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LEVALBUTEROL TARTRATE
LEVALBUTEROL TARTRATE
Levosalbutamol
cas 661464-94-4
4-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;(2R,3R)-2,3-dihydroxybutanedioic acid
MW 628.7, C30H48N2O12
- Xopenex HFA
- Levosalbutamol tartrate
- ADS4I3E22M
- UNII-ADS4I3E22M
- Levosalbutamol tartrate(levalbuterol) is the R-enantiomer of the short-acting β2-adrenergic receptor agonist salbutamol.
Levalbuterol Tartrate is the tartrate salt form of levalbuterol, the R-enantiomer of the short-acting beta-2 adrenergic receptor agonist albuterol, with bronchodilator activity. Levalbuterol selectively binds to beta-2 adrenergic receptors in bronchial smooth muscle, thereby activating intracellular adenyl cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cAMP). Increased cAMP levels cause relaxation of bronchial smooth muscle, relieve bronchospasms, improve mucociliary clearance and inhibit the release of mediators of immediate hypersensitivity from cells, especially from mast cells.
British patent document GB1298494A firstly discloses synthesis of levosalbutamol, which comprises the steps of carrying out crystallization resolution by using D- (+) -dibenzoyl tartaric acid, carrying out ester reduction reaction, and removing two benzyl protecting groups to obtain levosalbutamol, wherein the process route is as follows:
chinese patent CN1705634A, and using rhodium and chiral bidentate phosphine ligand combination, levosalbutamol can be obtained with good yield and good optical purity on a technical scale. The disadvantages are that the toxicity of the reagent is high, the hydrogenation risk is high, and the process route is as follows:
SCHEME
PATENTS
MX2012014342
IN2009MU01097
IN2007CH01847
US20040115136
CN1382685
PATENT
https://patents.google.com/patent/CN114539077A/en
The technical scheme adopted by the invention is as follows: 1) 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxin-6-yl) ethanol and titanium dioxide are used as initial raw materials, a solvent-free system is adopted, and 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxin is synthesized through dehydration.
Then, the 2, 2-dimethyl-6-vinyl-4H-benzo [ D ] [1,3] dioxin is subjected to epoxidation under the combined action of 1,2:4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-dione-2, 6-pyranose (Shi’s Catalyst), Oxone and potassium hydroxide to obtain (R) -2, 2-dimethyl-6- (oxirane-2-yl) -4H-benzo [ D ] [1,3] dioxin.
Reacting and condensing (R) -2, 2-dimethyl-6- (epoxy ethane-2-group) -4H-benzo [ D ] [1,3] dioxin and tert-butylamine in ethanol, and salifying with D- (+) -malic acid to obtain (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-group) ethanol D- (+) -malate.
And (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate is subjected to hydroaminolysis and reacts with hydrogen chloride ethanol to prepare the levosalbutamol hydrochloride.
The invention discloses a novel method for synthesizing levalbuterol hydrochloride, wherein the synthesis of a key intermediate is novel without cyclization oxidation, the total yield is 85-90%, and the method is higher than that of the conventional method. The process is convenient to operate, the raw materials are economical, and the method is suitable for large-scale industrial production.
EXAMPLE 12 preparation of 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxine
A1000 mL flask was charged with 208g (1.0 mol) of 1- (2, 2-dimethyl-4H-benzo [ d ] [1,3] dioxin-6-yl) ethanol, which was accurately weighed, and stirring was started. Then slowly adding 16g (0.2 mol) of titanium dioxide, installing a water separator and a water flow pipe, starting heating until the internal temperature is kept at 120-130 ℃, and stirring for 12 hours. After the reaction is finished, the temperature is reduced to below 50 ℃, the water separator is removed, the reduced pressure distillation device is changed, and 120 ℃ (less than 100 Pa) fraction is collected to obtain 180.7g of 2, 2-dimethyl-6-vinyl-4H-benzo [ d ] [1,3] dioxin with the yield of 95%.
Mass spectrum: EI (m/z): 190; hydrogen nuclear magnetic resonance spectroscopy:1HNMR（400MHz，CDCl3）δ7.55（d，J=4Hz，1H），7.11（s，1H），6.87（d，J=4Hz，1H），6.65~6.60（m，1H），5.63~5.60（m，1H），5.19~5.5（m，1H），4.59（s，2H），1.49（s，6H）。
EXAMPLE 2 Synthesis of (R) -2, 2-dimethyl-6- (oxiran-2-yl) -4H-benzo [ d ] [1,3] dioxine
A clean 5000mL three-neck flask is taken, 180.5g (0.95 mol) of the compound
2, 2-dimethyl-6-vinyl-4H-benzo [ D ] [1,3] dioxin obtained in the example 1 is added, 2000mL of acetonitrile is added for dissolution, 1,2:4, 5-di-O-isopropylidene-BETA-D-erythro-2, 3-dione-2, 6-pyranose 49.1g (0.19 mol) is added, potassium monopersulfate (Oxone) 876g (1.43 mol) is added under stirring, a proper amount of potassium hydroxide is added after the addition is finished, the pH of the system is kept between 10 and 11, and the stirring reaction is continued at 25 ℃ for 8 to 12 hours. After the reaction, the mixture was slowly poured into 2000ml of purified water prepared in advance, stirred sufficiently for 30min, and then was allowed to stand for layering, and the organic layer was collected. 2000ml of dichloromethane is added for extraction, organic layers are combined and washed by saturated sodium chloride solution, the organic layer is dried by adding anhydrous sodium sulfate and concentrated to dryness to obtain 196g of crude colorless liquid with the yield of 100 percent.
Mass spectrum: EI (m/z): 207; hydrogen nuclear magnetic resonance spectroscopy:1HNMR（400MHz，CDCl3）δ7.25（s，1H），7.18（d，J=4Hz，1H），6.85（d，J=4Hz，1H），4.59（s，2H），3.85~3.81（m，1H），2.96~2.71（m，2H），1.49（s，6H）。
EXAMPLE 3 preparation of (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate salt
A clean 5000mL three-neck flask is taken, the compound (R) -2, 2-dimethyl-6- (oxiranyl-2-yl) -4H-benzo [ d ] [1,3] dioxin obtained in the example 2 is added, 196g (0.95 mol) of the clean 5000mL three-neck flask is taken, 1000mL of ethanol is added for dissolution, 80.4g (1.1 mol) of tert-butylamine is added, stirring is started, heating is carried out till reflux, reaction is carried out for 3H, and the progress of the reaction is detected by TLC. After the reaction is finished, 127g (0.95 mol) of D- (+) -malic acid is added in batches, and stirring and refluxing are continued for 2h after the addition is finished. And then cooling to 5-15 ℃, precipitating a large amount of solid, stirring for 3H, filtering, washing the filter cake with ethanol, collecting the filter cake, and drying to obtain (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate 372g of white solid with the yield of 94.7%.
Mass spectrum: ESI (m/z): 280.1, respectively; hydrogen nuclear magnetic resonance spectroscopy:1HNMR（400MHz，d-DMSO）δ7.25（s，1H），7.18（d，J=4Hz，1H），6.85（d，J=4Hz，1H），4.90~4.76（m，2H），4.59（s，2H），4.44~4.40（m，2H），3.65（br，2H），3.15~2.90（m，2H），2.77~2.52（m，2H），2.03（s，1H），1.50（s，6H），1.27（s，9H）。
EXAMPLE 4 preparation of L-salbutamol hydrochloride
A5000 mL beaker was charged with 372g of the compound (R) -2- (tert-butylamine) -1- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) ethanol D- (+) -malate salt obtained in example 3, 1500mL of purified water was added, and the mixture was stirred to dissolve it, followed by addition of 1500mL of dichloromethane and cooling in an ice bath. Slowly adding a proper amount of concentrated ammonia water under stirring to adjust the pH value of the water phase to 9-10, continuously stirring for 30min, and standing for layering. Separating and collecting organic layer, adding 1000ml of dichloromethane into water layer, stirring for 10min, standing and demixing. Separating and collecting organic layers, combining the organic layers, adding 2000ml of saturated sodium chloride solution into the organic layers, stirring for 30min, standing for layering, collecting the organic layers, adding a proper amount of anhydrous sodium sulfate, drying, filtering, washing with dichloromethane, and collecting filtrate.
And (3) carrying out rotary evaporation and concentration on the filtrate to about 1500mL, transferring the concentrated filtrate into a 5000mL three-neck bottle, and placing the three-neck bottle in an ice bath to cool the three-neck bottle to 5-15 ℃. About 110g of 30% hydrogen chloride ethanol solution is dropwise added under stirring, and after the dropwise addition is finished, 2000mL of methyl tertiary butyl ether is dropwise added under stirring, so that a large amount of white solid is precipitated. And after the addition is finished, continuously stirring for 3 hours at the temperature of 5-15 ℃, filtering, adding methyl tert-butyl ether into a filter cake for washing, collecting the filter cake, and drying to obtain 241.5g with the yield of 97.3%. Through HPLC analysis, the purity is 99.95%, and the isomer content is not detected, as shown in figures 1-4. The total yield of the four-step reaction is 87.5 percent.
Publication numberPriority datePublication dateAssigneeTitle
CN1413976A *2002-09-132003-04-30苏州君宁新药开发中心有限公司New process for preparing levo-albuterol
US20050261368A1 *2004-05-202005-11-24Valeriano MerliPreparation of levalbuterol hydrochloride
CN103951568A *2014-05-192014-07-30苏州弘森药业有限公司New process for synthesizing salbutamol and sulfate of salbutamol
CN104557572A *2014-12-302015-04-29上海默学医药科技有限公司Levalbuterol intermediate and levalbuterol hydrochloride synthesis method
CN110963929A *2019-11-262020-04-07安徽恒星制药有限公司Preparation method of salbutamol hydrochloride suitable for industrial production
CN113227113A *2018-12-202021-08-06帝斯曼知识产权资产管理有限公司Improved synthesis of epoxidation catalysts
CN113801029A *2020-06-162021-12-17盈科瑞（天津）创新医药研究有限公司Preparation method of levalbuterol hydrochloride
//////////Levosalbutamol, LEVALBUTEROL TARTRATE, Xopenex HFA, Levosalbutamol tartrate, ADS4I3E22M, UNII-ADS4I3E22M
Ibuzatrelvir
Ibuzatrelvir
PF-07817883
CAS 2755812-39-4
| Molecular Weight | 489.49 |
|---|---|
| Formula | C21H30F3N5O5 |
- Ibuzatrelvir
- N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-[(1S)-1-cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl]-4-(trifluoromethyl)-L-prolinamide
- PF 07817883
- methyl N-[(2S)-1-[(2S,4R)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-4-(trifluoromethyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate
- KZ2X7QH2VT
Ibuzatrelvir (development code PF-07817883) is an experimental antiviral drug being developed by Pfizer for the treatment of COVID-19.[1] It is a second-generation improvement over nirmatrelvir which has a similar chemical structure.[2] One of the disadvantages of nirmatrelvir is that it has low metabolic stability and must be given in combination with ritonavir (as Paxlovid) to limit its metabolic degradation in the body.[3] Ibuzatrelvir incorporates modifications to the chemical structure of nirmatrelvir that give it enhanced oral bioavailability, so it does not require coadministration with ritonavir.[3]
Ibuzatrelvir (PF-07817883), a second-generation, orally bioavailable, is SARS-CoV-2 main protease (Mpro and 3CLpro) inhibitor with improved metabolic stability. Ibuzatrelvir has demonstrated pan-human coronavirus antiviral activity and off-target selectivity profile in vitro and in preclinical animal studies. Ibuzatrelvir is well tolerated with a safety profile similar to placebo and prevents viral infection and transmission. Ibuzatrelvir can be used to inhibit COVID-19.
SCHEME
SIDECHAIN
MAIN
PATENT
WO2021250648 PFIZER
WO2023215910
PAPER
The Pfizer scientists described ibuzatrelvir’s medicinal chemistry campaign in a Journal of Medicinal Chemistry paper that was published in April 2024 (DOI: 10.1021/acs .jmedchem.3c02469).
https://pubs.acs.org/doi/10.1021/jacsau.4c00508
Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (Mpro) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of Mpro hinders the processing of the proteins essential for viral replication in vivo. However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 Mpro at 2.0 Å resolution. In addition, we show that ibuzatrelvir also potently inhibits the Mpro of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV Mpro. In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with Mpro of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals.
General Boc-Deprotection and Coupling Procedure
This procedure was based on a literature procedure.1
The Boc-protected building block (1.0
equiv) was dissolved in 50/50 TFA/DCM and stirred for 1 h at room temperature. The reaction
mixture was then concentrated in vacuo and co-evaporated with DCM (5 × 5 mL). In a separate
RBF the carboxylic acid building block (1.0 equiv) and HATU (1.0 equiv) were dissolved in
DMF. HOAt (0.6 M in DMF) (0.1 equiv) and DIPEA (3.0 equiv) were added and the reaction
mixture was left to incubate at room temperature for 10 mins, as it turned yellow. The previously
concentrated Boc-deprotected building block was dissolved in DMF and added dropwise to the
incubating solution. The reaction mixture was capped under a blanket of argon and stirred at room
temperature for 2–3 h. The reaction mixture was diluted with 5 mL each of water and ethyl acetate
and the layers separated. The aqueous layer was extracted further with ethyl acetate (3 × 5 mL),
and all ethyl acetate layers combined and washed with sat. aq. NaHCO3 (10 mL), 1 M HCl (10
mL), water (2 × 10 mL) and brine (10 mL). It was then dried over Na2SO4, filtered, and
concentrated in vacuo to furnish the product.
Methyl ((S)-1-((2S,4R)-2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamoyl)-4-
(trifluoromethyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (1) Ibuzatrelvir
This known compound was synthesized according to the General Boc-Deprotection and
Coupling Procedure with building blocks 7 and 8. The characterization data matches the literature
report (IPN: WO2021250648A1). The crude material was obtained as a dark yellow sticky residue
that was then purified with flash column chromatography with an eluent of 92:8 EtOAc:MeOH.
The desired compound had an Rf
= 0.40 and was visible with KMnO4 stain. After concentration
of desired fractions, 1 was isolated as a clear, colorless oil that solidified to a white solid (0.051 g,
53%) This compound was isolated and used for all experiments as a mixture of diastereomers in a
ratio of about 2:1 and rotamers present, with only the major set of resonances reported, which are
for the desired isomer. It can be separated using high performance liquid chromatography (HPLC)
methods, as listed in the HPLC Separation of Ibuzatrelvir Diastereomers section.
IR (DCM cast film, vmax / cm–1) 3292, 3053, 2959, 2909, 2875, 1695, 1643, 1550, 1443, 1401,
1370, 1332, 1270, 1236, 1200, 1164, 1130
1H NMR (500 MHz, CDCl3) δH 8.32 (1H, d, J = 7.6 Hz), 6.22 (1H, br), 5.74 (1H, d, J = 9.3 Hz),
4.96 – 4.87 (1H, m), 4.54 (1H, dd, J = 8.6, 3.6 Hz), 4.30 (1H, d J = 9.9 Hz), 3.99 – 3.88 (2H, m),
3.65 (3H, s), 3.42 – 3.26 (2H, m), 2.66 – 2.57 (1H, m), 2.52 – 2.43 (1H, m), 2.40 – 2.28 (3H, m),
1.97 – 1.88 (1H, m), 1.84 – 1.75 (2H, m), 0.99 (9H, s)
13C {1H} NMR (125 MHz, CDCl3) δC 179.1, 171.4, 171.1, 156.9, 126.1 (q, J = 276.3 Hz), 118.3,
59.4, 58.9, 52.4, 47.3, 42.4 (q, J = 29.5 Hz), 40.4, 39.1 37.5, 35.6, 34.2, 28.2, 28.0, 26.3
SR: [α]D
26 = –35.71 (c = 0.21, DCM)
HRMS: (ESI) Calcd for C21H30F3N5NaO5 [M + Na]+
512.2091, found 512.2088
References
- ^ Allerton CM, Arcari JT, Aschenbrenner LM, Avery M, Bechle BM, Behzadi MA, et al. (August 2024). “A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19”. Journal of Medicinal Chemistry. 67 (16): 13550–13571. doi:10.1021/acs.jmedchem.3c02469. PMC 11345836. PMID 38687966.
- ^ Chen P, Van Oers TJ, Arutyunova E, Fischer C, Wang C, Lamer T, et al. (August 2024). “A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV”. JACS Au. 4 (8): 3217–3227. doi:10.1021/jacsau.4c00508. PMC 11350714. PMID 39211604.
- ^ Jump up to:a b Brewitz L, Schofield CJ (July 2024). “Fixing the Achilles Heel of Pfizer’s Paxlovid for COVID-19 Treatment”. Journal of Medicinal Chemistry. 67 (14): 11656–11661. doi:10.1021/acs.jmedchem.4c01342. PMC 11284777. PMID 38967233.
| Clinical data | |
|---|---|
| Other names | PF-07817883 |
| Routes of administration | Oral |
| Legal status | |
| Legal status | Investigational |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2755812-39-4 |
| PubChem CID | 163362000 |
| DrugBank | 111 |
| ChemSpider | 128942571 |
| UNII | KZ2X7QH2VT |
| Chemical and physical data | |
| Formula | C21H30F3N5O5 |
| Molar mass | 489.496 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
- [1]. Owen, et al. Preparation of peptidomimetic nitriles as SARS-CoV-2 3CL protease inhibitors and methods for the treatment of COVID-19. World Intellectual Property Organization, WO2021250648 A1. 2021-12-16.[2]. Mahta Mortezavi, et al. Virologic Response and Safety After Oral Administration of Ibuzatrelvir, a Novel SARS-CoV-2 Mpro Inhibitor, in Non-Hospitalized Adults With Symptomatic COVID-19. European Congress of Clinical Microbiology and Infectious Disease (ECCMID) 2024; 2024 April 27-30.[3]. Westberg M, et al. An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations[J]. Sci Transl Med. 2024 Mar 13;16(738):eadi0979.[4]. Allerton CMN, et al. A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19[J]. J Med Chem. 2024 Apr 30. [Content Brief]
////Ibuzatrelvir, PF 07817883, PF-07817883, PF07817883, KZ2X7QH2VT
Gamcemetinib
Gamcemetinib
CAS 1887069-10-4
CC-99677 , OS2IR8TV1O
| Molecular Weight | 469.94 |
|---|---|
| Formula | C22H20ClN5O3S |
- (10R)-3-[[2-Chloro-5-(ethoxymethyl)-4-pyrimidinyl]oxy]-9,10,11,12-tetrahydro-10-methyl-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one (ACI)
- (10R)-3-{[2-chloro-5-(ethoxymethyl)pyrimidin-4-yl]oxy}-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one
- BMS 986371
- BMS-986371
- CC 99677
- CC-99677
(R)-3-((2-Chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one
- OriginatorCelgene Corporation
- ClassAnti-inflammatories
- Mechanism of ActionMAP-kinase-activated kinase 2 inhibitors
- Orphan Drug StatusNo
- 14 Nov 2024Efficacy and adverse events data from a phase II trial in Ankylosing Spondylitis presented at the ACR Convergence 2024 (ACR-2024)
- 27 Mar 2024Pharmacokinetics and adverse events data from a phase I trial (In volunteers) presented at the 125th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics 2024 (ASCPT-2024)
- 26 Oct 2023Discontinued – Phase-I for Inflammation (In volunteers) in USA, United Kingdom (PO) prior to October 2023 (Bristol-Myers Squibb pipeline, October 2023)
Gamcemetinib (CC-99677) is a potent, covalent, and irreversible inhibitor of the mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MK2) pathway in both biochemical (IC50=156.3 nM) and cell based assays (EC50=89 nM). Gamcemetinib is extracted from patent WO2020236636, compound 1.
SCHEME
SIDECHAIN
SIDECHAIN
MAIN
REF
WO2018170203
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018170203&_cid=P11-MBK7CL-38003-1
PATENT
WO2018170199 CELGENE
WO2018170203
US20160075720
WO2020236636, compound 1
////////////Gamcemetinib, BMS 986371, BMS-986371, CC 99677, CC-99677, OS2IR8TV1O
Fexagratinib
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 49th 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
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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-d 6 ,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-d 6 ,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% Na 2 CO 3 (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-d 6 ,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-d 6 ,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% Na 2 CO 3 (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
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- ^ 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
New Drug Approvals 
