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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Imlunestrant
Imlunestrant
CAS 2408840-26-4
as tosylate: 2408840-41-3
(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol
- (5r)-5-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-8-(trifluoromethyl)-5h-(1)benzopyrano(4,3-c)quinolin-2-ol
- 5h-(1)benzopyrano(4,3-c)quinolin-2-ol, 5-(4-(2-(3-(fluoromethyl)-1-azetidinyl)ethoxy)phenyl)-8-(trifluoromethyl)-, (5r)-
MF C29H24F4N2O3 MW 524.516
FDA 9/25/2025, Inluriyo, LY3484356, LY-3484356, To treat estrogen receptor-positive, human epidermal growth factor receptor 2-negative, estrogen receptor-1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy
Imlunestrant, sold under the brand name Inluriyo, is an anti-cancer medication used for the treatment of breast cancer.[1] It is an is an estrogen receptor antagonist.[1] It is used as the salt, imlunestrant tosylate.[2] It is taken by mouth.[1] It was developed by Eli Lilly and Company.[2]
The most common adverse events and laboratory abnormalities include decreased hemoglobin, musculoskeletal pain, decreased calcium, decreased neutrophils, increased AST, fatigue, diarrhea, increased ALT, increased triglycerides, nausea, decreased platelets, constipation, increased cholesterol, and abdominal pain.[2]
Imlunestrant was approved for medical use in the United States in September 2025.[2]
SYN
- Imlunestrant with or without Abemaciclib in Advanced Breast CancerPublication Name: The New England journal of medicinePublication Date: 2025-03-27PMID: 39660834DOI: 10.1056/nejmoa2410858
- Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and ChallengesPublication Name: Journal of Medicinal ChemistryPublication Date: 2023-06-28PMID: 37377342DOI: 10.1021/acs.jmedchem.3c00136
- Novel endocrine therapies: What is next in estrogen receptor positive, HER2 negative breast cancer?Publication Name: Cancer Treatment ReviewsPublication Date: 2023-06PMID: 37146385DOI: 10.1016/j.ctrv.2023.102569
- Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical PerspectivePublication Name: International Journal of Molecular SciencesPublication Date: 2021-07-22PMCID: PMC8345926PMID: 34360578DOI: 10.3390/ijms22157812
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US281655517&_cid=P12-MG7DCV-14904-1
Example 1A
5-(4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol, Isomer 1Separate the two enantiomers of 5-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol by chiral SFC with the following conditions: Column: LUX® Cellulose-1, 5×25 cm; eluting with a mobile phase of 30% iPrOH (with 0.5% DMEA) in CO 2; column temperature: 40° C.; flow rate: 300 g/minute; UV detection wavelength: 270 nm to give Example 1A as the first eluting enantiomer (Isomer 1). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 1 by chiral analytical SFC, >99% ee, t (R): 1.30 minutes; column: CHIRALCEL® OD-H, 4.6×150 mm; eluting with a mobile phase of 30% MeOH (0.2% IPA) in CO 2; column temperature: 40° C.; flow rate: 5 mL/minute; UV detection wavelength: 225 nm. Isolate the title compound of Example 1B to give the second eluting enantiomer (Isomer 2). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 2 by chiral analytical SFC, 98% ee, t (R): 2.03 minutes; column: CHIRALCEL® OD-H, 4.6×150 mm; eluting with a mobile phase of 30% MeOH (0.2% IPA) in CO 2; column temperature: 40° C.; flow rate: 5 mL/minute; UV detection wavelength: 225 nm.
Alternate Preparation Example 1B
Crystalline 5-(4-{2-[3-(Fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[1]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020014435&_cid=P12-MG7DHN-18354-1
EXAMPLE 1
Racemic 5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [ 1 ]benzopyrano[4,3 -c]quinolin-2-ol
Cool a solution of (4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl){3-[2-fluoro-4-(trifluoromethyl)phenyl]-7-hydroxyquinolin-4-yl}methanone (5.27 g, 9.71 mmol) in 1,4-dioxane (100 mL) to 5 °C. Add lithium triethylborohydride (1 M in THF, 30.0 mL, 30.0 mmol). Remove the cooling bath and stir for 1.5 hours at room temperature. Quench the mixture with water. Add saturated NH4Cl solution and EtOAc. Separate the layers and extract the aqueous layer with EtOAc. Combine the organic extracts, dry over anhydrous MgS04, filter, and concentrate the filtrate. Dissolve the crude residue in THF (100 mL).
Add sodium hydride (60% in mineral oil, 1.94 g, 48.5 mmol). Reflux the solution for 1.5 hours. Add additional sodium hydride (60% in mineral oil, 1.94 g, 48.5 mmol), then reflux for an additional 30 minutes. Cool the solution to room temperature and quench with water. Add EtOAc and saturated NH4Cl solution. Separate the layers and extract the aqueous layer with EtOAc. Combine the organic extract, dry over anhydrous MgS04, filter, and concentrate the filtrate. Purify the residue by silica gel column chromatography eluting with a gradient of 5-7% MeOH in DCM to give the title compound (3.70 g, 72%) as a light yellow foam. ES/MS (m/z): 525.2 (M+H).
Prepare the following compounds in a manner essentially analogous to the method of Example 1, with the following variations in procedure. For the reduction, use 3 to 5 equivalents of lithium triethylborohydride with reaction times from 30 minutes to one hour and drying of the organic layers over magnesium sulfate or sodium sulfate. ETse the crude residue directly or purify by silica gel column chromatography eluting with a gradient of 0-5-7.5-10% MeOH in DCM before cyclization. Complete the cyclization by refluxing in THF for up to 16 hours, or in DMF, from 2 hours at room temperature for Ex 2, to 2 hours at 85 °C for Ex 8. Extract with DCM or EtOAc and dry organic layers over magnesium sulfate or sodium sulfate. Purify by silica gel column chromatography using up to 10% (MeOH or 7 M ammoniated MeOH) in DCM (Ex 2: gradient 0-10% MeOH in DCM; Ex 5: gradient 4-10% 7 M ammoniated MeOH in DCM; Ex 8: gradient 5-7.5% 7 M ammoniated MeOH in DCM) or by high pH reversed phase HPLC as noted.
EXAMPLE 1A
-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 1
and
EXAMPLE 1B
5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2
Separate the two enantiomers of 5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[l]benzopyrano[4,3-c]quinolin-2-ol by chiral SFC with the following conditions: Column: LUX® Cellulose-l, 5 x 25 cm; eluting with a mobile phase of 30% iPrOH (with 0.5% DMEA) in C02; column temperature: 40 °C; flow rate: 300 g/minute; UV detection wavelength: 270 nm to give Example 1 A as the first eluting enantiomer (Isomer 1). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 1 by chiral analytical SFC, >99% ee, /(R>: 1.30 minutes; column: CHFRALCEL® OD-H, 4.6 x 150 mm; eluting with a mobile phase of 30% MeOH (0.2% IP A) in C02; column temperature: 40 °C; flow rate: 5 mL/minute; UV detection wavelength: 225 nm. Isolate the title compound of Example 1B to give the second eluting enantiomer (Isomer 2). ES/MS (m/z): 525.2 (M+H). Confirm enantiomeric enrichment of Isomer 2 by chiral analytical SFC, 98% ee, /(R>: 2.03 minutes; column: CHIRALCEL® OD-H, 4.6 x 150 mm; eluting with a mobile phase of 30% MeOH (0.2% IP A) in C02; column temperature: 40 °C; flow rate: 5 mL/minute; UV detection wavelength: 225 nm.
Alternate Preparation EXAMPLE 1B
Crystalline 5-(4-{2-[3-(Fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H- [l]benzopyrano[4,3-c]quinolin-2-ol, Isomer 2
Stir 5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[l]benzopyrano[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid, Isomer 2 (23.8 g, 0.034 mol) in water (250 mL) at 1000 rpm. Add NaOH (76 pL) and stir the solution for 2 hours. Add DCM (600 mL). Separate the mixture, dry the DCM extract with magnesium sulfate, filter the material through a syringe filter (0.45 pm), and concentrate to dryness. Allow the material to sit under a N2 stream over a weekend. Add 1 : 1 EtOH/water (80 mL) and stir the mixture with sonication. Collect a tan solid by filtration on a nylon membrane to give the title compound (10.47 g, 0.02 mol, 59%).
PAT
- Selective estrogen receptor degradersPublication Number: US-2023234960-A1Priority Date: 2018-07-12
- Selective estrogen receptor degraderPublication Number: CN-112424205-BPriority Date: 2018-07-12Grant Date: 2023-10-31
- selective estrogen receptor degraderPublication Number: CN-117379428-APriority Date: 2018-07-12
- Selective estrogen receptor degradersPublication Number: US-11993608-B2Priority Date: 2018-07-12Grant Date: 2024-05-28
- Selective estrogen receptor degradersPublication Number: US-12128040-B2Priority Date: 2018-07-12Grant Date: 2024-10-29
PAT
https://patents.google.com/patent/US11926634B2/en
Selective estrogen receptor degraders (SERDs) bind to the estrogen receptor (ER) and downregulate ER-mediated transcriptional activity. The degradation and downregulation caused by SERDs can be useful in the treatment of various proliferative immune mediated disorders, cell proliferation disorders, including cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer as well as mutations due to emerging resistance. Some small molecule examples of SERDs have been disclosed in the literature (see, e.g., WO2005073204, WO2014205136, and WO2016097071). Nonetheless, there is a need for new SERDs to treat ER-positive cancers, such as breast cancer, gastric cancer, and/or lung cancer.
As described in U.S. Pat. No. 10,654,866 (the ‘866 patent) a series of SERDs of the following formula have been discovered, along with pharmaceutically acceptable salts thereof:
wherein one of R1 and R2 are independently Cl, F, —CF3, or —CH3, and the other is H.
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| Clinical data | |
|---|---|
| Trade names | Inluriyo |
| Other names | LY3484356, LY-3484356 |
| AHFS/Drugs.com | Inluriyo |
| License data | US DailyMed: Imlunestrant |
| Routes of administration | By mouth |
| Drug class | Estrogen receptor antagonist |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2408840-26-4as tosylate: 2408840-41-3 |
| PubChem CID | 146603228 |
| DrugBank | DB19043 |
| ChemSpider | 115010421 |
| UNII | 9CXQ3PF69Uas tosylate: F7UDT90EW5 |
| KEGG | D12216as tosylate: D12217 |
| ChEMBL | ChEMBL5095183 |
| Chemical and physical data | |
| Formula | C29H24F4N2O3 |
| Molar mass | 524.516 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218881s000lbl.pdf
- “FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer”. U.S. Food and Drug Administration (FDA). 25 September 2025. Retrieved 27 September 2025.
This article incorporates text from this source, which is in the public domain. - “U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer” (Press release). Eli Lilly. 25 September 2025. Retrieved 27 September 2025 – via PR Newswire.
- World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.
Further reading
- Jhaveri, Komal L.; Jeselsohn, Rinath; Lim, Elgene; Hamilton, Erika P.; Yonemori, Kan; Beck, J. Thaddeus; et al. (June 2022). “A phase 1a/b trial of imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) in ER-positive (ER+) advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Monotherapy results from EMBER”. Journal of Clinical Oncology. 40 (16_suppl): 1021. doi:10.1200/JCO.2022.40.16_suppl.1021. S2CID 249445691.
- Jhaveri, Komal; O’Shaughnessy, Joyce; Andre, Fabrice; Goetz, Matthew P.; Harbeck, Nadia; Martín, Miguel; et al. (March 2023). “Abstract OT1-01-02: EMBER-4: A phase 3 adjuvant trial of imlunestrant vs standard endocrine therapy (ET) in patients with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence who have previously received 2 to 5 years of adjuvant ET”. Cancer Research. 83 (5_Supplement): OT1–01–02-OT1-01–02. doi:10.1158/1538-7445.SABCS22-OT1-01-02.
- Neven, P.; Stahl, N.; Losada, M.J. Vidal; Jimenez, M. Martin; Kaufman, P.A.; Harbeck, N.; et al. (October 2023). “273P A preoperative window-of-opportunity (WOO) study of imlunestrant in ER+, HER2- early breast cancer (EBC): Final analysis from EMBER-2”. Annals of Oncology. 34: S292 – S293. doi:10.1016/j.annonc.2023.09.470. S2CID 264385454.
External links
- Clinical trial number NCT04975308 for “A Study of Imlunestrant, Investigator’s Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3)” at ClinicalTrials.gov
/////////Imlunestrant, FDA 2025, APPROVALS 2025, Inluriyo, CANCER, LY3484356, LY 3484356, 9CXQ3PF69U
Envonalkib
Envonalkib
- CAS 1621519-26-3
- QB7KTQ7VW9
- 5-((1R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((2S)-2-methyl-1-piperazinyl)(3,3′-bipyridin)-6-amine
- 506.4 g/mol, C24H26Cl2FN5O2
TQ-B3139, Chia Tai Tianqing, Anluoqing, cancer
ENVONALKIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
SYN
https://patentscope.wipo.int/search/en/WO2014117718
Example 27: 5-[(2,6-dichloro-3-fluorophenyl)ethoxy-4′-methoxy-6′ …
Step 1: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methyl-4-tert-butoxycarbonylpiperazin-1-yl)-3,3′-bipyridin-6-amine
To dioxane (10 mL) and water (1.5 mL) were added tert-butyl (S)-4-(5-bromo-4-methoxypyridin-2-yl)-3-methylpiperidin-1-carboxylate (106 mg, 0.275 mmol), (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-aminopyridine (140 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium (32 mg, 0.0275 mmol) and cesium carbonate (179 mg, 0.55 mmol), the atmosphere was replaced with nitrogen, and the reaction was carried out at 100 ° C. overnight. After cooling, the mixture was separated by silica gel column chromatography to give 5-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6-(5-(2-methyl-4-tert-butoxycarbonylpiperidin-1-yl)-3,3′-bipyridin-6-amine) (70 mg) in a yield of 42%. MS m/z [ESI]: 606.2 [M+1].
Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-3,3′-bipyridin-6-amine
To a stirred dichloromethane solution (10 mL) of 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methyl-4-tert-butoxycarbonylpiperidin-1-yl)-3,3′-bipyridin-6-amine (67 mg, 0.11 mmol) was added trifluoroacetic acid (1 mL) and stirred for 1 hour. The pH was adjusted to greater than 13 with sodium hydroxide solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by column chromatography (with dichloromethane:methanol = 8:1 as eluent) to give 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperidin-1-yl)-3,3′-bipyridin-6-amine (30 mg). Yield: 55%, MS m/z [ESI]: 506.1[M+1]. 1H-NM (400 MHz, CDC1 3 ):5= 7.94(1H, s), 7.71(1H, s), 7.28-7.32(lH, m), 7.07(1H, t, J=8.4Hz), 6.97(1H, s), 6.04-6.13(2H, m), 4.86 (2H : s), 4.57-4.59(lH, m), 4.03 (1H, d, J=14Hz), 3.76(3H, s), 3.07-3.33(4H, m), 2.88-3.00(lH, m), 1.84(3H, d, J=6.8Hz), 1.34 (3H, d, J=6.8Hz).
SYN
CN107949560
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US154015806&_cid=P11-MEF9W1-27198-1
Example 27: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine
General Synthetic Methods:
Step 1: (S)-tert-butyl 4-(6′-amino-5′-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4-methoxy-[3,3′-bipyridin]-6-yl)-3-methylpiperazine-1-carboxylate
Step 2: 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4′-methoxy-6′-((S)-2-methylpiperazin-1-yl)-[3,3′-bipyridin]-6-amine
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Envonalkib, also known as TQ-B3139, is a novel small-molecule TKI, developed by Chia Tai Tianqing Pharmaceutical Group. It targets ALK, ROS1, and c-Met kinases, exhibiting potent antitumor activity against cancers harboring these genetic alterations. In 2024, the NMPA approved Envonalkib under the brand name Anluoqing for the treatment of adult patients with ALK-positive locally advanced or metastatic NSCLC who have not received prior ALK inhibitor therapy [24]. Envonalkib exerts its therapeutic effects through selective inhibition of the kinase activities of ALK, ROS1, and c-Met, thereby interrupting the downstream signaling pathways that are crucial for tumor cell proliferation and survival [25]. The inhibition of these targets results in cell cycle arrest and apoptosis in cancer cells。The clinical efficacy of Envonalkib was evidenced in a Phase III randomized, open-label, multicenter clinical trial (NCT04009317), which compared Envonalkib with crizotinib in treatment-naïve patients with ALK-positive advanced NSCLC [25,26]. In the reported study, Envonalkib demonstrated a me dian PFS of 24.87 months, which was markedly superior to the 11.60 months achieved with crizotinib (hazard ratio [HR] = 0.47, p < 0.0001). Notably, in patients harboring brain metastases, Envonalkib exhibited a
central nervous system objective response rate (CNS-ORR) of 78.95 %, a substantial improvement over the 23.81 % observed with crizotinib. In terms of safety profile, Envonalkib was generally well-tolerated. Treat ment-related adverse events (TRAEs) of Grade ≥3 were noted in 55.73 % of patients receiving Envonalkib, contrasting with the 42.86 % incidence in the crizotinib cohort. The predominant TRAEs encompassed elevated liver enzymes, neutropenia, and gastrointestinal symptoms, all of which
were amenable to effective management through appropriate support ive care measures. The regulatory approval of Envonalkib thus in troduces a novel therapeutic modality for patients with ALK-positive NSCLC, effectively addressing a significant unmet medical need within this patient population [25].
The synthesis of Envonalkib, illustrated in Scheme 6, initiates with Mitsunobu coupling of Envo-001 and Envo-002, affording Envo-003 [27]. Sequential reduction and NBS-bromination converts Envo-003 to
Envo-005 via Envo-004. Miyaura borylation of Envo-005 constructs Envo-006, which undergoes Suzuki-Miyaura cross-coupling with Envo-007 followed by deprotection to deliver Envonalkib. In parallel,
Envo-009 reacts with Envo-010 through Buchwald-Hartwig cross coupling to form Envo-011. This intermediate is brominated to produce Envo-007, which is used in the Suzuki-Miyaura coupling with Envo-006
[24] X. Li, Y. Xia, C. Wang, S. Huang, Q. Chu, Efficacy of ALK inhibitors in Asian
patients with ALK inhibitor-naïve advanced ALK-Positive non-small cell lung
cancer: a systematic review and network meta-analysis, Transl. Lung Cancer Res.
13 (2024) 2015–2022.
[25] Y. Yang, J. Min, N. Yang, Q. Yu, Y. Cheng, Y. Zhao, M. Li, H. Chen, S. Ren, J. Zhou,
W. Zhuang, X. Qin, L. Cao, Y. Yu, J. Zhang, J. He, J. Feng, H. Yu, L. Zhang, W. Fang,
Envonalkib versus crizotinib for treatment-naive ALK-Positive non-small cell lung
cancer: a randomized, multicenter, open-label, phase III trial, Signal Transduct
Target Ther 8 (2023) 301.
[26] R. Garcia-Carbonero, A. Carnero, L. Paz-Ares, Inhibition of HSP90 molecular
chaperones: moving into the clinic, Lancet Oncol. 14 (2013) e358–e369.
[27] F. Gong, X. Li, R. Zhao, X. Zhang, X. Xu, X. Liu, D. Xiao, Y. Han, Process for
Preparation of Pyridine Substituted 2-aminopyridine Protein Kinase Inhibitor
Crystal, 2017. CN107949560B.
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- New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
- Efficacy of ALK inhibitors in Asian patients with ALK inhibitor-naïve advanced ALK-positive non-small cell lung cancer: a systematic review and network meta-analysisPublication Name: Translational Lung Cancer ResearchPublication Date: 2024-08-31PMCID: PMC11384493PMID: 39263024DOI: 10.21037/tlcr-24-604
- Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trialPublication Name: Signal Transduction and Targeted TherapyPublication Date: 2023-08-14PMCID: PMC10423717PMID: 37574511DOI: 10.1038/s41392-023-01538-w
- Pharmacokinetic, pharmacodynamic, and behavioural studies of deschloroketamine in Wistar ratsPublication Name: British Journal of PharmacologyPublication Date: 2021-10-31PMID: 34519023DOI: 10.1111/bph.15680
//////////Envonalkib, china 2024, approvals 2024, TQ-B3139, TQ B3139, Chia Tai Tianqing, Anluoqing, cancer, QB7KTQ7VW9
Befotertinib
Befotertinib
D-0316, 0XT2CPR891
CAS No. : 1835667-63-4, MESYLATE CAS No. 2226167-02-6
- 2-propenamide, n-(2-((2-(dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(1-(2,2,2-trifluoroethyl)-1h-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-
- N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-(2,2,2-trifluoroethyl)-1h-indol-3-yl)pyrimidin-2-yl)amino)phenyl)prop-2-enamide
- N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-[1-(2,2,2-trifluoroethyl)indol-3-yl]pyrimidin-2-yl]amino]phenyl]prop-2-enamide
| Molecular Weight | 567.61 |
|---|---|
| Formula | C29H32F3N7O2 |
Befotertinib (D-0316) is an orally active EGFR tyrosine kinase inhibitor. Befotertinib can inhibit the proliferation of tumor cells. Befotertinib can be used in the research of EGFR T790M-positive non-small cell lung cancer (NSCLC).
Befotertinib is an orally available inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. Upon administration, befotertinib specifically binds to and inhibits EGFR T790M, a secondarily acquired resistance mutation, which prevents EGFR-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. Compared to some other EGFR inhibitors, befotertinib may have therapeutic benefits in tumors with T790M-mediated drug resistance. EGFR, a receptor tyrosine kinase that is mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.
PAPER
J. Med. Chem. 2017, 60, 6480−6515.
PATENT
WO 2019218987
https://patentscope.wipo.int/search/en/WO2019218987
[0054]
U.S. Publication No. 2017/0355696 A1 describes a method of preparing Compound 4 and various pharmaceutically acceptable salts thereof. The exemplified synthetic process in U. S. Publication No. 2017/0355696 A1 includes a two-step conversion from the aniline compound, corresponding to Compound 1 of this disclosure, into the bismesylate of Compound 4, which has a low yield.
[0055]
As shown herein, representative methods of preparation of Compound 4, or a pharmaceutically acceptable salt, (or alternatively referred to as synthetic methods) , can provide the desired Compound 4, or a pharmaceutically acceptable salt, in improved yield and high purity and can be adapted for large-scale manufacture.
[0056]
In various embodiments, the present invention provides a novel method of preparing Compound 4, or a pharmaceutically acceptable salt thereof. The method typically includes converting a compound of Formula III, or a salt thereof, into compound 4, typically under an elimination reaction condition:
Syn
https://doi.org/10.1021/acs.jmedchem.4c02079
J. Med. Chem. 2025, 68, 2147−2182
Befotertinib (Surmana). Befotertinib (17), an oral, highly selective, third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed by Betta Pharmaceuticals and InventisBio, was approved in China in May 2023 for the second-line treatment of patients
with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) with positive EGFR T790 M mutation who have disease progression on previous EGFR TKI therapy. 140 139 NSCLC
has a high incidence and disease burden in China, which has spurred the development of multiple EGFR TKIs by Chinese companies.
Achromatography-free process route to befotertinib (17) has been reported in the patent literature by researchers at InventisBio (Scheme 29), although details about scale and yields were not provided.
141 142 The reaction sequence closely follows that of osimertinib, a third generation EGFR inhibitor
that was first approved in 2015 and was covered in our previous review.
Osimertinib and befotertinib share a common backbone, differing only in N-substitution on the indole ring.
Friedel−Crafts arylation of 1H-indole with 2,4-dichloropyrimidine (17.1) gave the 3-pyrimidinyl indole 17.2. The trifluoroethyl moiety in indole 17.4 was introduced via Nalkylation of 17.2 with triflate 17.3. This was followed by an SAr reaction with nitroaniline 17.5 to provide amino pyrimidine 17.6. Next, N,N,N′-trimethylethylenediamine (17.7) displaced the electrophilic aryl fluoride in an SNArreaction to generate intermediate 17.8. The acrylamide moiety was installed using a three-step sequence: hydrogenolytic
reduction of the nitro group to the corresponding aniline, acylation with 3-chloropropanoyl chloride, and immediate elimination to the acrylamide. Mesylate salt formation and crystallization furnished befotertinib mesylate (17) in eight steps from 17.1.
(139) Blair, H. A. Befotertinib: first approval. Drugs 2023, 83, 1433−
1437.
(140) Lau, S. C. M.; Ou, S.-H. I. And still they come over troubled
waters: can Asia’s third-generation EGFR tyrosine kinase inhibitors
(Furmonertinib, Aumolertinib, Rezivertinib, Limertinib, Befotertinib,
SH-1028, and Lazertinib) affect global treatment of EGFR+ NSCLC. J.
Thorac. Oncol. 2022, 17, 1144−1154.
(141) Dai, X.; Jiang, Y. Preparation of pyrimidine derivative and its
pharmaceutical salt as EGFR inhibitors for the treatment of cancer and
other diseases. WO 2019218987, 2019.
(142) Flick, A. C.; Ding, H. X.; Leverett, C. A.; Kyne, R. E.; Liu, K. K.
C.; Fink, S. J.; O’Donnell, C. J. Synthetic approaches to the new drugs
approved during 2015. J. Med. Chem. 2017, 60, 6480−6515.
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- [1]. Nagasaka M, et, al. Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC. J Thorac Oncol. 2021 May;16(5):740-763. [Content Brief][2]. Blair HA. Befotertinib: First Approval. Drugs. 2023 Oct;83(15):1433-1437. [Content Brief]
/////////Befotertinib, APPROVALS 2023, CHINA 2023, Betta Pharmaceuticals, InventisBio, CANCER, D-0316, D 0316, 0XT2CPR891
Olverembatinib
Olverembatinib
1257628-77-5- 3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
- HQP1351
- 4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide
- HQP1351 is under investigation in clinical trial NCT03883100 (A Pivotal Study of HQP1351 in Patients of Chronic Myeloid Leukemia in Accelerated Phase With T315I Mutation).
- 4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide
- D-824
- GZD824
WeightAverage: 532.571
Monoisotopic: 532.219844002, Chemical FormulaC29H27F3N6O
| Molecular Weight | 724.77 |
|---|---|
| Formula | C31H35F3N6O7S2 |
Olverembatinib (GZD824) dimesylate is a potent and orally active pan-Bcr-Abl inhibitor. Olverembatinib dimesylate potently inhibits a broad spectrum of Bcr-Abl mutants. Olverembatinib dimesylate strongly inhibits native Bcr-Abl and Bcr-AblT315I with IC50s of 0.34 nM and 0.68 nM, respectively. Olverembatinib dimesylate has antitumor activity. Olverembatinib (dimesylate) is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
Olverembatinib is a BCR-ABL1 tyrosine kinase inhibitor developed by Ascentage Pharma. In 2021, it was approved in China “for the treatment of adult patients with TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP) harbouring the T315I mutation”.[1][2][3]
SYN
Ren, Xiaomei;Pan, Xiaofen;Zhang, Zhang;Wang, Deping;Lu, Xiaoyun;Li, Yupeng;Wen, Donghai;Long, Huoyou;Luo, Jinfeng;Feng, Yubing;Zhuang, Xiaoxi;Zhang, Fengxiang;Liu, Jianqi;Leng, Fang;Lang, Xingfen;Bai, Yang;She, Miaoqin;Tu, Zhengchao;Pan, Jingxuan;Ding, Ke [Journal of Medicinal Chemistry,2013,vol. 56,# 3,p. 879 – 894]
https://pubs.acs.org/doi/10.1021/jm301581y
PATENT
CN 114163434
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN355399053&_cid=P10-MDPKRT-75688-1
| Example |
| The following examples further illustrate but do not limit the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the inventive concept of the present invention, all of which are included in the scope of protection of the present invention. |
| The specific conditions not disclosed in the experimental methods of the following examples can be selected according to conventional methods and conditions, or according to the product instructions. |
| Unless otherwise specified, “room temperature” in the following examples refers to 20°C to 25°C. The term “h” used herein refers to hours. |
| Example 1 |
| Step 1: |
| |
| Under nitrogen, N-methylpyrrolidone (137.6 g) was heated to 30-35°C to obtain the compound of Formula 1 (14.4 g, 1.3 eq) and the compound of Formula 2 (19.14 g, 1 eq). Bis(triphenylphosphate)palladium dichloride (0.46 g, 0.01 eq) and cuprous iodide (0.113 g, 0.01 eq) were added sequentially. Triethylamine (9.45 g, 1.5 eq) was then added under nitrogen. The reaction mixture was heated to 65-75°C and maintained at this temperature for 2 hours. The reaction process was monitored by liquid chromatography-mass spectrometry. The reaction was terminated when the content of the compound of Formula 2 was ≤0.1%. After completion of the reaction, the reaction solution was cooled to 35-45°C and N-acetyl-L-cysteine (1 g, 0.1 eq) was added directly. The reaction was stirred for 4-5 hours. The resulting product was cooled to room temperature, precipitated with water, centrifuged, and washed with pure water to obtain a crude filter cake. The crude filter cake was vacuum-dried and then slurried with a mixture of ethyl acetate and n-heptane (5 mL of the mixed solvent, wherein the volume ratio of ethyl acetate to n-heptane was 1:1) at a rate of 5 mL per gram of crude filter cake. The resulting slurry was vacuum-dried to yield the compound of Formula 3 with a yield of 85.97% and a purity of 98.2%. |
| The NMR data for the compound of Formula 3 are as follows : 1 H NMR (400 MHz, d-DMSO): δ ppm: 8.93 (1H, d, J = 2.0 Hz); 8.63 (1H, d, J = 2.0 Hz); 8.49 (1H, s); 8.11 (1H, d, J = 2.0 Hz); 7.92 (1H, dd, J = 1.6 Hz; J = 8.0 Hz); 7.52 (1H, d, J = 8.0 Hz); 3.88 (3H, s); 2.59 (3H, s); 1.65 (9H, s). |
| Step 2: |
| |
| Under nitrogen, methanol (160 g) and water (50 g) were sequentially added to the compound of formula 3 (20 g, 1.0 eq). The reaction system was stirred at reflux for 18 hours with process control. The resulting product was cooled to room temperature and filtered to obtain a filter cake (no drying required). Recrystallization was performed by adding 10 times the mass of the filter cake in methanol. The resulting mixture was stirred at 60-70°C for 8-10 hours, then cooled to 40-50°C and subjected to a gradient cooling process at a cooling rate of 5°C per 1 to 1.5 hours to slowly form a solid precipitate. The resulting mixture was filtered, the filter cake was washed with methanol, and vacuum dried to obtain the compound of formula 4 in a 91% yield and 99.7% purity. |
| The NMR data for the compound of Formula 4 are as follows : 1 H NMR (400 MHz, d-DMSO): δ ppm: 8.73 (1H, d, J = 2.0 Hz); 8.52 (1H, t, J = 2.0 Hz); 8.21 (1H, d, J = 2.0 Hz); 8.06 (1H, s); 7.86 (1H, dd, J1 = 2.0 Hz; J2 = 8.0 Hz); 7.49 (1H, dd, J1 = 1.6 Hz; J2 = 7.6 Hz); 3.86 (3H, s); 2.56 (3H, s). |
| Step 3: |
| |
| Under nitrogen, THF (448 mL), compound of formula 4 (29.1 g, 1 eq), and compound of formula 5 (24.6 g, 0.9 eq) were added, stirred, and cooled to -65°C to -60°C. At this temperature, potassium tert-butoxide (19 g x 3) was added in batches every 0.5 h. The reaction process was controlled by liquid phase detection. After 2 hours, the reaction temperature was raised to -5 to 0°C. The reaction solution was washed with purified water, stirred for 0.5-1 hour, washed with brine, and separated to obtain an organic phase. N-acetyl-L-cysteine (11.41 g, 0.7 eq) was added to the organic phase, stirred, washed with brine, neutralized, and concentrated under reduced pressure. The resulting filter cake was washed with purified water and made into a slurry. The resulting product was washed again with purified water and dried under vacuum to obtain compound of formula 6 with a yield of 88.2% and a purity of 98.6%. |
| The NMR data for the compound of formula 6 are as follows : 1 H NMR (400 MHz, d-DMSO): δ ppm: 10.53 (1H, s); 8.75 (d, J = 2.0); 8.53 (d, J = 2.4); 8.24 (1H, s); 8.23 (d, J = 2.4); 8.21 (d, J = 1.6); 8.09 (dd, J1 = 1.6; J2 = 8.4); 7.94 (dd, J1 = 2.0; J2 = 8.0); 7.71 (d, J = 8.8); 7.53 (d, J = 8.0); 3.56 (2H, s); 2.59 (3H, s); 2.34-2.35 (8H, m), 2.16 (3H, s). |
| Its carbon spectrum data are 13 C NMR (100 MHz, d-DMSO): δ ppm: 20.38, 45.65, 52.64, 54.67, 57.41, 88.26, 91.86, 111.76, 113.98, 117.19, 122.14, 123.43, 127.35 (q), 124.30 (q), 128.10, 129.89, 130.49, 131.15, 132.02, 132.13, 132.93, 133.66, 138.15, 143.65, 150.55, 164.64. |
PATENT
CN 101885722
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN84081329&_cid=P10-MDPKML-68458-1
| Example 23 |
| 3-((1H-pyrazolo[3,4-b]pyridine-5-substituted)ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-substituted)methyl)3-(trifluoromethyl)phenyl)benzamide (D824) |
| (3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)m ethyl)-3-(trifluoromethyl)phenyl)benzamide) |
| The synthesis method is the same as in Example 1. |
| 1 HNMR (400MHz, d-DMSO), δ13.92 (s, 1H), 10.55 (s, 1H), 8.72 (d, J=2.0Hz, 1H), 8.52 (d, J=2.0Hz, 1H), 8.17 (m, 3H), 8.10 (d, J=8.0Hz, 1H), 7.92 (dd, J=8.0, 2.0Hz, 1H), 7.70 (d, J=8.8Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 3.80 (s, 2H), 3.10 (brs, 8H), 2.71 (s, 3H), 2.57 (s, 3H). |
| MS(ESI), m/z: 533, (M + +H + ). |
SYN
Olverembatinib(24) wasdeveloped by Ascentage Pharma as anorally available, third-generation
tyrosinekinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), acute myeloid leukemia, acute lymphoblastic leukemia (ALL), and solid tumors.167 It received its first approval inChina inNovember 2021 and was approved for use in adults with TKI-resistant CML chronicphaseandCML-acceleratephaseharboringtheT315I “gatekeeper” mutation.168 The current mainstay of CML
treatmentiscenteredaroundTKIs;however,resistancetoTKItherapy, often through BCR-ABL1 kinase domain point mutations, remains a challenge for early generation therapies.169Olverembatinibretainsitsefficacybyfunctioningasan ATP-bindingsiteinhibitorofwild-typeBCR-ABL1kinaseand broadly relatedmutants including T315I, which otherwise confers resistance against all first and second generation TKIs.168
Thesynthesisofolverembatinibhasbeenreportedinseveral patents,170−172 aswell as a journal article173 that details the divergentapproachtorelatedanalogues. Inarecentpatent,170 the synthesis of olverembatinib began with a Sonogashira coupling of commercially available alkyne 24.1 with
bromopyridine24.2toaffordester24.3in98%yield(Scheme43). Cleavage of the N-Boc group was accomplished by refluxingcarbamate24.3inaMeOHandwatermixturetogive pyrazole24.4 in91%yield. AfinalKOtBumediatedamide formation with aniline 24.5 resulted in the isolation of
olverembatinib(24) in88%yield.
(167) Dhillon, S. Olverembatinib: First approval. Drugs 2022, 82,
469−475.
(168) Braun, T. P.; Eide, C. A.; Druker, B. J. Response and resistance
to BCR-ABL1-targeted therapies. Cancer Cell 2020, 37, 530−542.
(169) Shoukier, M.; Kubiak, M.; Cortes, J. Review of new-generation
tyrosine kinase inhibitors for chronic myeloid leukemia. Curr. Oncol.
Rep. 2021, 23, 91.
(170) Wen, J.; Feng, J.; Wu, T.; Cai, M.; Teng, S. Preparation
method of alkynyl containing compound and its intermediate. China
Patent CN 114163434, 2022.
(171) Guo, M.; Wen, J.; Teng, S.; Wu, T.; Feng, J. Preparation of
(trifluoromethylphenyl)(pyrazolo[3,4-b]pyridinylethynyl)benzamide
derivative. China Patent CN 113292556, 2021.
(172) Ding, K.; Wang, D.; Pei, D.; Zhang, Z.; Shen, M.; Luo, K.;
Feng, Y. Heterocyclic alkynylbenzene derivatives as cancer cell line
inhibitors and their preparation, pharmaceutical compositions and use
in the treatment of cancer. China Patent CN 101885722, 2010.
(173) Ren, X.; Pan, X.; Zhang, Z.; Wang, D.; Lu, X.; Li, Y.; Wen, D.;
Long, H.; Luo, J.; Feng, Y.; et al. Identification of GZD824 as an
orally bioavailable inhibitor that targets phosphorylated and non
phosphorylated breakpoint cluster region−abelson (Bcr-Abl) kinase
and overcomes clinically acquired mutation-induced resistance against
imatinib. J. Med. Chem. 2013, 56, 879−894.
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References
- Dhillon, Sohita (March 2022). “Olverembatinib: First Approval”. Drugs. 82 (4): 469–475. doi:10.1007/s40265-022-01680-9. PMID 35195876. S2CID 247027755.
- Jiang, Qian; Li, Zongru; Qin, Yazhen; Li, Weiming; Xu, Na; Liu, Bingcheng; Zhang, Yanli; Meng, Li; Zhu, Huanling; Du, Xin; Chen, Suning; Liang, Yang; Hu, Yu; Liu, Xiaoli; Song, Yongping; Men, Lichuang; Chen, Zi; Niu, Qian; Wang, Hengbang; Lu, Ming; Yang, Dajun; Zhai, Yifan; Huang, Xiaojun (18 August 2022). “Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial”. Journal of Hematology & Oncology. 15 (1): 113. doi:10.1186/s13045-022-01334-z. PMC 9389804. PMID 35982483.
- Jiang, Qian; Huang, Xiaojun; Chen, Zi; Niu, Qian; Shi, Dayu; Li, Zongru; Hou, Yue; Hu, Yu; Li, Weiming; Liu, Xiaoli; Xu, Na; Song, Yongping; Zhang, Yanli; Meng, Li; Hong, Zhenya; Liu, Bingcheng; Zeng, Shan; Men, Lichuang; Li, Yan; Chen, Suning; Xue, Mengxing; Zhu, Huanling; Li, He; Du, Xin; Lou, Jin; Zhang, Xiaohan; Liang, Yang; Dai, Yujun; Lu, Ming; Wang, Hengbang; Ji, Jiao; Yue, Changai; Yang, Dajun; Zhai, Yifan (5 November 2020). “Novel BCR-ABL1 Tyrosine Kinase Inhibitor (TKI) HQP1351 (Olverembatinib) Is Efficacious and Well Tolerated in Patients with T315I-Mutated Chronic Myeloid Leukemia (CML): Results of Pivotal (Phase II) Trials”. Blood. 136 (Supplement 1): 50–51. doi:10.1182/blood-2020-142142. S2CID 228875477.
| Clinical data | |
|---|---|
| Other names | GZD-824; GZD824 |
| Legal status | |
| Legal status | Investigational |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1257628-77-5 |
| PubChem CID | 51038269 |
| IUPHAR/BPS | 10630 |
| DrugBank | DB16185 |
| ChemSpider | 29395146 |
| UNII | KV1M7Q3CBP |
| ChEMBL | ChEMBL2316582 |
| CompTox Dashboard (EPA) | DTXSID301352011 |
| Chemical and physical data | |
| Formula | C29H27F3N6O |
| Molar mass | 532.571 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
[1]. Ren X, Pan X, Zhang Z, Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J Med Chem. 2013 Feb 14;56(3):879-94. [Content Brief]
//////////Olverembatinib, approvals 2021, china 2021, Ascentage Pharma, cancer, HQP1351, HQP 1351, D-824, D 824, KV1M7Q3CBP, GZD824
Sontigidomide
Sontigidomide
CAS 2560577-69-5
| Molecular Weight | 513.47 |
|---|---|
| Formula | C26H22F3N3O5 |
N-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α-oxo-4-[1-(trifluoromethyl)cyclopropyl]benzeneacetamide
enzeneacetamide, N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α-oxo-4-[1-(trifluoromethyl)cyclopropyl]-
FDD2NVW84X, Sontigidomida
Sontigidomide (Compound 5) is an antineoplastic compound. Sontigidomide inhibits MOLM-13 cell proliferation more than 80% at 1 μM (3 days).
SCHEME
COUPLER………….
MAIN……….
PATENTS
WO2023070120 BioTheryX, Inc.
PATENT
US20200369679
https://patentscope.wipo.int/search/en/detail.jsf?docId=US311579044&_cid=P20-MD87Y5-18242-1
Example 5
Compound I-5: N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide
Compound I-5 was synthesized as shown in Scheme 5.
To a solution of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 8 (80 mg, 0.258 mmol) in DCM (4 mL) at 0° C. was added TEA (52.2 mg, 0.516 mmol). After stirring for 2 min, 2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetyl chloride 13 (71.3 mg, 0.258 mmol) was added and the mixture was stirred at RT for 2 h. After concentration, the residue was purified using prep-HPLC eluting with ACN/H 2O (0.1% TFA) from 10% to 95% to afford compound I-5 (16.1 mg) in 12% yield. MS (ESI) m/z: 514.0 [M+H] +; 1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H), 9.57 (t, J=6.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.74-7.48 (m, 7H), 5.13-5.09 (m, 1H), 4.59-4.57 (m, 2H), 4.49-4.31 (m, 2H), 2.95-2.87 (m, 1H), 2.63-2.58 (m, 1H), 2.45-2.38 (m, 1H), 2.03-1.99 (m, 1H), 1.43-1.40 (m, 2H), 1.24-1.21 (m, 2H).
- Ketoamides for treating malignancyPublication Number: WO-2023070120-A1Priority Date: 2021-10-22
- Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: US-2020369679-A1Priority Date: 2019-05-24
- Compounds targeting proteins and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: WO-2020242960-A1Priority Date: 2019-05-24
- Compounds targeting proteins and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: AU-2020283744-A1Priority Date: 2019-05-24
- Targeted protein compound, its pharmaceutical composition and therapeutic applicationPublication Number: CN-114502543-APriority Date: 2019-05-24
- Compounds targeting proteins and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: EP-3976623-A1Priority Date: 2019-05-24
- Protein targeting compounds, pharmaceutical compositions thereof and therapeutic applications thereofPublication Number: KR-20220023343-APriority Date: 2019-05-24
- Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: US-11345712-B2Priority Date: 2019-05-24Grant Date: 2022-05-31
- Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applicationsPublication Number: US-2022298172-A1Priority Date: 2019-05-24
////////Sontigidomide, FDD2NVW84X, CANCER, Sontigidomida
..
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Taletrectinib
Taletrectinib
CAS 1505514-27-1
as salt: 1505515-69-4, Taletrectinib adipate
FDA 6/11/2025, Ibtrozi, To treat locally advanced or metastatic ROS1-positive non-small cell lung cancer ALSO CHINA 2024 APPROVED |
405.5 g/mol, C23H24FN5O, UNII-W4141180YD
3-[4-[(2R)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine
Taletrectinib adipate
WeightAverage: 551.619
Monoisotopic: 551.254397378
Chemical FormulaC29H34FN5O5
DS-6051B, CAS 1505515-69-4,
6KLL51GNBG, 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine; hexanedioic acid
Taletrectinib, sold under the brand name Ibtrozi, is an anti-cancer medication used for the treatment of non-small cell lung cancer.[1][2] It is used as the salt, taletrectinib adipate.[1] Taletrectinib is a kinase inhibitor.[1] It is taken by mouth.[1]
Taletrectinib was approved for medical use in the United States in June 2025.[3]
SYN
US20200062765
https://patentscope.wipo.int/search/en/detail.jsf?docId=US289038418&_cid=P12-MCIHV1-02369-1
Example 1
tert-Butyl [(2R)-1-(4-bromophenoxy)propan-2-yl]carbamate (1)
Example 2
6-Fluoroimidazo[1,2-b]pyridazine methanesulfonate (2)
Example 3
tert-Butyl {(2R)-1-[4-(6-fluoroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate (3)
Example 4
tert-Butyl {(2R)-1-[4-(6-{[(1R)-1-(3-fluorophenyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate hydrochloride (4)
Example 5
3-{4-[(2R)-2-Aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine dihydrochloride (5)
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023272701&_cid=P12-MCIHPU-95869-1
The NMR data for the crystalline form A of Compound 1 adipate are as follows: 1H NMR (500 MHz, DMSO) δ 1.13-1.14 (d, J=5.0 Hz, 3H) , 1.47-1.48 (d, J=5.0 Hz, 7H) , 2.15-2.18 (t, J=5.0 Hz, J=10.0 Hz, 4H) , 3.25-3.29 (m, 1H) , 3.79-3.83 (m, 2H) , 4.80-4.85 (m, 1H) , 6.76-6.77 (d, J=5.0 Hz, 1H) , 6.92-6.94 (d, J=10.0 Hz, 2H) , 7.01-7.05 (t, J=10.0 Hz, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.64-7.65 (d, J=5.0 Hz, 1H) , 7.72-7.76 (t, J=10.0 Hz, 4H) .
[0148]
The IR data for the crystalline form A of Compound 1 adipate are as follows: IR (cm -1) : 1701, 1628, 1612, 1586, 1463, 1333, 1246, 1110, 829, 821.
Example 5: Preparation and Characterization of Crystalline Form A of Compound 1 Free Base
[0212]
Compound 1 HCl (75.5 g) (e.g., obtained by using the method described in Example 5 of U.S. Application Publication No. 2020/0062765) was dissolved in ethanol (604 mL) at 50℃. Sodium hydroxide (68.1 g) was added to the above solution. The mixture was cooled to 1℃ in 1.5 hours and stirred for 18.5 hours. The mixture was then filtered, and the solid thus obtained was washed with a cooled mixture of ethanol (151 mL) and water (151 mL) and dried. The solid thus obtained was confirmed to be the crystalline form A of Compound 1 free base.
[0213]
The NMR data for the crystalline form A of Compound 1 free base are as follows: 1H NMR (500 MHz, DMSO) δ 1.09-1.10 (d, J=5.0 Hz, 3H) , 1.48-1.49 (d, J=5.0 Hz, 3H) , 3.16-3.20 (m, 1H) , 3.75-3.79 (m, 2H) , 4.82-4.86 (m, 1H) , 6.76-6.78 (d, J=10.0 Hz, 1H) , 6.92-6.94 (m, 2H) , 7.01-7.05 (m, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.62-7.63 (d, J=5.0 Hz, 1H) , 7.72-7.75 (m, 4H) .
[0214]
The IR data for the crystalline form A of Compound 1 free base are as follows: IR (cm -1) : 3350, 3247, 3055, 2961, 2923, 2864, 1611, 1586, 1349, 829, 819.
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Taletrectinib is an oral, next-generation ROS1 TKI developed by Nuvation Bio Inc. for the treatment of ROS1-positive NSCLC. In 2024, the NMPA approved taletrectinib for adult patients with locally advanced or metastatic ROS1-positive NSCLC, regardless of prior ROS1TKI treatment [47]. Under an exclusive license agreement, Innovent Biologics will commercialize taletrectinib in China under the brand
name DOVBLERON®. Taletrectinib exerts its pharmacological action through the mechanism of selectively impeding the ROS1 receptor tyrosine kinase, which effectively disrupts the signaling cascades which are responsible for facilitating the growth and survival of cancer cells in ROS1-positive NSCLC. This inhibition of the ROS1 receptor tyrosine kinase is a key event in the drug’s mode of action, as it specifically targets the molecular processes that drive the progression of the disease in ROS1-positive NSCLC cases [48]. The NMPA granted approval founded on the data sourced from the crucial Phase 2 TRUST – I study. This study substantiated that patients administered with taletrectinib achieved sustained responses and extended PFS. Regarding safety, taletrectinib boasted a generally good tolerability. It presented an advantageous safety profile and favorable tolerability characteristics, as evidenced by the low incidences of dose reduction and treatment discontinuation triggered by adverse effects. [49]. Overall, taletrectinib represents a promising therapeutic option for patients with advanced ROS1-positive NSCLC, offering efficacy in both TKI-naïve and TKI-pretreated populations, including those with CNS metastases [50–52].
The synthesis of Taletrectinib, illustrated in Scheme 12, commences with Mitsunobu coupling of Tale-001 and Tale-002 to afford Tale-003, which then undergoes Suzuki coupling with Tale-004 constructing
Tale-005 [53]. Sequential acidolysis/deprotection of Tale-005 ultimately delivers Taletrectinib
[47] M. P´ erol, N. Yang, C.M. Choi, Y. Ohe, S. Sugawara, N. Yanagitani, G. Liu, F.G.M.
D. Braud, J. Nieva, M. Nagasaka, 1373P efficacy and safety of taletrectinib in
patients (pts) with ROS1+ non-small cell lung cancer (NSCLC): interim analysis of
global TRUST-II study, Ann. Oncol. 34 (2023) S788–S789.
[48] G. Harada, F.C. Santini, C. Wilhelm, A. Drilon, NTRK fusions in lung cancer: from
biology to therapy, Lung Cancer 161 (2021) 108–113.
[49] W. Li, A. Xiong, N. Yang, H. Fan, Q. Yu, Y. Zhao, Y. Wang, X. Meng, J. Wu, Z. Wang,
Y. Liu, X. Wang, X. Qin, K. Lu, W. Zhuang, Y. Ren, X. Zhang, B. Yan, C.M. Lovly,
C. Zhou, Efficacy and safety of taletrectinib in Chinese patients with ROS1+ non-
small cell lung cancer: the phase II TRUST-I study, J. Clin. Oncol. 42 (2024)
2660–2670.
[50] M. Nagasaka, D. Brazel, S.I. Ou, Taletrectinib for the treatment of ROS-1 positive
non-small cell lung cancer: a drug evaluation of phase I and II data, Expert Opin
Investig Drugs 33 (2024) 79–84.
[51] S. Waliany, J.J. Lin, Taletrectinib: TRUST in the continued evolution of treatments
for ROS1 fusion-positive lung cancer, J. Clin. Oncol. 42 (2024) 2622–2627.
[52] M. Nagasaka, Y. Ohe, C. Zhou, C.M. Choi, N. Yang, G. Liu, E. Felip, M. P´ erol,
B. Besse, J. Nieva, L. Raez, N.A. Pennell, A. Dimou, F. Marinis, F. Ciardiello,
T. Seto, Z. Hu, M. Pan, W. Wang, S. Li, S.I. Ou, TRUST-II: a global phase II study of
taletrectinib in ROS1-positive non-small-cell lung cancer and other solid tumors,
Future Oncol. 19 (2023) 123–135.
[53] Y. Takeda, K. Yoshikawa, Y. Kagoshima, Y. Yamamoto, R. Tanaka, Y. Tominaga,
M. Kiga, Y. Hamada, Preparation of imidazo[1,2-b]pyridazine Derivatives as
Potent Inhibitors of ROS1 Kinase and NTRK Kinase, 2013. WO2013183578A1.
Medical uses
Taletrectinib is indicated for the treatment of adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer.[1][2]
Adverse effects
The FDA prescribing information for taletrectinib includes warnings and precautions for hepatotoxicity, interstitial lung disease/pneumonitis, QTc interval prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, skeletal fractures, and embryo-fetal toxicity.[1][3]
History
The efficacy of taletrectinib to treat ROS1-positive non-small cell lung cancer was evaluated in participants with locally advanced or metastatic, ROS1-positive non-small cell lung cancer enrolled in two multi-center, single-arm, open-label clinical trials, TRUST-I (NCT04395677) and TRUST-II (NCT04919811).[3] The efficacy population included 157 participants (103 in TRUST-I; 54 in TRUST-II) who were naïve to treatment with a ROS1 tyrosine kinase inhibitor (TKI) and 113 participants (66 in TRUST-I; 47 in TRUST-II) who had received one prior ROS1 tyrosine kinase inhibitor.[3] Participants may have received prior chemotherapy for advanced disease.[3] The US Food and Drug Administration (FDA) granted the application for taletrectinib priority review, breakthrough therapy, and orphan drug designations.[3]
Society and culture
Legal status
Taletrectinib was approved for medical use in the United States in June 2025.[3][4]
Names
Taletrectinib is the international nonproprietary name.[5]
Taletrectinib is sold under the brand name Ibtrozi.[3][4]
References
- ^ Jump up to:a b c d e f g “Prescribing Information for NDA 219713, Supplement 000” (PDF). Drugs@FDA. U.S. Food and Drug Administration. April 2025. Retrieved 14 June 2025.
- ^ Jump up to:a b Khan I, Sahar A, Numra S, Saha N, Nidhi, Parveen R (April 2025). “Efficacy and safety of taletrectinib for treatment of ROS1 positive non-small cell lung cancer: A systematic review”. Expert Opinion on Pharmacotherapy. 26 (6): 765–772. doi:10.1080/14656566.2025.2487150. PMID 40170301.
- ^ Jump up to:a b c d e f g h “FDA approves taletrectinib for ROS1-positive non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 11 June 2025. Retrieved 13 June 2025. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b “U.S. Food and Drug Administration Approves Nuvation Bio’s Ibtrozi (taletrectinib), a Next-Generation Oral Treatment for Advanced ROS1-Positive Non-Small Cell Lung Cancer”. Nuvation Bio (Press release). 12 June 2025. Retrieved 13 June 2025.
- ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85”. WHO Drug Information. 35 (1). hdl:10665/340684.
External links
- Clinical trial number NCT04395677 for “A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene” at ClinicalTrials.gov
- Clinical trial number NCT04919811 for “Taletrectinib Phase 2 Global Study in ROS1 Positive NSCLC (TRUST-II)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Ibtrozi |
| License data | US DailyMed: Taletrectinib |
| Routes of administration | By mouth |
| Drug class | Antineoplastic |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| CAS Number | 1505514-27-1as salt: 1505515-69-4 |
| PubChem CID | 72202474as salt: 72694302 |
| DrugBank | DB18711 |
| ChemSpider | 114934673as salt: 88297530 |
| UNII | W4141180YDas salt: 6KLL51GNBG |
| KEGG | D12363as salt: D12364 |
| ChEMBL | ChEMBL4650989as salt: ChEMBL4650361 |
| Chemical and physical data | |
| Formula | C23H24FN5O |
| Molar mass | 405.477 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
/////////Taletrectinib, FDA 2025, APPROVALS 2025, Ibtrozi, CANCER, AB-106, DS-6051a, UNII-W4141180YD, DS 6051B, APPROVALS 2024, CHINA 2024, Nuvation Bio Inc
Alflutinib, Furmonertinib, Firmonertinib
FIRMOMERTINIB, Furmonertinib, Alflutinib
CAS 1869057-83-9
, AST 2818, UNII-A49A7A5YN4
N-[2-[[2-(Dimethylamino)ethyl]methylamino]-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-2-propenamide
N-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]prop-2-enamide
C28H31F3N8O2 568.6 g/mol
2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]-6-(2,2,2-trifluoroethoxy)-3-pyridinyl]-
Alflutinib is under investigation in clinical trial NCT03452592 (Efficacy and Safety of Alflutinib in Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients With T790M).
Firmonertinib is an orally available selective inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. Upon administration, firmonertinib specifically binds to and inhibits the tyrosine kinase activity of EGFR T790M, a secondarily acquired resistance mutation. This prevents EGFR T790M-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. EGFR, a receptor tyrosine kinase that is mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. Compared to some other EGFR inhibitors, alflutinib may have therapeutic benefits in tumors with T790M-mediated drug resistance.
FIRMONERTINIB is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 4 investigational indications.
SCHEME
CONTD……..
REF
https://patentscope.wipo.int/search/en/detail.jsf?docId=US201062358&_cid=P22-MBFXFH-62339-1
Example 3: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide
Step 1: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridin-2,5-diamine
| The compound was synthesized in the same manner as those in Step 1 of Example 1 with a yield of 86%. MS m/z: 545 [M+1]. |
Step 2: Synthesis of N2-methyl-N2-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-N5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]pyridin-2,3,5-triamine
| The compound was synthesized in the same manner as those in Step 2 of Example 2 with a yield of 56%. MS m/z: 515 [M+1]. |
Step 3: Synthesis of N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide
| The compound was synthesized in the same manner as those in Step 3 of Example 1 with a yield of 23%. MS m/z: 569 [M+1]. |
PATENT
CN110606842
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN280196686&_cid=P22-MBFXJY-67679-1
Patent application CN105315259A protects the compound of formula I and discloses its preparation method as follows:
| Example 1: Preparation of 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (XI-1) |
| Add toluene (24.0L) to the reactor, then add 2,6-dichloro-3-nitropyridine (3000g, 15.54mol), adjust the internal temperature between -20℃ and -10℃, and add sodium hydrogen (933g, 23.33mol) in batches. Add 2,2,2-trifluoroethanol (1586g, 16.00mol) toluene (6.0L) solution dropwise. React for 2h, and monitor the reaction end point by TLC and HPLC. After the reaction is completed, add 10% ammonium chloride solution (6.0L) dropwise. Let stand and separate. Wash the organic phase with water (6.0L) and concentrate under reduced pressure. Add ethyl acetate (0.3L), heat to 40-50℃, add n-heptane (2.7L) dropwise, cool to -15 to -5℃ after dripping, and continue crystallization for 3 hours, and filter with suction. Obtain 3017g of product solid, with a yield of 75.65%. |
| 1H NMR(500MHz，DMSO-d6)δ8.60(d，J＝8.0Hz，1H)，7.50(d，J＝8.5Hz，lH)，5.13(q，J＝9.0Hz，2H)； |
| 13C NMR(126MHz，DMSO-d6)δ153.20，151.09，139.34，132.67，123.38(q，J＝277.2Hz)，119.14，63.34(q，J＝36Hz)； |
| MS m/z：256.99[M+1]。 |
| Example 2: Preparation of 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (X-1) |
| At room temperature, add acetonitrile (21.0L) and water (21.0L) to the reactor, start stirring, add 6-chloro-3-nitro-2-(2,2,2-trifluoroethoxy)pyridine (3017.0g, 11.76mol) obtained in Example 1, and add hydrosulfite (15.1Kg, 70.54mol). Control the temperature at 27-33°C to react for 2 hours. Add 36% concentrated hydrochloric acid (11.9Kg, 117.60mol) dropwise, and continue to react for 1.5 hours. Add solid sodium bicarbonate (12.8Kg, 12.96mol). Filter, separate the mother liquor, wash the organic phase with saturated brine (21.0L), and concentrate under reduced pressure to obtain an oily substance. Theoretically calculated for the next step reaction. |
| 1H NMR(500MHz，DMSO-d6)δ7.03(d，J＝8.0Hz，1H)，6.90(d，J＝8.0Hz，1H)，5.21(s，2H)，4.93(q，J＝9.0Hz，2H)； |
| 13C NMR(126MHz，DMSO-d6)δ148.16，131.72，130.55，123.93(q，J＝278.5Hz)，121.02，118.42，61.72(q，J＝34.0Hz)； |
| MS m/z：227.01[M+1]。 |
| Example 3: Preparation of 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (IX-1) |
| At room temperature, dichloromethane (10.4 L) was added to the reaction kettle, stirring was started, 6-chloro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (2664 g, 11.76 mol) obtained in Example 2 was added, diisopropylethylamine (2279 g, 17.64 mol) was added, the temperature was controlled at -15 to -10°C, a dichloromethane (5.2 L) solution of trifluoroacetic anhydride (2963 g, 14.11 mol) was added dropwise, and stirring was continued for 20 minutes after the addition was completed. Water (13.0 L) was added dropwise, the layers were separated, the organic phase was concentrated under reduced pressure, and the next step reaction was theoretically calculated. |
| 1 H NMR(400MHz,DMSO-d6)δ11.23(s,7H),7.95(d,J8.0Hz,1H),7.34(d,J8.0Hz,1H),5.03(q,J8.9Hz,2H) |
| 13C NMR(101MHz，DMSO-d6)δ155.74(q，J＝46.6Hz)，155.60，145.37，140.24，124.01(q，J＝278.8Hz)，119.07，118.30，116.19(q，J＝289.9Hz)，62.99(q，J＝35.4Hz)； |
| MS m/z.322.99[M+1]。 |
| Example 4: Preparation of 6-chloro-5-nitro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (VIII-1) |
| At room temperature, concentrated sulfuric acid (11.7 L) was added to the reaction kettle, stirring was started, 6-chloro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (3.9 Kg, 11.76 mol) obtained in Example 3 was added, and potassium nitrate solid (1783.4 g, 17.64 mol) was added in batches. After the addition, stirring was continued for about 40 minutes. After monitoring the reaction, the temperature was lowered to control the internal temperature at 10-25°C, and dichloromethane (27.3 L) was added dropwise. Stirring was continued, stirring was continued for 45 minutes, and the layers were separated. The organic phase was taken and washed once with water (11.7 L). The organic phase was concentrated under reduced pressure and theoretically calculated for the next step reaction. |
| 1H NMR(500MHz，DMSO-d6)δ11.58(s，1H)，8.78(s，1H)，5.17(q，J＝8.7Hz，2H)； |
| 13C NMR(126MHz，DMSO-d6)δ155.89，155.43(q，J＝37.8Hz)，138.84，138.57，135.05，123.22(q，J＝273.4Hz)，118.47，115.51(q，J＝278.5Hz)，63.65(q，J＝35.3Hz)； |
| MS m/z：367.98[M+1]。 |
| Example 5: Preparation of 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (VII-1) |
| At room temperature, methanol (13.0 L) was added to the reactor, 6-chloro-5-nitro-3-(2,2,2-trifluoroacetamido)-2-(2,2,2-trifluoroethoxy)pyridine (4322 g, 11.76 mol) obtained in Example 4 was added, p-toluenesulfonic acid monohydrate (3355 g, 17.64 mol) was added, the temperature was controlled at 60-65°C for 15 hours, and the methanol was removed under reduced pressure. Methyl tert-butyl ether (13.0 L) and water (6.5 L) were added, and the pH was adjusted to 7-8 with potassium carbonate. Layering was performed, the organic phase was washed once with water (8.6 L), separated, and concentrated under reduced pressure. n-heptane (21.5 L) was added, the temperature was controlled at 60-65°C and stirred for 1 hour, cooled to room temperature, filtered, and the filter cake was dried with air at 50°C for 18 hours to obtain 1475 g of the product. |
| The total yield of the five-step reaction from Example 1 to Example 5 is 34.9%. |
| 1H NMR(500 MHz，DMSO-d6)δ7.62(s，1H)，5.92(s，2H)，5.05(q，J＝8.9Hz，2H). |
| 13C NMR(126MHz，DMSO-d6)δ149.30，139.53，132.84，123.46，123.44(q，J＝278.5Hz)，116.25，62.52(q，J＝35.3Hz)； |
| MS m/z：272.00[M+1]。 |
| Example 6: Preparation of 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (V-1) |
| Toluene (50 mL) was added to a 100 mL reaction bottle, and the compound of formula VII-1, 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (5.0 g, 18.4 mmol), the compound of formula VI, 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (5.8 g, 23.8 mmol), p-toluenesulfonic acid monohydrate (1.8 g, 9.2 mmol) were added in sequence, and the reaction mixture was heated to 110-115°C and reacted for 24 hours. The temperature was lowered to 22°C, filtered by suction, and the filter cake was dried at 50°C for 20 hours to obtain the compound of formula V-1, 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (10.4 g, 74.7 HPLC area% purity). According to the HPLC purity conversion, the next step reaction was carried out. |
| 1H NMR(400MHz，DMSO-d6)δ9.43(s，1H)，8.76(s，1H)，8.46-8.45(d，J＝5.4Hz，1H)，8.39(s，1H)，8.38-8.36(d，J＝7.8Hz，1H)，7.57-7.55(d，J＝8.2Hz，1H)，7.41-7.40(d，J＝5.4Hz，1H)，7.31-7.27(t，J＝7.5Hz，1H)，7.20-7.16(t，J＝7.5Hz，1H)，5.23-5.16(q，J＝8.8Hz，2H)，3.90(s，3H)； |
| MS m/z：479.08[M+1]。 |
| Example 7: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV) |
| Add N,N-dimethylformamide (30 mL) to a 250 mL reaction bottle, add the compound of formula V-1 obtained in Example 6, 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (10.4 g, 16.22 mmol), stir, add potassium carbonate (4.48 g, 32.44 mol), N,N,N’-trimethylethylenediamine (2.48 g, 24.33 mol) in sequence, heat the reaction mixture to 77-82°C, keep warm for 1-1.5 hours. Add water (60 mL), and cool to room temperature after addition. Filter by suction, transfer the filter cake to a 50 L reactor, add acetonitrile (40 mL), and heat to reflux for 2 hours. The mixture was cooled to room temperature and filtered with suction. The filter cake was dried at 50°C for 18 hours to give a compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (6.7 g). The total yield of the two-step reaction with Example 6 was 66.8%. |
| 1H NMR(500MHz，DMSO-d6)δ8.62(s，1H)，8.41(s，1H)，8.26(s，2H)，8.24(s，1H)，7.48(d，J＝8.2Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.16(d，J＝5.3Hz，1H)，7.05(t，J＝7.3Hz，1H)，5.04(q，J＝8.9Hz，2H)，3.84(s，3H)，3.69(t，J＝6.9Hz，2H)，2.89(s，3H)，2.55(t，J＝6.9Hz，2H)，2.17(s，6H)； |
| 13C NMR(126MHz，DMSO-d6)δ162.15，160.55，156.99，154.98，148.42，137.53，132.83，132.68，125.50，123.58(q，J＝279.7Hz)，124.38，122.11，122.06，120.67，113.38，112.27，110.30，107.11，62.14(q，J＝35.3Hz)，56.10，49.51，45.34，45.33，39.35，32.98。 |
| MS m/z.：545.22[M+1]。 |
| Example 8: Preparation of 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (V-1′) |
| Toluene (7.43 L) was added to a 20 L reactor, and compound VII-1 6-chloro-5-nitro-3-amino-2-(2,2,2-trifluoroethoxy)pyridine (743.0 g, 2.74 mol), compound VI 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (866.7 g, 3.56 mol), p-toluenesulfonic acid monohydrate (780.7 g, 4.10 mol) were added in sequence, stirred, and the reaction mixture was heated to 110-115°C and reacted for 36 hours. The temperature was controlled at 15-30°C, tetrahydrofuran (3.72 L) was added and stirred for 30 minutes. Filtered by suction, the filter cake was transferred to a 50 L reactor, tetrahydrofuran (4.46 L) was added, and heated to reflux for 3 hours. The temperature was lowered to 15-25°C, filtered, and the filter cake was dried at 50°C for 17 hours to obtain 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1719 g, 85.96 HPLC area% purity). The purity was calculated according to HPLC and used for the next step reaction. |
| Melting point: 216.0-218.3℃ |
| 1H NMR(500MHz，DMSO-d6)δ9.70(s，1H)，9.21(s，1H)，8.62(s，1H)，8.40(d，J＝6.2Hz，1H)，8.24(d，J＝7.8Hz，1H)，7.59(d，J＝8.3Hz，1H)，7.50(d，J＝6.5Hz，1H)，7.49(d，J＝8.3Hz，2H)，7.32(t，J＝7.6Hz，1H)，7.18(t，J＝7.5Hz，1H)，7.12(d，J＝7.9Hz，2H)，5.17(q，J＝8.8Hz，2H)，3.91(s，3H)，2.29(d，J＝5.2Hz，3H)； |
| 13C NMR(126MHz，DMSO-d6)δ166.66，157.35，155.72，147.40，140.87，139.90，139.72，138.59，135.83，130.09，129.99，129.98，129.97，127.39，127.38，127.37，127.15，125.22(q，J＝278.5Hz)，124.97，123.85，123.69，113.63，112.97，110.27，63.58(q，J＝35.3Hz)，35.57，22.81。 |
| Example 9: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV) |
| Add N,N-dimethylformamide (5.14L) to a 50L reactor, add 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1714.0g, 2.261mol) obtained in Example 8, stir, add potassium carbonate (624.7g, 4.52mol), N,N,N’-trimethylethylenediamine (346.2g, 3.39mol) in sequence, heat the reaction mixture to 77-82°C, keep warm for 1-1.5 hours. Add water (10.28L), and cool to room temperature after adding. Filter by suction, transfer the filter cake to a 50L reactor, add acetonitrile (6.86L), and heat to reflux for 2 hours. The temperature was lowered to 15-25°C, filtered with suction, and the filter cake was dried at 50°C for 18 hours to obtain the compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1142 g). The total yield of the two-step reaction with Example 8 was 76.54%. |
| 1H NMR(500MHz，DMSO-d6)δ8.62(s，1H)，8.41(s，1H)，8.26(s，2H)，8.24(s，1H)，7.48(d，J＝8.2Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.16(d，J＝5.3Hz，1H)，7.05(t，J＝7.3Hz，1H)，5.04(q，J＝8.9Hz，2H)，3.84(s，3H)，3.69(t，J＝6.9Hz，2H)，2.89(s，3H)，2.55(t，J＝6.9Hz，2H)，2.17(s，6H)； |
| 13C NMR(126MHz，DMSO-d6)δ162.15，160.55，156.99，154.98，148.42，137.53，132.83，132.68，125.50，123.58(q，J＝279.7Hz)，124.38，122.11，122.06，120.67，113.38，112.27，110.30，107.11，62.14(q，J＝35.3Hz)，56.10，49.51，45.34，45.33，39.35，32.98。 |
| MS m/z：545.22[M+1]。 |
| Example 10: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (IV) |
| Acetonitrile (10 mL) was added to a 50 L reactor, and 2-chloro-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine p-toluenesulfonate (1.0 g, 1.5 mmol) obtained in Example 8 was added, and stirred. Potassium carbonate (577 mg, 3 mmol) and N,N,N’-trimethylethylenediamine (320 mg, 2.25 mmol) were added in sequence. The reaction mixture was heated to 77-82°C and kept for 1-2 hours. Water (10 mL) was added and the temperature was cooled to room temperature after the addition. The product was filtered to give a compound of formula IV, 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (629 mg) with a purity of 95.94%. The total yield of the two-step reaction with Example 8 was 77%. |
| Example 11: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’) |
| Add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0 g, 7.34 mmol) to a 100 mL reaction bottle at room temperature, add tetrahydrofuran (27 mL) and water (13 mL), and stir for 10 to 20 minutes. Add hydrosulfite (9.6 g, 44.1 mmol) to the reactor in batches. After addition, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 30 to 35 ° C for reaction. The purity of the product compound of formula III’ was 64.68% after sampling the liquid phase after 2 hours of reaction. The reaction was continued until 17 hours after the reaction. 40 mL of water was added to the reaction solution, and the layers were separated by standing. The tetrahydrofuran phase was taken, and the aqueous phase was extracted twice with 100 mL of dichloromethane. The organic phases were combined, washed with saturated brine, separated by standing, and concentrated under reduced pressure to obtain 3.2 g of solid with a purity of 62.32%. |
| 1H NMR(500MHz，DMSO)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，2H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)； |
| MS m/z：515.24[M+1]。 |
| Example 12: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’) |
| In a 100mL single-mouth bottle, there is 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (2.0g, 3.67mmol), palladium carbon (200mg), ethanol (20mL), hydrogen balloon replacement twice, hydrogen gas, magnetic stirring, room temperature overnight (17 hours). After the reaction is completed, suction filtration, the filtrate is taken, and it is concentrated to dryness under reduced pressure to obtain 2.1g of product with a purity of 56.93%. |
| Example 13: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’) |
| At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1317.0 g, 2.42 mol) to a 50 L reactor, add tetrahydrofuran (8.8 L) and water (4.3 L), and stir for 10 to 20 minutes. Add hydrosulfite (2970.0 g, 14.52 mol) to the reactor in batches. After adding, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 40-45 ° C and react for 2 hours. Add concentrated hydrochloric acid (5882.2 g, 58.08 mol) to the reactor. After the addition is complete, heat to 42 to 47 ° C and react for 15 hours. Add 30% sodium hydroxide (2323.2g, 58.08mol) aqueous solution dropwise, and then add solid sodium bicarbonate (1219.7g, 14.52mol) in batches to adjust the pH value to 6-8. After stirring for 20 minutes, filter with suction, let the filtrate stand and separate. The organic phase is concentrated under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine, with a purity of 97.1%. Calculated based on the theoretical yield of 100%, it is directly used in the next step reaction. |
| 1H NMR(500MHz，DMSO)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，2H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)； |
| MS m/z：515.24[M+1]。 |
| Example 14: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (III-1) |
| To the 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine obtained in Example 13, THF (5.3 L) and ethanol (4.0 L) were added, the temperature was raised to 50-70°C, and concentrated hydrochloric acid (617.8 g, 6.1 mol) was added dropwise. After the addition was completed, the mixture was cooled to room temperature and stirred for 12 hours. Filtered by suction, the filter cake was dried by air at 50°C to obtain 1507.4 g of a crude product. Methanol (6.0 L) and ethanol (4.5 L) were added to a 20 L reaction bottle, and the above crude product was added, the temperature was raised to 55-60 ° C, hot slurry was added for 1-2 hours, the temperature was lowered to room temperature, and suction was filtered to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (1335.6 g), the liquid phase purity was 99.80%, and the total yield of the two-step reaction with Example 13 was 94.0%. Melting point: 236.6-240.8 ° C. |
| 1H NMR(500MHz，DMSO-d6)δ10.67(s，1H)，10.36(s，1H)，8.82(s，1H)，8.18(s，1H)，8.01(s，1H)，7.59(d，J＝8.2Hz，1H)，7.45(d，J＝6.8Hz，1H)，7.32(t，J＝7.5Hz，1H)，7.24(s，1H)，4.97(q，J＝8.7Hz，1H)，3.93(s，3H)，3.75(s，2H)，3.41(s，2H)，3.10(s，3H)，2.78(s，6H)； |
| 13C NMR(126MHz，DMSO-d6)δ166.81，153.27，152.17，150.76，138.61，138.16，138.15，125.46，124.94，123.83(q.J＝278.5Hz)，123.42，123.41，122.60，122.59，120.52，111.34，111.17，106.29，62.14(q，J＝35.3Hz)，53.53，46.28，42.27，42.26，40.92，33.67。 |
| Example 15: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (III-1) |
| At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1136.0 g, 2.09 mol) to a 50 L reactor, add acetonitrile (7.95 L) and water (7.95 L), and stir for 10 to 20 minutes. Add hydrosulfite (2563.9 g, 12.50 mol) to the reactor in batches. After adding, continue stirring for 10 to 20 minutes. Control the temperature of the reactor to 35 to 40 ° C and react for 3 hours. Add concentrated hydrochloric acid (2505.3 g, 25.08 mol) to the reactor. After the addition is complete, heat to 35 to 45 ° C and react for 18 hours. 30% sodium hydroxide (1003.2 g, 25.08 mol) aqueous solution was added dropwise to adjust the pH value to 6-8. Solid sodium bicarbonate (1053.5 g, 12.54 mol) was added to adjust the pH value to 7-8. After stirring for 40 minutes, the mixture was filtered, the filtrate was allowed to stand, the layers were separated, and the organic phase was concentrated under reduced pressure. The purity of the liquid phase was detected to be 97.60%. |
| Add ethanol (5.68 L) to the product of the previous step, raise the temperature to 50-70°C, and drop concentrated hydrochloric acid (522 g, 5.23 mol). After the dropwise addition is completed, cool to room temperature and stir for 15 hours. Filter by suction, and air dry the filter cake at 50°C to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (780 g), with a liquid phase purity of 98.74%. |
| Example 16: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (II-1) |
| 2-[2-(Dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine dihydrochloride (1543.5 g, 2.63 mol) was added to a 50 L reactor, and dichloromethane (13.1 L) and triethylamine (532.2 g, 5.26 mol) were added. The mixture was stirred and cooled to -10 to -5 °C, and a solution of 3-chloropropionyl chloride (501.5 g, 3.95 mol) in dichloromethane (10.0 L) was added dropwise. After the addition is completed, keep warm and stir for 10 to 20 minutes, filter with suction, and the filter cake is formula II-12-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride wet product (2683.5g), which is calculated based on the theoretical yield of 100% and is directly used in the next reaction. |
| Melting point: 233.2-238.7℃ |
| 1H NMR(500MHz，DMSO-d6)δ10.18(s，1H)，8.57(s，1H)，8.42(s，1H)，8.27(t，J＝6.6Hz，2H)，8.17(s，1H)，7.51(d，J＝8.1Hz，1H)，7.26-7.22(m，1H)，7.22-7.17(m，2H)，4.99(q，J＝9.1Hz，2H)，3.91(d，J＝6.3Hz，2H)，3.89(s，3H)，3.55(s，2H)，3.13(s，2H)，3.02(t，J＝6.1Hz，2H)，2.85(s，3H)，2.64(s，6H)； |
| 13C NMR(126MHz，DMSO-d6)δ168.41，161.88，160.22，157.34，148.05，146.73，137.62，133.25，130.86，125.43，124.09(q，J＝279.2Hz)，122.04，121.74，120.88，118.51，116.60，112.33，110.40，107.09，61.65(q，J＝35.3Hz)，54.90，40.96，40.95，40.60，38.71，32.96，32.95，32.94。 |
| Example 17: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product) |
| The wet product (2683.5 g) of Formula II 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride obtained in Example 16 was added to a 20L reactor, and acetonitrile (16.8L) and triethylamine (1329.3g, 13.15mol) were added, stirred, and heated to reflux for 4 hours. Cooled to room temperature, purified water (4.20L) was added, stirred at room temperature for 3-4 hours, and filtered. The filter cake was transferred to a 50L reactor, dichloromethane (17L) was added, and the pH value was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution (17L). Liquid separation, the organic phase was transferred to a 20L reactor, activated carbon (84.3g) was added, refluxed for 1 hour, cooled to 20-30°C, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain the compound of formula I 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1390g), with a total yield of 92.9% and a purity of 99.21% for the two-step reaction with Example 16. |
| 1H NMR(500MHz，DMSO-d6)δ9.96(s，1H)，8.71(s，1H)，8.44(s，1H)，8.29(d，J＝5.3Hz，1H)，8.26(d，J＝7.7Hz，1H)，8.13(s，1H)，7.51(d，J＝8.2Hz，1H)，7.24(t，J＝7.2Hz，1H)，7.20(d，J＝5.3Hz，1H)，7.15(t，J＝7.2Hz，1H)，6.51(dd，J＝17.0，10.2Hz，1H)，6.28(dd，J＝17.0，1.8Hz，1H)，5.78(dd，J＝10.2，1.8Hz，1H)，5.00(q，J＝9.1Hz，2H)，3.89(s，3H)，3.18(t，J＝6.5Hz，2H)，2.87(s，3H)，2.48(t，J＝6.5Hz，2H)，2.22(s，6H)； |
| 13C NMR(126MHz，DMSO-d6)δ163.40，161.84，160.26，157.35，148.07，147.15，137.60，133.23，131.61，130.07，126.67，125.41，124.03(q，J＝278.5Hz)，122.00，121.68，120.80，118.39，116.13，112.36，110.37，107.02，61.29(q，J＝35.3Hz)，56.57，52.44，45.60，45.59，38.54，32.93； |
| MS m/z：569.25[M+1]。 |
| Example 18: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (III’) |
| At room temperature, add the compound of formula IV 2-[2-(dimethylaminoethyl)methylamino]-3-nitro-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (20.0 g, 36.73 mmol) to a 1L reaction bottle, add tetrahydrofuran (134 mL) and water (66 mL), and stir for 10 to 20 minutes. Add hydrosulfite (47.9 g, 220.38 mmol) to the reaction bottle in batches. After addition, continue stirring for 10 to 20 minutes. Control the internal temperature to 35-40°C and react for 3 hours. Add concentrated hydrochloric acid (89.3 g, 881.52 mmol) to the reaction bottle. After the addition is complete, heat to 42 to 47°C and react for 17 hours. 30% sodium hydroxide (35.26 g, 881.52 mmol) aqueous solution was added dropwise, and solid sodium bicarbonate (18.5 g, 220.38 mmol) was added in batches to adjust the pH value to 6-8. After stirring for 30 minutes, the mixture was filtered, and the filtrate was allowed to stand and separated. The organic phase was concentrated to dryness under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (19.2 g) with a purity of 95.8% and a yield of 97.12%. |
| Example 19: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (II-1) |
| Add 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5 g, 9.72 mmol) to a 250 mL reaction bottle, add dichloromethane (42 mL), stir, protect with argon, cool to -5 to 0°C, and add 3-chloropropionyl chloride (1.851 g) and dichloromethane (33 mL) dropwise. After the addition is complete, the mixture is stirred for 10-20 minutes at a temperature maintained at room temperature. After the reaction is complete, the mixture is concentrated under reduced pressure to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride (7.0 g) with a purity of 85.67%. Melting point: 233.5-238.9°C. |
| 1H NMR(500MHz，DMSO-d6)δ10.18(s，1H)，8.57(s，1H)，8.42(s，1H)，8.27(t，J＝6.6Hz，2H)，8.17(s，1H)，7.51(d，J＝8.1Hz，1H)，7.26-7.22(m，1H)，7.22-7.17(m，2H)，4.99(q，J＝9.1Hz，2H)，3.91(d，J＝6.3Hz，2H)，3.89(s，3H)，3.55(s，2H)，3.13(s，2H)，3.02(t，J＝6.1Hz，2H)，2.85(s，3H)，2.64(s，6H)； |
| 13C NMR(126MHz，DMSO-d6)δ168.41，161.88，160.22，157.34，148.05，146.73，137.62，133.25，130.86，125.43，124.09(q，J＝279.2Hz)，122.04，121.74，120.88，118.51，116.60，112.33，110.40，107.09，61.65(q，J＝35.3Hz)，54.90，40.96，40.95，40.60，38.71，32.96，32.95，32.94。 |
| Example 20: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product) |
| The 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine hydrochloride obtained in Example 19 was added to a 250 mL reaction bottle, and acetonitrile (45 mL) and triethylamine (4.9 g) were added. The mixture was stirred magnetically and protected by argon. The temperature was raised to reflux in an oil bath. The reaction was allowed to react for 6 h. Water (23 mL) was added dropwise, and the mixture was naturally cooled to room temperature in an oil bath. The mixture was filtered with suction, and the filter cake was transferred to a 500 mL reaction bottle. Dichloromethane (100 mL) was added, and the pH value was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution (100 mL). The liquids were separated and the organic phase was concentrated under reduced pressure. The solid was dried in an oven at 50°C to give 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.1 g) with a purity of 97.7%. The total yield of the two-step reaction with Example 19 was 74.17%. |
| Comparative Example 1: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product) |
| 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1 g, 1.94 mmol) was added to a 50 mL multi-necked flask, tetrahydrofuran (10 mL) was used as the solvent, argon was replaced three times, and stirring was maintained at 0-5°C under argon protection, and 3-chloropropionyl chloride (0.37 g, 2.92 mmol), the addition was completed in 15 minutes, and the mixture was stirred at 0-5°C for 1 hour. Sodium hydroxide (0.31 g, 7.77 mmol) and water (1 mL) were added to the reaction solution, and the temperature was raised to 65°C and stirred for 15 hours. Saturated ammonium chloride solution (10 mL) was added, and the liquids were separated. The organic phase was washed with saturated sodium bicarbonate solution (10 mL). The liquids were separated and the organic phase was concentrated to dryness to obtain 1.04 g of a yellow solid with a yield of 94.9% and a purity of 87.35%. |
| Comparative Example 2: Preparation of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I, crude product) |
| Add 2-[2-(dimethylaminoethyl)methylamino]-3-amino-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g) to a 250 mL reaction bottle, add acetone (50 mL) and potassium carbonate (940 mg), stir, protect with argon, cool to -50°C, and add 3-chloropropionyl chloride (1.481 g) dropwise. After the addition is completed, the temperature is raised to -20°C and stirred for 30 minutes. A solution of sodium hydroxide (350 mg) and water (60 ml) is added dropwise over 10 minutes. The mixture is stirred at room temperature for 3 to 4 hours. The mixture is filtered and the filter cake is dried in an oven at 50°C to obtain a compound of formula II-1′, 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamide)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.28 g) with a purity of 64.18%. |
| 1H NMR(400MHz，DMSO-d 6 )δ10.32(s，1H)，10.21(s，1H)，8.54(s，1H)，8.43(s，1H)8.29-8.28(d，J＝5.1Hz，1H)，8.28-8.26(d，J＝6.2Hz，1H)，8.19(s，1H)，7.54-7.52(d，J＝8.0Hz，1H)，7.27-7.18(m，3H)，5.77(s，2H)，5.00(q，J＝9.1Hz，1H)，3.92(t，J＝6.2Hz，1H)，3.63(t，J＝5.7Hz，2H)，3.28(t，J＝5.7Hz，2H)，3.06-3.03(t，J＝6.2Hz，2H)，2.85(s，3H)，2.74(s，6H). |
| MS m/z：605.23[M+1]。 |
| Add 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.28 g) to a 250 mL reaction bottle, add acetonitrile (45 ml) and triethylamine (3.606 g), stir magnetically, protect with argon, heat in an oil bath to reflux, and react for 6 h. Water (23 ml) was added dropwise, the temperature was naturally lowered in an oil bath and stirring was continued overnight (16 h), filtered with suction, and the solid was dried to obtain 2-[2-(dimethylaminoethyl)methylamino]-3-(3-chloro-propionamido)-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.3 g) with a purity of 95.13% and a two-step yield of 59.42%. |
| Example 21: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| The crude product (1390 g) of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine was transferred to a 50L reactor, acetone (25.0L) was added, argon was replaced 3 times, the temperature was raised to 45-50°C, all the solids were dissolved, and purified water (6.95L) was added dropwise. After the addition was completed, the mixture was cooled to 20-25°C and stirred for 2 hours. The mixture was filtered and the filter cake was vacuum dried at 50°C for 24 hours to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (895g). The reaction yield is 66.7% and the purity is 99.89%. |
| Example 22: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add ethyl acetate 100mL, heat to 70-75°C in an oil bath to dissolve all the solids, then cool naturally to 25°C in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.1g) with a purity of 99.73% and a yield of 62.0%. |
| Example 23: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add ethyl acetate 100mL, heat to 70-75°C in an oil bath, dissolve all the solids, continue to stir for 30min, and drop 150mL of n-heptane. After the drop is complete, cool to 25°C in an oil bath, filter by suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0g), with a purity of 99.32% and a yield of 80%. |
| Example 24: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add acetonitrile 75mL, heat in an oil bath to 77-82°C, dissolve all the solids, and drop 25mL of water. After dripping, naturally cool to 25°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.3g), with a purity of 99.64% and a yield of 86%. |
| Example 25: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add acetonitrile 75mL, heat in an oil bath to 77-82°C, dissolve all the solids, and continue to stir for 30min. Cool naturally to 25°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.0g), with a purity of 99.45% and a yield of 80%. |
| Example 26: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g), add 20mL of tetrahydrofuran, heat in an oil bath to 45-50°C to dissolve all the solids, continue to stir and maintain the temperature for 30 minutes, and add 40mL of n-heptane dropwise. After the addition was completed, the mixture was naturally cooled to 25°C in an oil bath, filtered and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.23 g) with a purity of 99.51% and a yield of 84.6%. |
| Example 27: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 100mL of isopropanol, heat to 50°C in an oil bath, dissolve all the solids, and continue to stir for 30 minutes. Cool naturally to 22°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (4.25g), with a purity of 99.51% and a yield of 85%. |
| Example 28: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 75mL of methanol, and heat to 55-60°C in an oil bath to dissolve all the solids. Cool naturally to 17°C in the oil bath, stir overnight, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.55g), with a purity of 99.63% and a yield of 71%. |
| Example 29: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0 g), add 50mL of dichloromethane, heat in an oil bath to 40°C to dissolve all the solids, continue to stir and maintain the temperature for 30 minutes, and add 100mL of n-heptane dropwise. The mixture was naturally cooled to 15°C in an oil bath, stirred overnight, filtered and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.78 g) with a purity of 99.56% and a yield of 75.6%. |
| Example 30: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (5.0g), add 100mL of toluene, heat to 65°C in an oil bath, dissolve all the solids, and continue to stir for 30 minutes. Cool naturally to 20°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.27g), with a purity of 99.57% and a yield of 65.4%. |
| Example 31: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add DMF50mL, heat to 80°C in an oil bath, dissolve all the solids, continue to stir for 30min, and drop 25mL of water. Naturally cool to 20°C in the oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.84g), with a purity of 99.77% and a yield of 76.8%. |
| Example 32: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| To a 25 mL single-necked bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add tetrahydrofuran (6 mL), protect with argon, heat in an oil bath to 40-45°C until all the solution is dissolved, continue to stir and keep warm for 30 min, cool naturally to 22°C in an oil bath, filter and obtain a solid. The solid was transferred to a crystallization dish and dried to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (622 mg) with a purity of 99.83% and a yield of 62.2%. |
| Example 33: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add acetone (15 mL), protect with argon, heat in an oil bath to 45-50° C. until all the solution is dissolved, and then continue to stir and keep warm for 30 min, cool naturally to 22° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (537 mg) with a purity of 99.83% and a yield of 53.7%. |
| Example 34: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add tetrahydrofuran (8 mL), protect with argon, heat in an oil bath to 40-45° C. until all the solution is dissolved, and continue to stir and keep warm for 30 min. Add water (16 mL) dropwise, cool naturally to 21° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (880 mg) with a purity of 99.68% and a yield of 88.0%. |
| Example 35: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| To a 100 mL single-mouth bottle, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1.0 g), add ethanol (35 mL), protect with argon, heat in an oil bath to 75-80° C. until all the solution is dissolved, add water (10 mL) dropwise over 10 min, cool naturally to 20° C. in an oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (915 mg), with a yield of 91.5% and a purity of 99.49%. |
| Example 36: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| To a 50 mL single-mouth bottle, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (1.0 g), add xylene (20 mL), protect with argon, heat in an oil bath to 80° C. until all the solution is dissolved, cool naturally to 20° C. in an oil bath, filter with suction, and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (798 mg), with a yield of 79.8% and a purity of 99.48%. |
| Example 37: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| In a 250mL three-necked flask, add 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine crude product (5.0g), add ethanol 125mL, heat in an oil bath to 75-80°C to dissolve all the solids, continue to stir and keep warm for 30min, then cool naturally to 25°C in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (3.7g) with a purity of 99.66% and a yield of 74%. |
| Example 38: Purification of 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamido-5-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (I) |
| To a 100 mL single-mouth bottle, add crude 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (1.0 g), add methanol (35 mL), protect with argon, heat in an oil bath to 80° C. until all the solution is dissolved, add water (10 mL) dropwise over 10 min, cool naturally to 20° C. in an oil bath, filter and dry to obtain purified 2-[2-(dimethylaminoethyl)methylamino]-3-acrylamide-5-[4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amino]-6-(2,2,2-trifluoroethoxy)pyridine (912 mg), with a yield of 91.2% and a purity of 99.53%. |
PATENT
CN110606842
WO2019238103
PAPER
https://www.nature.com/articles/s41401-020-0389-3
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT02973763 | Allist Pharmaceuticals, Inc. | NSCLC | December 30, 2016 | Phase 1 |
| NCT03787992 | Allist Pharmaceuticals, Inc. | Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non-small Cell Lung Cancer | May 30, 2019 | Phase 3 |
| NCT03452592 | Allist Pharmaceuticals, Inc. | Advanced NSCLC Patients With T790M | April 30, 2018 | Phase 2 |
- [1]. Y. Shi, et al. P2.03-028 Third Generation EGFR Inhibitor AST2818 (Alflutinib) in NSCLC Patients with EGFR T790M Mutation: A phase1/2 Multi-Center Clinical Trial.[2]. Alexander I. Spira, et al. FURVENT: Phase 3 trial of furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertion mutations (FURMO-004). Journal of Clinical Oncology. Volume 42, Number 16_suppl.
/////////FIRMOMERTINIB, Furmonertinib, Alflutinib, AST 2818, UNII-A49A7A5YN4, PHASE 2, CANCER
Tibremciclib
Tibremciclib
cas 2397678-18-9, GTPL12881
CRB7BT5JDQ
518.6 g/mol, C28H32F2N8
N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-[(1R)-6-fluoro-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-8-yl]pyrimidin-2-amine
Tibremciclib is a CDK4 inhibitor with antineoplastic activity[1].
- Originator Betta Pharmaceuticals Co Ltd
- Class Antineoplastics; Small molecules
- Mechanism of Action Cyclin-dependent kinase 4 inhibitors; Cyclin-dependent kinase 6 inhibitors
- Phase III Breast cancer; Solid tumours
13 Sep 2024 Efficacy and adverse event data from a phase III trial in Breast cancer presented at the 49th European Society for Medical Oncology Congress 2024 (ESMO-2024)
- 30 Jun 2023Phase-III clinical trials in Breast cancer (Metastatic disease, Late-stage disease, Combination therapy, Second-line therapy or greater) in China (PO) (NCT05433480)
- 02 Jun 2023Efficacy, adverse events and PK data from a phase I trial in Solid tumours presented at the 59th Annual Meeting of the American Society of Clinical Oncology (ASCO-2023)
Cyclin-dependent kinases (CDKs) are a class of serine / threonine protein kinases that participate in the regulation of the cell cycle, transcription initiation, and control of certain specific metabolic cascades. Different CDKs and cyclins form CDK-cyclin complexes. If the CDK activity is dysregulated, it will directly or indirectly cause uncontrolled cell proliferation, genomic instability (increased DNA mutation, chromosome deletion, etc.) and chromosomal instability (change in chromosome number). )Wait.
The CDKs family has identified more than 20 subtypes. CDK1, CDK2, CDK4, and CDK6 are involved in cell cycle regulation; CDK7, CDK8, CDK9, and CDK11 are involved in transcription regulation; and other kinases include CDK3 and CDK5. Among them, CDK4 / 6 (cyclin-dependent kinases 4 and 6) is a key factor in regulating the cell cycle. Cancer-related cell cycle mutations mainly exist in the G1 and G1 / S phase transformation. CDK4 / 6 binds to CyclinD A complex with kinase activity is formed and phosphorylation of the tumor suppressor gene Rb product pRb releases the bound transcription factor E2F to initiate transcription of genes related to the S phase, prompting cells to pass the checkpoint and transfer from the G1 phase to the S phase. The specific activation of CDK4 / 6 is closely related to the proliferation of some tumors. About 80% of human tumors have abnormalities in the cyclin D-CDK4 / 6-INK4-Rb pathway. CDK4 / 6 inhibitors block the cell cycle in the G1 phase, thereby inhibiting tumor proliferation.
The development of drugs targeting CDK4 / 6 kinases is a significant area. The advantages of anti-tumor targets are: (1) Most proliferating cells rely on CDK2 or CDK4 / 6 to proliferate, but CDK4 / 6 inhibitors do not show Cytotoxicity of “pan-CDK inhibitors”, such as bone marrow suppression and intestinal response; (2) Preclinical experiments show that if the level of cyclin D or the inactivation of P16INK4a can increase the sensitivity of cells to drugs, due to tumors Compared with normal cells, cells have the above phenomenon, so the targeting of drugs is increased to a certain extent.
PCT International Application PCT / CN2017 / 117950 describes a class of benzimidazole derivatives that are used as CDK4 / 6 protein kinase inhibitors, and most of these compounds effectively inhibit CDK4 and CDK6. Because there are still unmet needs in the treatment options for kinase-mediated diseases, here we further screen the salt forms and crystal forms of benzimidazole derivatives to meet the medical needs of patients.
SCHEME
SIDE CHAIN
SIDE CHAIN
MAIN
Patent
Betta Pharmaceuticals Co., Ltd., WO2019242719
https://patents.google.com/patent/WO2019242719A1/en
Synthesis of 1-A1-01 (Step 1)
In a 50L reactor, add 20L of dichloromethane (DCM), 1-A1-S1 (300g), and triethylamine (390g). While stirring, lower the temperature to below -5 ° C, and add benzyl chloroformate / Cbz- Cl (570 g) was added dropwise for 5 hours, and the temperature was naturally raised to room temperature. TLC (ethyl acetate: n-hexane = 1: 3) was monitored until the reaction was completed. Water (1.5 L) was added, and concentrated hydrochloric acid (80 mL) was slowly added dropwise to control the pH to 1-2. The solution was allowed to stand and separate. The organic phase was washed with 15 L of water, dried over anhydrous sodium sulfate for 0.5 hours, filtered to remove the desiccant, and collected the filtrate. And concentrated to obtain 730 g of light yellow oily liquid, which is crude 1-A1-01, yield 95.4%
Synthesis of 1-A1-02 (Step 2)
720mL of DCM, N, N-dimethylsulfoxide (90g) was added to a 20L reaction flask, protected by nitrogen, and the temperature was lowered below -65 ° C under stirring, and oxalyl chloride (106g) was added dropwise. The addition was completed in 2 hours. Stir for 20 minutes under heat preservation; add 1-A1-01’s dichloromethane solution (143g / 500mL DCM) dropwise. After 40 minutes, the addition is complete and the reaction is held for 15 minutes. Controlled at this temperature, TEA was added dropwise. After the addition was completed for 2 hours, the temperature was naturally raised to -20 ° C. 250 L of water was added to the system. The pH of the system was adjusted to 1-2 with hydrochloric acid. × 2) Washed, dried over anhydrous sodium sulfate, filtered to remove the desiccant, collected the filtrate and concentrated to obtain 432 g of a yellow oily liquid, which is the crude product 1-A1-02, which was directly used in the next reaction.
Synthesis of 1-A1-03 (Step 3)
In a stirred state, 400 mL of tetrahydrofuran (THF) and potassium tert-butoxide (215 g) were sequentially added to a 1 L reaction kettle, the temperature was lowered to 5-15 ° C., and triethyl phosphoryl acetate (430 g) was added dropwise. The dropwise addition was completed in 50 minutes. At a controlled temperature of 15 ° C, a tetrahydrofuran solution of 1-A1-02 (431 g / 100 mL of THF) was added dropwise. After the dropwise addition was completed for 1 hour, TLC (ethyl acetate: n-hexane = 1: 3) was monitored to complete the reaction, and the system was added. Saturated aqueous sodium chloride solution (1.5L), allowed to stand and separate, and collected the tetrahydrofuran phase; the aqueous phase was extracted with dichloromethane (2L), and the organic phases were combined and dried over anhydrous sodium sulfate for 0.5 hours, and the drying agent was removed by filtration. The filtrate was collected and concentrated, and the concentrate was purified by column chromatography to obtain 390 g of a pale yellow oily liquid, which was 1-A1-03 product.
Synthesis of 1-A1-041 (step 4)
In a 5L reactor, an aqueous solution of sodium hydroxide (301 g / 1.5 L of water) was added to a tetrahydrofuran (601 g / 2.3 L of THF) solution of 1-A1-03, and the mixture was heated to reflux for 3-4 hours to stop the reaction. The temperature was lowered to 40-50 ° C, and the layers were left to stand. The organic phase (THF) was collected and concentrated to a large amount of solids; the solids were dissolved by adding water (20L), and the aqueous phase was sequentially treated with methyl tert-butyl ether (2L) and ethyl acetate. Ester (2L), methyl tert-butyl ether (2L) washing; the aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid, extracted twice with ethyl acetate (1.5L, 3L), the organic phases were combined, and anhydrous sulfuric acid was used Sodium was dried for 0.5 hours; the desiccant was removed by filtration, and the filtrate was collected and concentrated to a large amount of solids. The solids were added with isopropyl ether (3L) and slurried for 2 hours. The solids were collected by filtration and the solids were rinsed with isopropyl ether (1L). The solid was air-dried at 50 ° C for 3-4 hours to obtain 331 g of a pale yellow solid, which is a 1-A1-041 product with a yield of 52.7%.
Synthesis of 1-051 (step 5)
In a stirred state, 1-A1-041 (600g), methanol (25L), and concentrated sulfuric acid were added to a 50L reactor, and the reaction was heated under reflux for 3-4 hours. After the reaction was completed, the temperature was reduced to room temperature. Dichloromethane (15L) was added to the concentrate, and the pH was adjusted to 9-10 with an aqueous solution of potassium carbonate. The organic phase was collected by stirring, standing, and separating. The organic phase was dried over anhydrous sodium sulfate for 0.5 hours. The desiccant was removed by filtration and the filtrate was collected. And concentrated to obtain 6.37 kg of off-white solid, which is 1-A1-051 product, with a yield of 97.3%.
Synthesis of 1-A1 (step 6)
In a 2L hydrogenation kettle, add 1-A1-051 (500g), methanol (1.8L), and palladium on carbon. The system replaces nitrogen 3 times and hydrogen 3 times in sequence. The system maintains a hydrogen atmosphere, and the temperature is increased to 85 ° C and the pressure is 3.0. The reaction was carried out at Mpa for 3 hours, and the reaction was completed. The temperature was lowered to room temperature, the palladium on carbon was removed by filtration, and the organic phase was collected and concentrated until a large amount of light yellow solid appeared. Isopropyl ether (3L) was added to freeze (-20 ° C) for crystallization, and the solid product was collected by filtration. Ether (500 mL) was rinsed to obtain 234 g of a pale yellow solid, which was a 1-A1 product with a yield of 90.5%.
Synthesis of 1-A2 (Step 7)
In a stirred state, 1-A1 (200g), 4-bromo-2,6-difluoroaniline (410g), and toluene (1.2L) were added to a 50L reactor, and phosphorus oxychloride (413g) was added dropwise to the system. The addition was completed in 1 hour. Triethylamine was added dropwise under an ice bath, and the addition was completed in 1 hour. The temperature was raised to 110 ° C, and the reaction was performed for 1 hour. Reduce the temperature of the system to 2-10 ° C, add 1L of water, adjust the pH = 9-10 with saturated potassium carbonate aqueous solution, extract twice with ethyl acetate (1.5L, 1L), and combine the organic phases with 2L saturated sodium chloride aqueous solution. Wash, dry with anhydrous sodium sulfate for 0.5 hours, remove the desiccant by filtration, collect the filtrate and concentrate to the appearance of a solid product, add isopropyl ether (1L) to beat the solid for 10 minutes, filter, and collect 460 g of a yellow solid as a 1-A2 product.
Synthesis of 1-A3 (step eight)
Under stirring, 1-A2 (450g), N, N-dimethylformamide (2L), and cesium carbonate (700g) were added to the reaction kettle, and the reaction was heated to 110 ° C for 24 hours, and the reaction was detected by TLC. Ethyl acetate (3L) was added to the system, and solid impurities were removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (1L × 5), and the organic phase was dried over anhydrous sodium sulfate for 0.5 hours, concentrated to the appearance of a large amount of solid, Butyl ether (1L × 2) was beaten for 30 minutes, and 382 g of pale yellow solid product was obtained by filtration, that is, 1-A3, and the yield was 90.10%.
Synthesis of 1-01 (step 9)
With stirring, 1-A3 (380 g), pinacol diborate (400 g), potassium acetate (340 g), palladium acetate (6 g), tricyclohexyl phosphorus (7 g), and 1,4-dioxane were sequentially added. The ring was added to the reaction kettle, protected by nitrogen, and heated to 90 ° C for 2 hours. TLC was monitored until the reaction was complete. The temperature was reduced to room temperature, and the filtrate was concentrated to remove a large amount of 1,4-dioxane. The concentrate was purified by n-hexane and dichloromethane column chromatography, and n-hexane (1.2 L) was slurried for 1 hour to obtain 334 g of a gray solid. That is 1-01, and the yield is 70.10%.
Synthesis of 1-02 (step 10)
Under stirring, take 1-01 (128g), 1,4-dioxane (1L), 1-S3 (85g), potassium carbonate (110g), and purified water and add them to a 2L three-necked flask in sequence. [1,1′-Bis (diphenylphosphine) ferrocene] palladium dichloromethane complex (Pd (dppf) Cl 2 .DCM) was added. The temperature was raised to 60 ° C. After 4 hours of reaction, the reaction was complete. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove most of 1,4-dioxane. Dichloromethane (1.5 L) and purified water (1.1 L) were added, stirred, and allowed to stand and separate. The layers were separated, and water was added. The phases were extracted with dichloromethane (10 L), the organic phases were combined, washed with 0.5% dilute hydrochloric acid (1 L x 2), saturated aqueous sodium chloride solution (1 L), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate (500 g), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. Ethyl acetate (0.5 L) was added to the concentrate and the mixture was stirred for 30 minutes to precipitate a solid. After filtration, the obtained solid was rinsed with ethyl acetate (0.5 L) and dried under vacuum at 45 ° C for 3 hours to obtain 120 g of a yellow solid.
Synthesis of 1-03 (step 11)
Under stirring, take 1-02 (100g), 1,4-dioxane (1L), 1-C2 (80g), and cesium carbonate (163g) into a 2L three-necked bottle in sequence, protected by nitrogen, and add palladium acetate ( 2g) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthracene (Xantphos) (4g), heated to 85 ° C. until the reaction was complete. The reaction solution was cooled to room temperature and filtered to obtain a solid product. The solid was rinsed with ethyl acetate, and then added to a mixed system of dichloromethane (1.5 L) and purified water (1.1 L), stirred, allowed to stand, and separated into layers. The aqueous phase was extracted with dichloromethane (700 mL). The organic phases were combined and washed with purified water (700 mL x 2). The organic phase was dried by adding anhydrous sodium sulfate (700 g), filtered to remove the desiccant, and the filtrate was concentrated. Methanol (0.5 L) was added, heated to 55-65 ° C. and stirred for 0.5 hours, lowered to room temperature, and filtered. The solid product was filtered and rinsed with 500 mL of ethyl acetate. The solid was dried under vacuum at 45 ° C for 8 hours to obtain 111.79 g of a pale yellow solid 1-03.
Synthesis of compound II (step twelve)
Under stirring, take 1-03 (500g) and anhydrous methanol (3.8L), add them to a 10L reactor in sequence, and heat to 65 ° C. After the reaction system is clarified for 0.5 hours, add L-tartaric acid in methanol (150.89) dropwise. g of tartaric acid is dissolved in 500mL of anhydrous methanol), and the dropping time is controlled to be 45 to 60 minutes. After the addition is complete, the reaction is kept at 65 ° C for 4 hours. ), Control the dropwise addition time to 30 to 45 minutes. After the dropwise addition is complete, hold the reaction at 65 ° C for 1 hour. Continue to dropwise add L-tartaric acid in methanol (36.55g of tartaric acid dissolved in 250mL of anhydrous methanol) and control the dropwise addition time to 30. To 45 minutes, the dropwise addition was completed. The temperature was kept at 65 ° C for 1.5 hours, and the heating was stopped. The temperature was naturally lowered to 20-30 ° C, filtered, the filter cake was rinsed with methanol (400mL × 2), and dried at 45 ° C under vacuum for 36 hours. 530.64 g of crystalline powder was Compound II, which was identified by X-ray powder diffraction, and showed that the crystal form was Form A of Compound II.
WO2022199656
WO2023131179
///Tibremciclib, GTPL12881, BETTA, PHASE 3, CANCER
Amcenestrant (SAR 439859)
Amcenestrant (SAR 439859)
アムセネストラント
| Molecular Weight | 554.48 |
|---|---|
| Formula | C31H30Cl2FNO3 |
| CAS No. | 2114339-57-8 |
6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
8-(2,4-dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro – 5H- Benzo[7]annulene-3-carboxylic acid
8-(2,4-Dichlorophenyl)-9-(4-{[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5 H -benzo [7]annulene-3-carboxylic acid
C31H30Cl2FNO3 : 554.48 [ 2114339-57-8 ] _ _ _ _ _ _
| Efficacy | Antineoplastic, Selective estrogen receptor downregulator |
|---|---|
| Comment | Selective estrogen receptor downregulator (SERD) Treatment of breast cancer |
SAR439859 (compound 43d) is an orally active, nonsteroidal and selective estrogen receptor degrader (SERD). SAR439859 is a potent ER antagonist and has ER degrading activity with an EC50 of 0.2 nM for ERα degradation. SAR439859 demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer.
Amcenestrant is an orally available, nonsteroidal selective estrogen receptor degrader/downregulator (SERD), with potential antineoplastic activity. Upon oral administration, amcenestrant specifically targets and binds to the estrogen receptor (ER) and induces a conformational change that promotes ER degradation. This prevents ER-mediated signaling and inhibits both the growth and survival of ER-expressing cancer cells.
Amcenestrant is reported to be a selective estrogen receptor degrader (SERD) which has estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor. Amcenestrant is under clinical investigation as an anticancer agent, in particular for treatment of breast cancer.
The compound and processes for preparation thereof are described in International Publication No. WO 2017/140669.
Crystalline forms are described in International Publication No. WO 2021/116074.
PAPER
Journal of Medicinal Chemistry (2020), 63(2), 512-52
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01293
6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3- yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic Acid (43d).
To a solution of 6-(2,4-dichloro-phenyl)-5-[4-[1-(3-fluoropropyl)-pyrrolidin-3-yloxy]-phenyl]-8,9-dihydro-7H-benzocycloheptene-2-carboxylic acid methyl ester (42d) (80 mg, 140.72 μmol) in methanol (5 mL) was added 5 N NaOH (562.88 μL), the reaction mixture was heated to 60 °C for 5 h, and the solvent was removed under reduced pressure. The residue was taken up in water (10 mL), and aqueous HCl (5 M) was added to pH 7. The slurry was extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of dichloromethane, acetonitrile, and methanol (90/5/5 v/v/v) to give 60 mg (77%) of 6- (2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]- oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d). 1 H NMR (400 MHz, DMSO-d6): 1.68 (m, 1H), 1.79 (dm, J = 25.3 Hz, 2 H), 2.07 to 2.23 (m, 5H), 2.38 (m, 1H), 2.46 (t, J = 7.2 Hz, 2H), 2.52 (m, 1H), 2.62 (m, 1H), 2.55 to 2.89 (m, 3H), 4.47 (td, J = 6.2 and 47.6 Hz, 2H), 4.72 (m, 1H), 6.63 (d, J = 8.9 Hz, 2H), 6.71 (m, 3H), 7.18 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 2.0 and 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 12.3 (m, 1H). LCMS: 554 (M + H)+ .
PATENT
Amcenestrant can be prepared according to methods known from the literature, for example U.S. Patent No. 9,714,221.
Example 1: Preparation of amorphous Amcenestrant
[00164] Amcenestrant (20 mg, prepared according to U.S. Patent No. 9,714,221) was dissolved in ethyl acetate (0.2 mL) at room temperature (25°C). Solution was left in opened flask at RT for 16 days, until all the solvent evaporated. Obtained solid was analyzed by XRPD.
PATENT
U.S. Patent No. 9,714,221
https://patents.google.com/patent/US9714221B1/en
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017140669
Example 51. 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
Methode B:
Step 1 : 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.
To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (D5) (150 mg, 298.56 μιηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηηοΙ), Cs2C03 (204.48 mg, 626.97 μηιοΙ), and Pd(dppf)CI2 (14.63 mg, 17.91 μιηοΙ). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.
LC/MS (m/z, MH+): 568
Step 2 : 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (80 mg, 140.72μιηο!) in MeOH (5 ml) was added a solution of NaOH (562.88 μΙ, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCI (5 M) added to pH
7. The slurry was extracted with DCM, dried over MgS04 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019020559
Intermediate (c). Tert-butyl (3S)-3-[4-(4,4!5!5-tetramethyl-1 !3,2-dioxaborolan-2yl)phenoxy]pyrrolidine-1 -carboxylate
To a solution of commercially available 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (a) (82.7 g, 364.51 mmol) in THF (2 L) was added under argon (R)-1 -N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) followed by Ν,Ν,Ν’,Ν’-tetramethylazodicarboxamide (99.1 g, 546.77 mmol). The clear reaction mixture turned orange and triphenylphosphine (143.41 g, 546.77 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, meanwhile a precipitate of triphenylphosphine oxide formed (Ph3P=0). The reaction mixture was poured in water (1 .5 L) and extracted with ethyl acetate (AcOEt) (3×1 .5 L). Gathered organic phases were dried over magnesium sulfate (MgS04), filtered and concentrated under reduced pressure. The residue was taken up into diisopropylether (1 .5 L) and the solid formed (Ph3P=0) was filtered. The solvent was concentrated under reduced pressure and the residue purified by column chromatography eluting with a mixture of heptane with AcOEt (90/10; v/v) to give 145 g (100%) of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1 -carboxylate (c) as a colorless oil.
1H NMR (400 MHz, DMSO-d6, δ ppm): 1 .27 (s : 12H); 1 .39 (s : 9H); 2.05 (m : 1 H); 2.14 (m : 1 H); 3.37 (3H); 3.55 (m : 1 H); 5.05 (s : 1 H); 6.94 (d, J = 8.4 Hz : 2H); 7.61 (d, J = 8.4 Hz : 2H)
Intermediate (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride
To a solution of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1 -carboxylate (c) (80 g, 195.23 mmol) in MeOH (450 ml) was added slowly HCI 4N in dioxane (250 ml).
After 1 .5 hours, the reaction mixture was concentrated under reduced pressure and the residue was taken up into Et20 with stirring to give a solid which then was filtered and dried under vacuum to give 61.8 g (95%) of (3S)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride (d) as a white powder.
1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (s : 12H); 2.10 (m : 1 H); 2.21 (m : 1 H); 3.31 (3H); 3.48 (m : 1 H); 5.19 (m : 1 H); 6.97 (d, J = 8.4 Hz : 2H); 7.63 (d, J = 8.4 Hz : 2H); 9.48 (s : 1 H); 9.71 (s : 1 H).
LC/MS (m/z, MH+): 290
Intermediate (e). (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine
To a suspension of (S)-3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine hydrochloride (d) (20 g, 61.42 mmol) in acetonitrile (100 ml), was added K2C03 (21 .22 g, 153.54 mmol) and 1 -iodo-3-fluoropropane (12.15 g, 61.42 mmol), under argon. The reaction
mixture was stirred at 40°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure and the residue was taken up in DCM and the solid formed was filtered and washed with DCM. The filtrate was concentrated to give 21.5 g (100%) of (3S)-1 -(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) as a yellow foam.
1H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s : 12H); 1 .77 (m : 2H); 1 .84 (m : 1 H); 2.27 (m : 1 H); 2.41 (m : 1 H); 2.49 (2H); 2.62 (dd, J = 2.6 and 10.4Hz : 1 H); 2.69 (m : 1 H); 2.83 (dd, J = 6.2 and 10.4Hz : 1 H); 4.47 (td, J = 6.2 and 47Hz : 2H) ; 4.99 (m : 1 H); 6.77 (d , J = 8.4 Hz : 2H); 7.58 (d, J = 8.4 Hz : 2H).
LC/MS (m/z, MH+): 350
Intermediate (B). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate
To a solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (1 .52 g, 8.63 mmol), in acetone (60 ml), was added K2C03 (1 .19 g, 8.63 mmol) and pivaloyl chloride (1.06 ml, 8.63 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane in AcOEt (100/0 to 85/15, v/v) to give 1.55 g (69%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) as a colorless oil.
1H NMR (400 MHz, DMSO-d6, δ ppm): 7.65 (d, 1 H); 7.10-7.04 (m, 2H); 2.95 (t, 2H); 2.68 (t, 2H); 1 .85-1 .65 (m, 4H).
LC/MS (m/z, MH+): 261
Intermediate (C). 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate
To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) (15 g, 57.62 mmol) in DCM (500 ml) was added dropwise under argon pyridine (7.28 ml, 86.43 mmol) and trifluoromethanesulfonic anhydride (19.58 ml, 1 15.24 mmol). The reaction mixture was stirred at room temperature for 2 hours and ice (200 g) was added. The phases were separated, the aqueous phase was washed with DCM and the gathered organic phases were dried over MgS04, filtered and evaporated under reduced pressure to give 22 g (97%) of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (C) as a white solid.
LC/MS (m/z, MH-): 391
Intermediate (D). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimeth lpropanoate
To a solution of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (C) (22 g, 56.07 mmol) and (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (20.56 g, 58.87 mmol) in dioxane (420 ml) and water (120 ml) was added under argon Pd(dppf)CI2 (2.75 g, 3.36 mmol) and Cs2C03 (36.57 g, 1 12.13 mmol). The reaction mixture was stirred for 1 hour at room temperature and was partitioned between water and DCM. The aqueous phase was washed with DCM and the gathered organic phases dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0 to 5%; V/V) to give 31 g (100 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D).
LC/MS (m/z, MH+): 466
Intermediate (E). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol
To a solution under argon of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D) (24.8 g, 53.26 mmol) in MeOH (300 ml), was added NaOH 5M (23 ml, 1 15.00 mmol). The reaction mixture was stirred for 2 hours at room temperature. pH was then adjusted to 7 by addition of 6N aqueous HCI solution. The MeOH was concentrated under reduced pressure, then DCM was added. The organic phase was dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/ MeOH from 100/0 to 95/05 to give 18.8 g (93%) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) as a beige solid.
LC/MS (m/z, MH+): 382
Intermediate (F). 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate
To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) (20.6 g, 54.00 mmol) in DCM (200 ml) and pyridine (6.55 ml, 81 .00 mmol), cooled to 5°C (ice bath), was added dropwise trifluoromethanesulfonic anhydride (18.93 ml, 108.00 mmol) under argon, and the reaction temperature was maintained <15°C. The ice bath was removed, and the brown suspension was stirred at room temperature for 2 hours. Ice (200 g) and DCM (200 ml) were added and the phases separated. The organic phase was dried over MgS04, and concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 24.7 g (89.1 %) of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) as a brown oil.
LC/MS (m/z, MH+): 514
Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
To a solution of 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) (10.1 g, 19.67 mmol) in DMF (66 ml) and MeOH (33 ml), were added Pd(dppf)CI2 (909 mg, 1.18 mmol) and diisopropylethylamine (7.21 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure. The residue was partitioned between AcOEt and water. The organic phase was washed with water (2x 100 ml), dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCIW MeOH from 100/0 to 95/05 to give 7.13 g (86%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.
LC/MS (m/z, MH+): 424
Intermediate (A1 ). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate
To a solution of commercially available 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (18.5 g, 105 mmol) in DCM (185 ml) and lutidine (13.35 ml, 1 13.505 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (20.22 ml,
123.29 mmol) while keeping temperature between 10 and 20°C. The reaction mixture was stirred for 1 hour at 5°C then at room temperature for 1 hour.
Then, ice (200 g) was added and the slurry partitioned between water and DCM. The organic phase was washed with aqueous NaHC03 solution, dried over MgS04, filtered off and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100 to 90/10 to give 28.2 g (87%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) as an orange oil. LC/MS (m/z, MH+): 309
Intermediate (B1 ). Methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate
To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1 ) (5.03 g, 16.32 mmol) in DMF (24 ml) and MeOH (12 ml), were added Pd(dppf)CI2 (754 mg, 0.98 mmol) and diisopropylethylamine (6 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 2.5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure, and the residue, was partitioned between AcOEt and water. The organic phase was washed with water (2x 75 ml) and aqueous HCI 0.5 N, dried over MgS04 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100/0 to 90/10 to give 3.4 g (95%) of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) as a colorless oil.
LC/MS (m/z, MH+): 219
Intermediate (C1 ). Methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
To a solution of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1 ) (18,19 g, 83,34 mmol) in DCM (500 ml) and anhydrous pyridine (1 1 ml, 130,56 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (30 ml, 176,54 mmol). The reaction mixture, a thick suspension, was stirred at room temperature for 24 hours, then ice was added and partitioned between water and DCM. The organic phase was dried over MgS04, filtered off and concentrated under reduced pressure to give 29 g (100%) of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) as a yellow gum.
LC/MS (m/z, MH+): 351
Intermediate (G). Methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
To a solution of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1 ) (29 g, 82.9 mmol), (3S)-1 -(3-fluoropropyl)-3-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (28.9 g, 82.9 mmol), in dioxane (225 ml) were added Pd(dppf)CI2 under argon, complex with DCM (3.73 g, 4.57 mmol) and Cs2C03 1 .5 M aqueous solution (1 1 1.12 ml, 166.68 mmol). The reaction mixture was stirred at 60°C for 1 hour.
After cooling to room temperature, the reaction mixture was poured into a mixture of water (500 ml) and AcOEt (400ml). The organic phase was washed with brine, dried over MgS04, filtered on celite and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 23 g (65%) of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.
LC/MS (m/z, MH+): 424
Intermediate (H). Methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide
To a solution of methyl 9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate (G) (13.93 g, 32.89 mmol), in DCM (150 ml) was added under argon pyridinium tribromide (15.78 g, 44.41 mmol). The reaction mixture was stirred for 1 hour at room temperature. Water (200 ml) was added, organic phase was then dried over MgS04, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 16.4 g (85%) of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3-carboxylate hydrobromide (H) as a yellow meringue.
LC/MS (m/z, MH+): 502
Intermediate (I). 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}- -dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.
To a solution of methyl 8-bromo-9-(4-{[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (H) (150 mg, 298.56 μηηοΙ), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 μηιοΙ), Cs2C03 (204.48 mg, 626.97 μπιοΙ), and Pd(dppf)CI2 (14.63 mg, 17.91 mol). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by column
chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I).
LC/MS (m/z, MH+): 568
Compound (1 ). 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen -2-carboxylic acid
To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1 -(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I) (80 mg, 140.72 μηηοΙ) in MeOH (5 ml) was added a solution of NaOH (562.88 μΙ, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCI (5 M) added to pH 7. The slurry was extracted with DCM, dried over MgS04 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1 -(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid. 1H NMR (400 MHz, DMSO-d6, δ ppm): 1 .68 (m, 1 H); 1 ,79 (dm, J=25.3 Hz, 2 H); 2.07 to 2.23 (m, 5 H); 2.38 (m, 1 H); 2.46 (t, J=7.2 Hz, 2 H); 2.52 (m, 1 H); 2.62 (m, 1 H); 2.55 to 2.89 (m, 3 H); 4.47 (td, J=6.2 and 47.6 Hz, 2 H); 4.72 (m, 1 H); 6.63 (d, J=8.9 Hz, 2 H); 6.71 (m, 3 H); 7.18 (d, J=8.4 Hz, 1 H); 8.26 (dd, J=2.0 and 8.4 Hz, 1 H); 7.58 (d, J=2,0 Hz, 1 H); 7.63 (d, J=8.4 Hz, 1 H); 7.79 (s, 1 H); 12.3 (m, 1 H)
LC/MS (m/z, MH+): 554
//////////////
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/////Amcenestrant, SAR439859, アムセネストラント , Antineoplastic, CANCER
C1CC2=C(C=CC(=C2)C(=O)O)C(=C(C1)C3=C(C=C(C=C3)Cl)Cl)C4=CC=C(C=C4)OC5CCN(C5)CCCF
LORPUCITINIB
LORPUCITINIB
JNJ 64251330
2230282-02-5
UNII-OE1QTY7C25
| Molecular Weight | 408.50 |
|---|---|
| Formula | C22H28N6O2 |
| 1-(TRANS-4-(CYANOMETHYL)CYCLOHEXYL)-1,6-DIHYDRO-N-(2-HYDROXY-2-METHYLPROPYL)IMIDAZO(4,5-D)PYRROLO(2,3-B)PYRIDINE-2-ACETAMIDE |
2-[3-[4-(cyanomethyl)cyclohexyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-4-yl]-N-(2-hydroxy-2-methylpropyl)acetamide
is a Gut-Restricted JAK Inhibitor for the research of Inflammatory Bowel Disease.
Lorpucitinib is an orally bioavailable pan-inhibitor of the Janus associated-kinases (JAKs), with potential immunomodulatory and anti-inflammatory activities. Upon oral administration, lorpucitinib works in the gastrointestinal (GI) tract where it targets, binds to and inhibits the activity of the JAKs, thereby disrupting JAK-signal transducer and activator of transcription (STAT) signaling pathways and the phosphorylation of STAT proteins. This may inhibit the release of pro-inflammatory cytokines and chemokines, reducing inflammatory responses and preventing inflammation-induced damage. The Janus kinase family of non-receptor tyrosine kinases, which includes tyrosine-protein kinase JAK1 (Janus kinase 1; JAK1), tyrosine-protein kinase JAK2 (Janus kinase 2; JAK2), tyrosine-protein kinase JAK3 (Janus kinase 3; JAK3) and non-receptor tyrosine-protein kinase TYK2 (tyrosine kinase 2), plays a key role in cytokine signaling and inflammaton.
PATENT
WO2019239387
WO2018112379
WO2018112382
PATENT
WO/2022/189496LORPUCITINIB FOR USE IN THE TREATMENT OF JAK MEDIATED DISORDERS
Example 1
[0117] 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide
Step A: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. To ensure dry starting material, ethyl 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 3) was heated under vacuum at 50 °C for 18 h prior to the reaction. In a 1 L flask, ethyl 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (Intermediate 3, 52.585 g, 104.01 mmol) was suspended in DMA (50 mL). 1-Amino-2-methylpropan-2-ol (50 mL) was added and the reaction was heated to 110 °C for 45 minutes, then to 125 °C for 5 hours. The reaction was cooled to room temperature and diluted with EtOAc (800 mL). The organic layer was extracted three times with a solution of water/ brine wherein the solution was made up of 1 L water plus 50 mL brine. The aqueous layers were back extracted with EtOAc (2 × 600 mL). The combined organic layers were dried over anhydrous MgSO4,
concentrated to dryness, and then dried for 3 days under vacuum to provide the title compound (65.9 g, 98% yield) as a yellow foam. The product was taken to the next step with no further purification. MS (ESI): mass calcd. for C28H32N6O4S, 548.22; m/z found, 549.2 [M+H]+.1H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.26 – 8.19 (m, 2H), 7.84 (d, J = 4.1 Hz, 1H), 7.60 – 7.53 (m, 1H), 7.50 – 7.44 (m, 2H), 6.84 (d, J = 4.2 Hz, 1H), 4.76 – 4.61 (m, 1H), 3.97 (s, 2H), 3.45 (s, 1H), 3.27 (d, J = 5.9 Hz, 2H), 2.41 (d, J = 6.5 Hz, 2H), 2.38 – 2.25 (m, 2H), 2.23 – 2.12 (m, 2H), 2.09 -1.94 (m, 4H), 1.48 (qd, J = 13.6, 4.0 Hz, 2H), 1.21 (s, 6H).
[0118] Step B: 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide. 2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide (65.90 g, 102.1 mmol) was added to a 1 L flask containing a stir bar. 1,4-dioxane (300 mL) was added, followed by aq KOH (3 M, 150 mL). The reaction was heated at 80 °C for 2 h. The reaction was cooled to room temperature and the solvent volume was reduced to about 200 mL on a rotovap. The residue was treated with a solution of water/brine (100 mL/100mL), then extracted with 10% MeOH in CH2Cl2 (2 x 1L). The organic layers were combined, dried over anhydrous MgSO4, and concentrated to dryness to provide a yellow solid. The solid was suspended in CH2Cl2 (200 mL), stirred vigorously for 30 minutes, and then collected by filtration. The solid was rinsed with CH2Cl2 (100 mL), dried by pulling air through the filter, and then further dried under vacuum at room temperature for 16 h to provide the title compound (41.59 g, 89% yield) as a white solid. MS (ESI): mass calcd. for C22H28N6O2, 408.23; m/z found, 409.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6): δ 11.85 (s, 1H), 8.50 (s, 1H), 8.21 – 8.10 (m, 1H), 7.49 – 7.43 (m, 1H), 6.74 – 6.65 (m, 1H), 4.53 – 4.42 (m, 2H), 4.07 (s, 2H), 3.08 (d, J = 6.0 Hz, 2H), 2.58 (d, J = 6.1 Hz, 2H), 2.41 – 2.28 (m, 2H), 2.09 – 1.92 (m, 5H), 1.42 – 1.31 (m, 2H), 1.09 (s, 6H). The synthesis and active compound characterization of each of the aspects of this invention are provided herein in the form of examples. Due to the crystal structure of some of the aspects of this invention, polymorph screening may be pursued to further characterize specific forms of any such compound. This is illustrated in a non-limiting manner for compound of Formula I by the example under the heading polymorph screening.
[0119] The following compounds were prepared in reference to the foregoing synthesis:
Intermediate 1
[0120] 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile
[0121] Step A: tert-butyl N-[(1r,4r)-4-(Hydroxymethyl)cyclohexyl]carbamate. To a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (1r,4r)-4-[[(tert-butoxy)carbonyl]amino]cyclohexane-1-carboxylic acid (1066 g, 4.38 mol, 1.00 equiv) and THF (10 L). This was followed by the dropwise addition of BH3-Me2S (10 M, 660 mL) at -10 °C over 1 h. The resulting solution was stirred for 3 h at 15 °C. This reaction was performed three times in parallel and the reaction mixtures were combined. The reaction was then quenched by the addition of methanol (2 L). The resulting mixture was concentrated under vacuum. This resulted in of tert-butyl N-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]carbamate (3000 g, 99.6%) as a white solid. MS (ESI): mass calcd. for C12H23NO3, 229.32; m/z found, 215.2 [M-tBu+MeCN+H]+; 1H NMR: (300 MHz, CDCl3): δ 4.40 (s, 1H), 3.45 (d, J = 6.3 Hz, 2H), 3.38 (s, 1H), 2.05-2.02 (m, 2H), 1.84-1.81 (m, 2H), 1.44 (s, 11H), 1.17-1.01 (m, 4H).
[0122] Step B: tert-butyl N-[(1r,4r)-4-[(Methanesulfonyloxy)methyl]cyclohexyl]carbamate. To a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[(1r,4r)-4-(hydroxymethyl)cyclohexyl]carbamate (1000 g, 4.36 mol, 1.00 equiv.), dichloromethane (10 L), pyridine (1380 g, 17.5 mol, 4.00 equiv.). This was followed by the dropwise addition of MsCl (1000 g, 8.73 mol, 2.00 equiv.) at -15 °C. The resulting solution was stirred overnight at 25 °C. This reaction was performed in parallel for 3 times and the reaction mixtures were combined. The reaction was then quenched by the addition of 2 L of water. The
water phase was extracted with ethyl acetate (1 x 9 L). The organic layer was separated and washed with 1 M HCl (3 x 10 L), NaHCO3 (saturated aq.) (2 x 10 L), water (1 x 10 L) and brine (1 x 10 L). The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. This resulted in of tert-butyl N-[(1r,4r)-4-[(methanesulfonyloxy)methyl]cyclohexyl]carbamate (3300 g, 82%) as a white solid. LC-MS: MS (ESI): mass calcd. for C13H25NO5S, 307.15; m/z found 292.1, [M-tBu+MeCN+H]+; 1H NMR: (300 MHz, CDCl3): δ 4.03 (d, J = 6.6 Hz, 2H), 3.38 (s, 1H), 3.00 (s, 3H), 2.07-2.05 (m, 2H), 1.87-1.84 (m, 2H), 1.72-1.69 (m, 1H), 1.44 (s, 9H), 1.19-1.04 (m, 4H).
[0123] Step C: tert-butyl N-[(1r,4r)-4-(Cyanomethyl)cyclohexyl]carbamate. To a 10 L 4-necked round-bottom flask, was placed tert-butyl N-[(1r,4r)-4-[(methanesulfonyloxy)methyl]cyclohexyl]carbamate (1100 g, 3.58 mol, 1.00 equiv.), DMSO (5500 mL) and NaCN (406 g, 8.29 mol, 2.30 equiv.). The resulting mixture was stirred for 5 h at 90 °C. This reaction was performed in parallel 3 times and the reaction mixtures were combined. The reaction was then quenched by the addition of 15 L of water/ice. The solids were collected by filtration. The solids were washed with water (3 x 10 L). This resulted in tert-butyl N-[(1r,4r)-4-(cyanomethyl)cyclohexyl]carbamate (2480 g, 97%) as a white solid. MS (ESI): mass calcd. for C13H22N2O2, 238.17; m/z found 224 [M-tBu+MeCN+H]+; 1H NMR: (300 MHz, CDCl3): δ 4.39 (s, 1H), 3.38 (s, 1H), 2.26 (d, J = 6.9 Hz, 2H), 2.08-2.04 (m, 2H), 1.92-1.88 (m, 2H), 1.67-1.61 (m, 1H), 1.44 (s, 9H), 1.26-1.06 (m, 4H).
[0124] Step D: 2-[(1r,4r)-4-Aminocyclohexyl]acetonitrile hydrochloride. To a 10-L round-bottom flask was placed tert-butyl N-[(1r,4r)-4-(cyanomethyl)cyclohexyl]carbamate (620 g, 2.60 mol, 1.00 equiv.), and 1,4-dioxane (2 L). This was followed by the addition of a solution of HCl in 1,4-dioxane (5 L, 4 M) dropwise with stirring at 10 °C. The resulting solution was stirred overnight at 25 °C. This reaction was performed for 4 times and the reaction mixtures were combined. The solids were collected by filtration. The solids were washed with 1,4-dioxane (3 x 3 L), ethyl acetate (3 x 3 L) and hexane (3 x 3 L). This resulted in 2-[(1r,4r)-4-aminocyclohexyl]acetonitrile hydrochloride (1753 g, 96%) as a white solid. MS (ESI): mass calcd. for C8H14N2, 138.12; m/z found 139.25, [M+H]+; 1H NMR: (300 MHz, DMSO-d6): δ 8.14 (s, 3H), 2.96-2.84 (m, 1H), 2.46 (d, J = 6.3 Hz, 2H), 1.98 (d, J = 11.1 Hz, 2H), 1.79 (d, J = 12.0 Hz, 2H), 1.64-1.49 (m, 1H), 1.42-1.29 (m, 2H), 1.18-1.04 (m, 2H).
[0125] Step E: 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile. To a 1000 mL round bottom flask containing 2-[(1r,4r)-4-aminocyclohexyl]acetonitrile hydrochloride (29.10 g, 166.6 mmol) was added DMA (400 mL). The resulting suspension was treated with 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (51.53 g, 152.6 mmol), followed by DIPEA (63.0 mL, 366 mmol). The reaction mixture was placed under N2 and heated at 80 °C for 4 h. The crude reaction mixture was cooled to room temperature and slowly poured into a vigorously stirred 2 L flask containing 1.6 L water. The resulting suspension was stirred for 15 minutes at room temperature, then filtered and dried for 16 h in a vacuum oven with heating at 70 °C to provide the title compound (63.37 g, 95%) as a yellow solid. MS (ESI): mass calcd. for C21H21N5O4S, 439.1; m/z found, 440.1 [M+H]+. 1H NMR (500 MHz, CDCl3): δ 9.10 (s, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.23 – 8.15 (m, 2H), 7.66 – 7.59 (m, 2H), 7.56 – 7.49 (m, 2H), 6.67 (d, J = 4.2 Hz, 1H), 3.95 – 3.79 (m, 1H), 2.38 (d, J = 6.2 Hz, 2H), 2.32 -2.21 (m, 2H), 2.08 – 1.98 (m, 2H), 1.88 – 1.76 (m, 1H), 1.60 – 1.32 (m, 4H).
Intermediate 2
[0126] 2-((1r,4r)-4-((5-Amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile
[0127] 2-((1r,4r)-4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 1, 58.60 g, 133.3 mmol) was dissolved in THF/MeOH (1:1, 4800 mL). The mixture was passed through a continuous-flow hydrogenation reactor (10% Pd/C), such as a Thales Nano H-Cube®, at 10 mL/min with 100 % hydrogen (atmospheric pressure, 80 °C), then the solution was concentrated to provide the product as a purple solid. The solid was triturated with EtOAc (400 mL) and then triturated again with MeOH (200 mL) then filtered and dried under vacuum to provide the title compound (50.2 g, 91.9% yield).
MS (ESI): mass calcd. for C21H23N5O2S, 409.2; m/z found, 410.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.10 – 8.03 (m, 2H), 7.76 (s, 1H), 7.51 – 7.43 (m, 1H), 7.43 – 7.34 (m, 3H), 6.44 (d, J = 4.2 Hz, 1H), 4.61 (d, J = 8.5 Hz, 1H), 3.65 – 3.51 (m, 1H), 2.74 (s, 2H), 2.26 (d, J = 6.4 Hz, 2H), 2.19 – 2.05 (m, 2H), 1.97 – 1.86 (m, 2H), 1.76 – 1.59 (m, 1H), 1.33 – 1.12 (m, 4H).
Intermediate 3
[0128] Ethyl 2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-6-(phenylsulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate
[0129] To a 1L round bottom flask containing a stir bar and 2-((1r,4r)-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (Intermediate 2, 58.31 g, 142.4 mmol) was added ethyl 3-ethoxy-3-iminopropanoate (60.51 g, 309.3 mmol), followed by EtOH (600 mL, dried over 3Å molecular sieves for 48 h). A reflux condenser was attached to the reaction flask, the reaction was purged with N2, and was heated at 90 °C for 9 h. The reaction mixture was cooled to room temperature and left to stand for 30 h where the product crystallized out as brown needles. The solids were broken up with a spatula and the reaction mixture was transferred to a 2 L flask. Water (1.4 L) was added slowly via separatory funnel with vigorous stirring. After addition of the water was complete, the suspension was stirred for 30 minutes. The brown needles were isolated by filtration and then dried by pulling air through the filter for 1 h. The product was transferred to a 500 mL flask and treated with EtOAc (200 mL). A small quantity of seed crystals were added, which induced the formation of a white solid precipitate. The suspension was stirred for 30 minutes at room temperature, filtered, rinsed with EtOAc (25 mL), and dried under vacuum to provide the product as a white solid (48.65 g, 68% yield). MS (ESI): mass calcd. for C26H27N5O4S, 505.2; m/z found, 506.2 [M+H]+. 1H NMR (400
MHz, CDCl3) δ 8.85 (s, 1H), 8.28 – 8.19 (m, 2H), 7.84 (d, J = 4.0 Hz, 1H), 7.61 – 7.53 (m, 1H), 7.52 – 7.43 (m, 2H), 6.84 (d, J = 4.1 Hz, 1H), 4.32 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.09 (s, 2H), 2.44 (d, J = 6.2 Hz, 2H), 2.40 – 2.27 (m, 2H), 2.16 (d, J = 13.3 Hz, 2H), 2.12 – 1.96 (m, 3H), 1.54 – 1.38 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H).
Polymorph screening example
[0130] Some embodiments of compound of Formula I as free bases present multiple crystalline configurations that have a complex solid-state behavior, some of which in turn can present distinguishing features among themselves due to different amounts of incorporated solvent. Some embodiments of compound of Formula I are in the form of pseudopolymorphs, which are embodiments of the same compound that present crystal lattice compositional differences due to different amounts of solvent in the crystal lattice itself. In addition, channel solvation can also be present in some crystalline embodiments of compound of Formula I, in which solvent is incorporated within channels or voids that are present in the crystal lattice. For example, the various crystalline configurations given in Table 2 were found for compound of Formula I. Because of these features, non-stoichiometric solvates were often observed, as illustrated in Table 2. Furthermore, the presence of such channels or voids in the crystal structure of some embodiments according to this invention enables the presence of water and/or solvent molecules that are held within the crystal structure with varying degrees of bonding strength. Consequently, changes in the specific ambient conditions can readily lead to some loss or gain of water molecules and/or solvent molecules in some embodiments according to this invention. It is understood that “solvation” (third column in Table 2) for each of the embodiments listed in Table 2 is the formula solvation, and that the actual determination of the same as a stoichiometry number (fourth column in Table 2) can slightly vary from the formula solvation depending on the actual ambient conditions when it is experimentally determined. For example, if about half of the water molecules in an embodiment may be present as hydrogen-bonded to the active compound in the crystal lattice, while about the other half of water molecules may be in channels or voids in the crystal lattice, then changes in ambient conditions may alter the amount of such loosely contained water molecules in voids or channels, and hence lead to a slight difference between the formula solvation that is assigned according to, for example, single crystal diffraction, and the
stoichiometry that is determined by, for example, thermogravimetric analysis coupled with mass spectroscopy.
Table 2. Embodiments of crystalline forms of compound of Formula I
[0131] The compound that was obtained as described in Example 1 was further crystallized by preparing a slurry in DCM (1:3, for example 10 g of compound in 30 ml DCM) that was stirred at 40oC for 4 hours, and further stirred for 14 hours at 25oC, then heptane was slowly added (1:2, for example 20 ml of heptane into the compound/DCM slurry/solution) at 25oC, stirred at 40oC for 4 hours, cooled to 25oC and stirred for further 14 hours at 25oC. Subsequent filtration led to compound of Formula I in the form of an off-white solid, that was identified as a monohydrate, a 1s embodiment.
CLIP
Journal of Medicinal Chemistry (2020), 63(6), 2915-2929
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https://clinicaltrials.gov/ct2/show/NCT04552197
The purpose of this study is to evaluate: systemic and local gut (rectum and sigmoid colon) exposure to JNJ-64251330, local tissue Pharmacodynamics (PD) using gut (rectum and sigmoid colon) biopsies (Part 1) and the effect of food on the rate and extent of absorption of JNJ-64251330 from oral tablet dosed with or without food (Part 2).
Familial adenomatous polyposis (FAP) is the most common polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. JNJ-64251330 (lorpucitinib) is an oral, small molecule, potent pan-janus kinase (JAK) inhibitor that blocks phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. pSTAT induces transcription of multiple genes involved in the progression of inflammatory disease. JNJ-64251330 has chemical properties that limits the amount of drug in the blood while delivering the drug to the tissues of the gut. Local inhibition of JAK in the gut may present a promising method to treat inflammatory diseases of the intestinal tract, such as FAP. The study consists of 3 phases: screening phase (30 days) a treatment phase (24 weeks), and follow-up visit (up to 30 days after last dose of study drug). The total duration of the study will be up to 32 weeks. Study evaluations will include efficacy via endoscopies, safety (monitoring of adverse events (AE), serious adverse events (SAEs), events of infections including tuberculosis (TB), clinical laboratory blood tests (complete blood count and serum chemistries), vital signs, and concomitant medication review), pharmacokinetics, pharmacodynamic and biomarkers evaluations.
Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene.[4] The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer.[5]
APC is classified as a tumor suppressor gene. Tumor suppressor genes prevent the uncontrolled growth of cells that may result in cancerous tumors. The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor. The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, how the cell polarizes and the morphogenesis of the 3D structures,[6] or whether a cell moves within or away from tissue. This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling. The activity of one protein in particular, beta-catenin, is controlled by the APC protein (see: Wnt signaling pathway). Regulation of beta-catenin prevents genes that stimulate cell division from being turned on too often and prevents cell overgrowth.
The human APC gene is located on the long (q) arm of chromosome 5 in band q22.2 (5q22.2). The APC gene has been shown to contain an internal ribosome entry site. APC orthologs[7] have also been identified in all mammals for which complete genome data are available.
////////////////JNJ-64251330, JNJ 64251330, LORPUCITINIB, PHASE 1, CANCER, Adenomatous Polyposis Coli
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