reaction bottle, add 51.2g of crude ketoconazole derivative and 400g of ethyl acetate, heat to dissolve, add 0.5g of activated carbon, reflux for half an hour; filter, wash the filter cake with hot ethyl acetate, combine ethyl acetate, and concentrate to 250g; cool naturally to room temperature, then continue to cool to 0°C with ice water, and keep warm for 1 hour, filter, and vacuum dry to obtain 44.8g of white powder (HPLC content greater than 99%), with a yield of 84.5%.

REF

[1]. Pierard GE, et al. Modulation of sebum excretion from the follicular reservoir by a dichlorophenyl-imidazoldioxolan. Int J Cosmet Sci. 1996 Oct;18(5):219-27. [Content Brief]

////////////ELUBIOL, AMY 925, Dichlorophenyl imidazoldioxolan, OristaR DCI

Elfucose

May 24, 2025 2:58 am / Leave a comment

Elfucose

Cas 87-96-7

Chemical Formula: C6H12O5
Exact Mass: 164.07
Molecular Weight: 164.157

L-fucopyranose (6-deoxy-L-galactopyranose)

(3S,4R,5S,6S)-6-methyloxane-2,3,4,5-tetrol

6-Deoxy-L-galactose (ACI)
Fucose, L- (8CI)
(-)-Fucose
46: PN: US20220380460 SEQID: 47 claimed sequence
6-Desoxygalactose
L-(-)-Fucose
L-Fucose
L-Galactomethylose
L-Galactopyranose, 6-deoxy-
CERC 803
Elfucose
Fucose
NSC 1219
congenital glycosylation disorders
6-Deoxy-L-galactopyranose
L-galactomethylose
87-96-7
Fucose, L-
6-deoxy-galactose

Fucose is under investigation in clinical trial NCT03354533 (Study of ORL-1F (L-fucose) in Patients With Leukocyte Adhesion Deficiency Type II).

L-fucopyranose is the pyranose form of L-fucose. It has a role as an Escherichia coli metabolite and a mouse metabolite. It is a L-fucose and a fucopyranose.

SCHEME

PATENT

PATENT

WO2016150629

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016150629&_cid=P10-MB1MYE-34318-1

Examples

The invention will now be illustrated in more detail by the following non-limiting examples.

Example 1: Production of L-fucose by biocatalytic oxidation of L-fucitol with galactose oxidase in the presence of peroxidase and catalase

A solution of L-fucitol (6.0 mL aqueous solution containing 600 mg L-fucitol, CAS 13074-06-1, Santa Cruz Biotechnology) was added to a round-bottom three-neck bottle (50 mL), followed by the addition of 1.2 mL K2HPO4 _/ KH2PO4 ₍₁₀₀₀_mM , pH=7.0) and 0.095 mL catalase (from bovine liver, SIGMA, 21,300 U/mg, 34 mg/mL), 0.120 mL peroxidase (from horseradish, 173 U/mg solid, SIGMA ) and 2.218 mL galactose oxidase (38.4 mg/mL, 2,708 U/mL). The resulting solution was purged with O ₂ at room temperature until all L-fucitol was converted to L-fucose. The reaction was monitored by HLPC. The final product was isolated and analyzed by 1 H and 13C NMR. The results are summarized in Table 1.

[Table 1]

Reaction time [h] Conversion [%]

3,5 54,0

24 95,8

29 96,0

PATENT

WO2010022244

WO2007021879

////////////Elfucose, 6-Deoxy-L-galactose, Fucose, L- , (-)-Fucose, 6-Desoxygalactose, L-(-)-Fucose, L-Fucose, L-Galactomethylose, L-Galactopyranose, 6-deoxy-, CERC 803, Elfucose, Fucose, NSC 1219, congenital glycosylation disorders, 6-Deoxy-L-galactopyranose, L-galactomethylose, 87-96-7, Fucose, L-, 6-deoxy-galactose

Durlobactam

May 23, 2025 9:13 am / Leave a comment

Durlobactam

CAS 1467829-71-5

WeightAverage: 277.25
Monoisotopic: 277.03685626

Chemical FormulaC₈H₁₁N₃O₆S

Ingredient	UNII	CAS	InChI Key
Durlobactam sodium	F78MDZ9CW9	1467157-21-6	WHHNOICWPZIYKI-IBTYICNHSA-M

FDA 5/23/2023, Xacduro, To treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex
Press Release
Drug Trials Snapshots

(2S,5R)-2-CARBAMOYL-3-METHYL-7-OXO-1,6-DIAZABICYCLO(3.2.1)OCT-3-EN-6-YL SULFATE

SULFURIC ACID, MONO((2S,5R)-2-(AMINOCARBONYL)-3-METHYL-7-OXO-1,6-DIAZABICYCLO(3.2.1)OCT-3-EN-6-YL) ESTER
ETX 2514, ETX-2514, ETX2514, WHO 10824
Durlobactam is a non-beta-lactam, beta-lactamase inhibitor used to treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.

Durlobactam is a beta-lactamase inhibitor used in combination with sulbactam to treat susceptible strains of bacteria in the genus Acinetobacter^[1] It is an analog of avibactam.

The combination therapy sulbactam/durlobactam was approved for medical use in the United States in May 2023.^[1]

PATENT

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9309245	No	2016-04-12	2033-04-02
US9623014	No	2017-04-18	2033-04-02
US9968593	No	2018-05-15	2035-11-17
US10376499	No	2019-08-13	2035-11-17

SYN

https://doi.org/10.1021/acs.jmedchem.4c02079
J. Med. Chem. 2025, 68, 2147−2182

Durlobactam (1) is a copackaged antibiotic combination being developed by Entasis Therapeutics for the treatment of infections caused by Acinetobacter baumannii-calcoaceticus. 13,14
Entasis Therapeutics obtained the worldwide development rights for durlobactam (1) from AstraZeneca in 2015.13 The drug combination was approved by the USFDA in 2023 for use in patients 18 years of age and older as an intravenous infusion.13 Acinetobacter baumannii is a critical bacterial pathogen that has
become highly resistant to various β-lactam antibiotics for Gram-negative infections, including penicillin.15,16 The inventors targeted β-lactam resistance via coadministration of a β-lactamase inhibitor to restore the activity of β-lactam antibiotics. Sulbactam is a β-lactam antibiotic that inhibits penicillin binding proteins (PBP 1 and 3) essential for cell wall synthesis. Durlobactam is a β-lactamase inhibitor that protects sulbactam from degradation by Ambler class A, C, and D serine β-lactamases produced byAcinetobacter baumannii-calcoaceticus. Durlobactam binds covalently with these β-lactamases by
carbamoylating the active site serines, thus safeguarding sulbactam from enzymatic degradation.17,18 The covalent bond between durlobactam and the active site serine isreversible due to the ability of sulfated amine of durlobactam to recyclize back into urea. This allows durlobactam to exchange from one
enzyme molecule to another via a mechanism known as acylation exchange

(13) Keam, S. J. Sulbactam/Durlobactam: first approval. Drugs 2023, 83, 1245−1252.
(14) El-Ghali, A.; Kunz Coyne, A. J.;Caniff, K.; Bleick,C.; Rybak, M. J.Sulbactam-durlobactam: a novel β-lactam-β-lactamase inhibitor combination targeting carbapenem-resistant Acinetobacter baumannii
infections. Pharmacotherapy 2023, 43, 502−513.
(15) O’Donnell, J.; Tanudra, A.; Chen, A.; Miller, A. A.; McLeod, S.M.; Tommasi, R. In vitro pharmacokinetics/pharmacodynamics of the β-lactamase inhibitor, durlobactam, in combination with sulbactam against Acinetobacter baumannii-calcoaceticus complex. Antimicrob.Agents Chemother. 2024, 68, e00312-23.
(16) Arya, R.; Goldner, B. S.; Shorr, A. F. Novel agents in development for multidrug-resistant Gram-negative infections: potential new options facing multiple challenges. Curr. Opin. Infect. Dis. 2022, 35, 589−594.
(17) Shapiro, A. B.; Moussa, S. H.; McLeod, S. M.; Durand-Réville, T.; Miller, A. A. Durlobactam, a new diazabicyclooctane β-lactamase inhibitor for the treatment of Acinetobacter infections in combination
with Sulbactam. Front. Microbiol. 2021, 12, No. 709974.
(18) Iyer, R.; Moussa, S. H.; Durand-Reville, T. F.; Tommasi, R.; Miller, A. Acinetobacter baumannii OmpA is a selective antibiotic permeant porin. ACS Infect. Dis. 2018, 4, 373−381.

The route below was chosen as it was demonstrated on a multikilogram scale (Scheme 1), although some reagents (e.g.,triphosgene) are not typical for large-scale manufacturing.20,22 The synthesis commenced with the condensation of glyoxylic acid monohydrate (1.1) with (S)-tert-butylsulfinamide (1.2) to generate a solution of 2-(tert-butylsulfinylimino)acetic acid 1.3. In parallel, commercially available trans-crotyl alcohol (1.4) was treated with diboronic acid (1.5) in the presence of a palladium catalyst to produce a solution of crotylboronic acid 1.6. These two solutions were mixed to afford chiral α-amino acid 1.7 in
58% overall yield. Diastereo- and enantioselectivity were not reported for the transformation.
Conversion of 1.7 into durlobactam sodium (1) is described in Scheme 2. First, the carboxylic acid 1.7 was converted to an amide and the sulfinamide was removed to afford amino amide 1.8 as an HCl salt. The primary amine in 1.8 was subsequently alkylated with allyl bromide (1.9) and the resulting allyl amine
was protected with Boc anhydride to provide olefin metathesis precursor 1.10. Bisolefin 1.10 was then subjected to Grubbs first-generation catalyst (Grubbs-I) to generate a tetrahydropyridine precursor, which participated in a one-pot nitroso-ene reaction with N-Boc hydroxylamine (1.11) to produce allyl
hydroxylamine 1.12 in 61% overall yield. This key transformation efficiently installed the amine stereocenter required for formation of the bridged urea. Next, the hydroxyl moiety in 1.12 was protected as the TBS ether and the two Boc groups were removed with ZnBr2 to unveil bis-amine 1.13. The intramolecular urea formation was accomplished by the treatment with triphosgene to generate diazabicyclooctene 1.14 in 50% yield over 3 steps. The TBS ether was then removed, and the hydroxyl urea intermediate was treated with sulfur trioxide-pyridine complex and tetrabutylammonium
hydrogen sulfate to afford durlobactam tetrabutylammonium salt 1.15. Finally, tetrabutylammonium durlobactam 1.15 was converted to a calcium salt and subsequently to the targeted sodium salt providing 1. The authors mentioned that the salt formations were required to improve the purity of the final API
(>99%), however, the yields of these steps were not reported.22

(19) McGuire, H.; Bist, S.; Bifulco, N.; Zhao, L.; Wu, Y.; Huynh, H.; Xiong, H.; Comita-Prevoir, J.; Dussault, D.; Geng, B.; et al. Preparation of oxodiazabicyclooctenyl hydrogen sulfate derivatives for use as betalactamase inhibitors. WO 2013150296, 2013.
(20) Basarab, G. S.; Moss, B.; Comita-Prevoir, J.; Durand-Reville, T. F.; Gauthier, L.; O’Donnell, J.; Romero, J.; Tommasi, R.; Verheijen, J.C.; Wu, F.; et al. Preparation of substituted 2-(1,6-diazabicyclo[3.2.1]-
oct-3-en-6-yloxy)acetates as beta-lactamase inhibitors. WO2018053215, 2018.
(21) Durand-Reville, T. F.;Comita-Prevoir, J.; Zhang, J.; Wu, X.; MayDracka, T. L.; Romero, J. A. C.; Wu, F.; Chen, A.; Shapiro, A. B.; Carter, N. M.; et al. Discovery of an orally available diazabicyclooctane
inhibitor (ETX0282) of class A, C, and D serine β-lactamases. J. Med.Chem. 2020, 63, 12511−12525.
(22) Durand-Reville, T. F.; Wu, F.; Liao, X.; Wang, X.; Zhang, S.Preparation of Durlobactam crystalline forms. WO 2023206580, 2023

syn

https://www.mdpi.com/1424-8247/15/3/384

Synthesis of Durlobactam

Chemically, durlobactam is [(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] hydrogen sulfate which can be prepared from the key intermediate hydroxyurea 6-hydroxy-3-methyl-7-oxo-1,6-diaza-bicyclo [3.2.1] oct-3-ene-2-carboxylic acid amide I, which is the structural isomer of III prepared to synthetize ETX-1317 [101]. Then, according to Scheme 15, compound 1 obtained in the synthesis of III (Scheme 14) was reacted with penta-1,3-diene in place of isoprene, and, by an aza-Diels−Alder reaction, compound 2 was obtained.

Scheme 15. Synthesis of durlobactam (C₈H₁₁N₃O₆S, MW = 277.36, IUPAC name, [(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl] hydrogen sulphate.

Compound 2 underwent deprotection of the tert-butyl sulfinyl group to afford 3, subsequently Boc protected, to give compound 4. The saponification of the ester followed by amide coupling using ammonium acetate afforded compound 5. The reaction of alkene 5 with N-Boc-hydroxylamine in the presence of oxygen or air gave the desired compound 6 in a single step. Compound 6 was then protected with TBS group, using TBSCl to afford 7, which was Boc deprotected using zinc bromide obtaining compound 8. Cyclization of the diamine 8 with tri-phosgene provided the corresponding cyclic urea 9, which was TBS deprotected with HFPy to give the key intermediate I. This compound was then immediately sulfated with the DMF:SO₃ complex to obtain the sulfate, which was isolated as its tetrabutylammonium salt 10 by reacting with tetrabutylammonium acetate. The tetrabutylammonium salt was converted to durlobactam in the form of sodium salt by passing 10 through a column filled with Indion 225 sodium resin.

REF

https://sioc-journal.cn/Jwk_yjhx/EN/abstract/abstract350784.shtml

References

^ Jump up to:^a ^b “FDA Approves New Treatment for Pneumonia Caused by Certain Difficult-to-Treat Bacteria”. U.S. Food and Drug Administration (Press release). 24 May 2023. Retrieved 24 May 2023. This article incorporates text from this source, which is in the public domain.

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Clinical data

Other names	ETX2514
Routes of administration	Intravenous
Drug class	Antibacterial, beta-lactamase inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only co-packaged with sulbactam
Identifiers
showIUPAC name
CAS Number	1467829-71-5
PubChem CID	89851852
DrugBank	DB16704 DBSALT003190
ChemSpider	57617784 71060725
UNII	PSA33KO9WA F78MDZ9CW9
KEGG	D11591 D11592
ChEMBL	ChEMBL4298137 ChEMBL4297378
Chemical and physical data
Formula	C₈H₁₁N₃O₆S
Molar mass	277.25 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

Monthly Archives: May 2025

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Research

References

Share this:

References

Share this:

Share this:

Share this:

Share this:

References

Share this:

Medical uses

References

External links

Share this:

Share this:

Share this:

Synthesis of Durlobactam

References

Further reading

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email