Supplementary Note 1: Synthetic Chemistry Procedures

Similar documents
Supporting Information

All solvents and reagents were used as obtained. 1H NMR spectra were recorded with a Varian

Supporting Material. 2-Oxo-tetrahydro-1,8-naphthyridine-Based Protein Farnesyltransferase Inhibitors as Antimalarials

Minoru Tanaka 1,2,#, Justin M. Roberts 1,#, Hyuk-Soo Seo 3, Amanda Souza 1, Joshiawa Paulk 1,

An Efficient Total Synthesis and Absolute Configuration. Determination of Varitriol

SUPPLEMENTARY INFORMATION

Supporting Information

SUPPLEMENTARY INFORMATION

Supporting Information. Visualization of Phagosomal Hydrogen Peroxide Production by A Novel Fluorescent Probe That Is Localized via SNAP-tag Labeling

hydroxyanthraquinones related to proisocrinins

(Supplementary Information)

Compound Number. Synthetic Procedure

Fast and Flexible Synthesis of Pantothenic Acid and CJ-15,801.

Supporting Information

Discovery of 3-substituted 1H-indole-2-carboxylic Acid Derivatives as a Novel Class of CysLT 1 Selective Antagonists

A Facile and General Approach to 3-((Trifluoromethyl)thio)- 4H-chromen-4-one

SUPPLEMENTARY INFORMATION

Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is The Royal Society of Chemistry 2012

Drastically Decreased Reactivity of Thiols and Disulfides Complexed by Cucurbit[6]uril

Supplementary Information

Supporting Information:

Supporting Information. Rh (III)-Catalyzed Meta-C H Olefination Directed by a Nitrile Template

Supporting Text Synthesis of (2 S ,3 S )-2,3-bis(3-bromophenoxy)butane (3). Synthesis of (2 S ,3 S

SUPPLEMENTARY INFORMATION

Practical Synthesis of -oxo benzo[d]thiazol sulfones: Scope and Limitations

Supporting Information. Application of the Curtius rearrangement to the synthesis of 1'- aminoferrocene-1-carboxylic acid derivatives

Supporting Information

ELECTRONIC SUPPLEMENTARY INFORMATION FOR. Cyclizations and Cycloadditions of Acetylenic Sulfones on Solid Supports. Thomas G. Back* and Huimin Zhai

Supplementary Figure 1. Primary protein sequence alignment of engineered AcEZH2_ X,

Supporting Information

Supporting Information. Identification and synthesis of impurities formed during sertindole

Supplementary Note 1 : Chemical synthesis of (E/Z)-4,8-dimethylnona-2,7-dien-4-ol (4)

Supporting Information. (1S,8aS)-octahydroindolizidin-1-ol.

The First Asymmetric Total Syntheses and. Determination of Absolute Configurations of. Xestodecalactones B and C

Supporting Information for: Direct Conversion of Haloarenes to Phenols under Mild, Transition-Metal-Free Conditions

Synthesis and Use of QCy7-derived Modular Probes for Detection and. Imaging of Biologically Relevant Analytes. Supplementary Methods

Supplementary Information

Supporting Information

Diaza [1,4] Wittig-type rearrangement of N-allylic-N- Boc-hydrazines into -amino-n-boc-enamines

Synthesis of Trifluoromethylated Naphthoquinones via Copper-Catalyzed. Cascade Trifluoromethylation/Cyclization of. 2-(3-Arylpropioloyl)benzaldehydes

Supplementary Note 2. Synthesis of compounds. Synthesis of compound BI Supplementary Scheme 1: Synthesis of compound BI-7273

Supporting Information

(Supplementary Information)

Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-

Synthesis of Secondary and Tertiary Amine- Containing MOFs: C-N Bond Cleavage during MOF Synthesis

Tetrahydrofuran (THF) was distilled from benzophenone ketyl radical under an argon

Formal Total Synthesis of Optically Active Ingenol via Ring-Closing Olefin Metathesis

SUPPLEMENTARY INFORMATION

Synthesis of Pyridazine-Based α-helix Mimetics

Accessory Information

Significant improvement of dye-sensitized solar cell. performance by a slim phenothiazine based dyes

Supplementary Table 1. Small molecule screening data

Effect of Conjugation and Aromaticity of 3,6 Di-substituted Carbazole On Triplet Energy

Efficient Pd-Catalyzed Amination of Heteroaryl Halides

Discovery of Decamidine as a New and Potent PRMT1 Inhibitor

Catalytic Reductive Dehydration of Tertiary Amides to Enamines under Hydrosilylation Conditions

Solvent-Controlled Pd(II)-Catalyzed Aerobic Chemoselective. Intermolecular 1,2-Aminooxygenation and 1,2-Oxyamination of

Supporting Information for Sonogashira Hagihara reactions of halogenated glycals. Experimental procedures, analytical data and NMR spectra

Hualong Ding, Songlin Bai, Ping Lu,* Yanguang Wang*

Supporting Information

Supporting Information for

Electronic Supplementary Material

Supporting Information

Electronic Supplementary Information. ligands for efficient organic light-emitting diodes (OLEDs)

Supporting Information

Supporting Information

Supporting Information for Synthesis of C(3) Benzofuran Derived Bis-Aryl Quaternary Centers: Approaches to Diazonamide A

with EDCI (5.73 g, 30.0 mmol) for 10 min. Bromoethylamine hydrobromide (6.15

Tunable Visible Light Emission of Self-Assembled Rhomboidal Metallacycles

An efficient one pot ipso-nitration: Structural transformation of a dipeptide by N-terminus modification

Block: Synthesis, Aggregation-Induced Emission, Two-Photon. Absorption, Light Refraction, and Explosive Detection

Immobilized and Reusable Cu(I) Catalyst for Metal Ion-Free Conjugation of Ligands to Fully Deprotected Oligonucleotides through Click Reaction

Introduction 1. DSC scan 5-bromo-2-aminopyridine..3. DSC scan 5-bromo-2-nitropyridine...4

Reactive fluorescent dye functionalized cotton fabric as a Magic Cloth for selective sensing and reversible separation of Cd 2+ in water

One-pot synthesis of dual functional peptides by Sortase A-mediated on-resin cleavage and ligation

Supporting Information for: Synthesis of Chiral Tryptamines via a Regioselective Indole Alkylation

Supporting Information For:

Enantioselective Conjugate Addition of 3-Fluoro-Oxindoles to. Vinyl Sulfone: An Organocatalytic Access to Chiral. 3-Fluoro-3-Substituted Oxindoles

1G (bottom) with the phase-transition temperatures in C and associated enthalpy changes (in

Supporting Information. Adventures in Atropisomerism: Development of a Robust, Diastereoselective, Lithium-Catalyzed Atropisomer-Forming API Step

Supplemental data. Supplemental Figure 1: Alignment of potential ERRE1 and 2 in human, mouse and rat. PEPCK promoter.

Carbonylative Coupling of Allylic Acetates with. Arylboronic Acids

Synthesis of hydrophilic monomer, 1,4-dibromo-2,5-di[4-(2,2- dimethylpropoxysulfonyl)phenyl]butoxybenzene (Scheme 1).

How to build and race a fast nanocar Synthesis Information

dichloropyrimidine (1.5 g, 10.1 mmol) in THF (10 ml) added at -116 C under nitrogen atmosphere.

Supplementary Material for: Unexpected Decarbonylation during an Acid- Mediated Cyclization to Access the Carbocyclic Core of Zoanthenol.

Supporting Information

Hyperbranched Poly(N-(2-Hydroxypropyl) Methacrylamide) via RAFT Self- Condensing Vinyl Polymerization

Simplified platensimycin analogues as antibacterial agents

(A) Effect of I-EPI-002, EPI-002 or enzalutamide on dexamethasone (DEX, 10 nm)

Total Synthesis of (±)-Vibsanin E. Brett D. Schwartz, Justin R. Denton, Huw M. L. Davies and Craig. M. Williams. Supporting Information

Rh(III)-catalyzed Redox-Neutral Unsymmetrical C-H. Alkylation and Amidation Reactions of

Supplemental Information. Covalent Protein Labeling at Glutamic Acids

Aziridine in Polymers: A Strategy to Functionalize Polymers by Ring- Opening Reaction of Aziridine

The Enantioselective Synthesis and Biological Evaluation of Chimeric Promysalin Analogs Facilitated by Diverted Total Synthesis

Novel Process for Preparation of Tetrabenazine and Deutetrabenazine. Purna Chandra Ray*, Yogesh Dadaji Pawar, Dnyaneshwar Tukaram Singare, Tushar

Molecular Imaging of Labile Iron(II) Pools in Living Cells with a Turn-on Fluorescent Probe

SYNTHESIS OF A 3-THIOMANNOSIDE

Coupling of 6 with 8a to give 4,6-Di-O-acetyl-2-amino-2-N,3-O-carbonyl-2-deoxy-α-Dglucopyranosyl-(1 3)-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose.

Asymmetric Synthesis of Hydrobenzofuranones via Desymmetrization of Cyclohexadienones using the Intramolecular Stetter Reaction

Transcription:

Supplementary Note 1: Synthetic Chemistry Procedures Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs John D. McCorvy 1 *, Kyle V. Butler 2 *, Brendan Kelly 3*, Katie Rechsteiner 1, Joel Karpiak 4, Robin M. Betz 3, Bethany L. Kormos 5, Brian K. Shoichet 4, Ron O. Dror 3, Jian Jin 2, Bryan L. Roth 1 1 National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA. 2 Center for Chemical Biology and Drug Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 3 Departments of Computer Science and Molecular and Cellular Physiology, Institute for Computational and Mathematical Engineering, and Biophysics Program, Stanford University, Stanford, California, 94305, USA. 4 Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, 1700 4 th Street, San Francisco, California, 94158, USA. 5 Neuroscience and Pain Medicinal Chemistry, Pfizer Worldwide R&D, 610 Main Street, Cambridge, Massachusetts, 02139, USA * These authors contributed equally Correspondence and requests for materials should be addressed to: B.L.R. (bryan_roth@med.unc.edu), R.O.D. (ron.dror@stanford.edu ) J.J. (jian.jin@mssm.edu).

Synthesis Scheme for indole-aripiprazole hybrids

General procedure for alkylation of indole. 7-(4-(4-(1H-Indol-4-yl)piperazin-1- yl)butoxy)-3,4-dihydroquinolin-2(1h)-one (1) (39 mg, 0.094 mmol), was dissolved in DMF (1 ml), followed by addition of NaH (60 wt% in mineral oil, 27 mg, 1.11 mmol). The mixture was stirred for 30 min at room temperature, followed by addition of the alkyl halide (0.094 mmol). This was stirred for 2 hours, quenched with water, and purified by HPLC. tert-butyl 4-(piperazin-1-yl)-1H-indole-1-carboxylate (8) A sealed tube was filled with dioxane (25 ml), tert-butyl 4-bromo-1H-indole-1-carboxylate (3.00 g, 10.1 mmol), piperazine (1.747 g, 20.3 mmol), cesium carbonate (6.613 g, 20.3 mmol), palladium acetate (45 mg, 0.20 mmol), and BINAP (318 mg, 0.51 mmol). The tube was filled with argon, sealed, and heated at 100 o C for 18h. The reaction mixture was diluted with EtOAc, filtered through celite, and washed with water. Purification by MPLC (0 to 20% MeOH in DCM, 1% NH 3 ) gave the product. 1 H NMR (Methanol-d 4 ): δ 7.91 (d, 1H), 7.62 (d, 1H), 7.27 (t, 1H), 6.86 (d, 1H), 6.72 (d, 1H), 3.48 (m, 4H), 3.40 (m, 4H), 1.69 (s, 9H). MS (ESI) m/z [M + H] + Calcd for [C 17 H 23 N 3 O 2 + H] + : 302; Found: 302. Yield: 1.363 g, 4.52 mmol, 45%. 7-(4-(4-(1H-Indol-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (1) tert- Butyl 4-(piperazin-1-yl)-1H-indole-1-carboxylate (8) (1.30 g, 4.31 mmol), 7-(4- bromobutoxy)-3,4-dihydroquinolin-2(1h)-one (1.672 g, 5.61 mmol), and potassium carbonate (1.191 g, 8.62 mmol) were stirred in dimethylformamide (DMF) (12 ml) overnight at 70 o C. Purification by MPLC (0 to 20% MeOH in DCM, 1% NH 3 ) gave tertbutyl 4-(4-(4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)butyl)piperazin-1-yl)-1H-indole- 1-carboxylate (1.690 g, MS (ESI) m/z: 519). This intermediate was stirred for 2h in DCM (25 ml) and trifluoroacetic acid (TFA) (25 ml). The reaction mixture was concentrated to an oil and then made basic by addition of saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The product was purified by MPLC (0 to 10% MeOH in dichloromethane). 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.21 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 8.2, 1H), 7.11-7.01 (m, 2H), 6.58 (m, 2H), 6.50-6.44 (m, 2H), 4.05 (t, J = 5.8 Hz, 2H), 3.83 (d, J = 13.4 Hz, 2H), 3.72 (d, J = 12.1 Hz, 2H), 3.40 (t, J = 12.0 Hz,

2H), 3.35-3.31 (m, 3H), 3.10 (t, J = 12.7 Hz, 2H), 2.91-2.82 (m, 2H), 2.57-2.49 (m, 2H), 2.01 (m, 2H), 1.91 (q, J = 6.8, 6.3 Hz, 2H). 13 C NMR (101 MHz, Methanol-d 4 ) δ 172.61, 158.32, 143.05, 138.43, 137.48, 128.27, 123.39, 121.36, 121.24, 116.12, 109.99, 108.38, 107.23, 105.96, 101.78, 98.87, 66.70, 56.47, 52.29, 30.48, 25.98, 23.98, 20.89. MS (ESI) m/z: [M + H] + Calcd for [C 25 H 30 N 4 O 2 + H] + : 419; Found: 419. Yield: 1.23 g, 2.30 mmol, 53%. HRMS (ESI-TOF) m/z: [M + H] + Calcd for [C 25 H 31 N 4 O 2 + H] + : 419.2447; Found: 419.2451. HPLC Purity: Method A, >95%, t R = 4.103 min. 7-(4-(4-(1-Methyl-1H-indol-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)- one, trifluoroacetic acid salt (2) Synthesized according to general procedure for alkylation of indole. Methyl iodide was the alkyl halide source. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.20-7.10 (m, 2H), 7.06 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.70 (d, J = 7.3, 1H), 6.53 (dd, J = 8.3, 2.4 Hz, 1H), 6.39 (d, J = 3.2, 1H), 6.34 (d, J = 2.4 Hz, 1H), 3.97 (d, J = 5.6 Hz, 2H), 3.79 (s, 7H), 3.48 (d, J = 9.0 Hz, 2H), 3.31-3.16 (m, 4H), 2.93-2.85 (m, 2H), 2.63 (dd, J = 8.5, 6.6 Hz, 2H), 2.10-1.97 (m, 2H), 1.94-1.81 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 158.17, 142.08, 137.96, 137.58, 128.83, 128.39, 122.22, 121.42, 116.12, 109.07, 107.76, 106.32, 102.50, 98.30, 66.94, 57.01, 52.05, 48.53, 33.11, 30.75, 26.25, 24.30, 20.88. MS (ESI) m/z: [M + H] + Calcd for [C 26 H 32 N 4 O 2 + H] + : 433; Found: 433. Yield: 13 mg, 0.024 mmol, 25%. HRMS (ESI-TOF) m/z: [M + H] + Calcd for [C 26 H 33 N 4 O 2 + H] + : 433.2604; Found: 433.2599. HPLC Purity: Method A, >95%, t R = 4.424 min. 7-(4-(4-(1-Propyl-1H-indol-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)- one, trifluoroacetic acid salt (3) Synthesized according to general procedure for alkylation of indole. 1-Bromopropane was the alkyl halide source. 1 H NMR (400 MHz, Chloroform-d) δ 8.48 (s, 1H), 7.16-7.10 (m, 2H), 7.09 (dd, J = 3.2, 0.7 Hz, 1H), 7.07-6.99 (m, 1H), 6.69-6.61 (m, 1H), 6.51 (dt, J = 8.3, 1.5 Hz, 1H), 6.38 (d, J = 3.2 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 4.07 (t, J = 7.0 Hz, 2H), 4.00-3.93 (m, 2H), 3.87-3.67 (m, 4H), 3.50-3.34 (m, 2H), 3.29-3.11 (m, 4H), 2.88 (t, J = 7.5 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.02 (q, J = 7.7 Hz, 2H), 1.86 (p, J = 7.0 Hz, 4H), 0.92 (t, J = 7.4, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 158.17, 142.56, 137.88, 137.23, 128.75, 127.40, 122.02,

121.60, 116.11, 109.99, 108.90, 107.46, 106.30, 102.41, 98.24, 66.96, 56.94, 52.12, 48.47, 48.31, 30.88, 26.28, 24.40, 23.50, 20.87, 11.46. MS (ESI) m/z: [M + H] + Calcd for [C 28 H 36 N 4 O 2 + H] + : 461; Found: 461.Yield: 30 mg, 0.052 mmol, 56%. HRMS (ESI- TOF) m/z: [M + H] + Calcd for [C 28 H 37 N 4 O 2 + H] + : 461.2917; Found: 461.2908. HPLC Purity: Method A, >95%, t R = 4.722 min. 7-(4-(4-(1-Isopropyl-1H-indol-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)- one, trifluoroacetic acid salt (4) Synthesized according to general procedure for alkylation of indole. 2-Bromopropane was the alkyl halide source. 1 H NMR (600 MHz, Methanol-d 4 ) δ 7.35 (s, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.16-7.06 (m, 2H), 6.64 (d, J = 7.2 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 13.1 Hz, 2H), 4.74 (s, 1H), 4.07 (t, J = 5.5 Hz, 2H), 3.84 (d, J = 13.4 Hz, 2H), 3.74 (d, J = 11.9 Hz, 2H), 3.42 (s, 2H), 3.36 (d, J = 11.1 Hz, 2H), 3.12 (t, J = 12.9 Hz, 2H), 2.90 (d, J = 7.6 Hz, 2H), 2.56 (d, J = 7.6 Hz, 2H), 2.03 (s, 2H), 1.92 (s, 2H), 1.52 (d, J = 6.5 Hz, 6H). 13 C NMR (151 MHz, Methanold 4 ) δ 172.65, 158.30, 143.32, 138.38, 136.81, 128.27, 122.53, 121.81, 121.29, 116.07, 108.36, 106.18, 105.52, 101.73, 98.59, 66.68, 56.44, 52.23, 49.53, 48.40, 30.44, 25.93, 23.92, 21.52, 20.83. MS (ESI) m/z: [M + H] + Calcd for [C 28 H 36 N 4 O 2 + H] + : 461; Found: 461. HRMS (ESI-TOF) m/z: [M + H] + Calcd for C 28 H 37 N 4 O 2 + H: 461.2917; Found: 461.2924. Yield: 19 mg, 0.035 mmol, 37%. HPLC Purity: Method A, >95%, t R = 4.423 min. 7-(4-(4-(1-Benzyl-1H-indol-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)- one, trifluoroacetic acid salt (5) Synthesized according to general procedure for alkylation of indole. Bromobenzene was the alkyl halide source. 1 H NMR (400 MHz, Chloroform-d) δ 7.68-7.58 (m, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.33-7.26 (m, 2H), 7.15-7.06 (m, 4H), 6.86-6.81 (m, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.66 (d, J = 7.3, 1H), 6.44 (d, J = 3.2, 1H), 6.26 (d, J = 9.5 Hz, 1H), 5.31 (s, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.88-3.68 (m, 4H), 3.50-3.38 (m, 2H), 3.28-3.10 (m, 4H), 2.64 (s, 4H), 2.07 (dd, J = 10.2, 5.9 Hz, 2H), 1.94 (q, J = 7.1, 6.5 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 13 C NMR (101 MHz, Chloroform-d) δ 173.02, 162.09, 148.58, 143.41, 138.85, 138.02, 137.51, 128.19, 127.40, 127.31, 126.46, 122.08, 121.99, 109.99, 109.95, 106.48, 105.89,

103.85, 98.90, 64.61, 56.48, 52.25, 49.53, 48.41, 30.27, 25.80, 22.44, 20.80. MS (ESI) m/z: [M + H] + Calcd for [C 32 H 36 N 4 O 2 + H] + : 509; Found: 509. Yield: 32 mg, 0.053 mmol, 56%. HRMS (ESI-TOF) m/z: [M + H] + Calcd for [C 32 H 37 N 4 O 2 + H] + : 509.2917; Found: 508.2914. HPLC Purity: Method A, >95%, t R = 5.941 min. 7-(4-(4-(2-methyl-1H-indol-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)- one (6) 2-Methyl-4-(piperazin-1-yl)-1H-indole (11) (HCl salt, 50 mg, 0.2 mmol) and 7-(4- bromobutoxy)-3,4-dihydroquinolin-2(1h)-one (89 mg, 0.2 mmol) and potassium carbonate (55 mg, 0.4 mmol) were stirred in 1.5 ml DMF for 24 hours. The product was purified by HPLC, giving the product as the TFA salt (36 mg, 33%). HRMS (ESI-TOF) [M + H] + calcd for [C 26 H 32 N 4 O 2 + H] +, 433.2604; found, 433.2610. 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.97 (s, 1H), 10.04 (s, 1H), 9.50 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.52 (dd, J = 8.3, 2.5 Hz, 1H), 6.45 (m, 2H), 6.14 (s, 1H), 3.97 (t, J = 5.9 Hz, 2H), 3.70 (d, J = 13.1 Hz, 4H), 3.63 (d, J = 12.1 Hz, 4H), 2.97 (t, J = 12.4 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H), 2.37 (s, 3H), 1.85 (m, 2H), 1.78 (d, J = 8.2 Hz, 2H). 13 C NMR (151 MHz, DMSO-d 6 ) δ 170.76, 158.09, 142.81, 139.64, 137.51, 134.55, 128.85, 121.72, 120.88, 116.11, 107.85, 106.64, 106.20, 102.13, 98.07, 67.01, 55.66, 51.86, 48.11, 31.17, 26.23, 24.40, 20.81, 13.76. HPLC Purity: Method B, >95%, t R = 3.80 min. tert-butyl 4-(2-methyl-1H-indol-4-yl)piperazine-1-carboxylate (10) 4-Bromo-2-methyl-1H-indole (210 mg, 1 mmol), 1-Boc-piperazine (279 mg, 1.5 mmol), tbubrettphos (10 mg, 0.02 mmol), and tbubrettphos Precatalyst G1 (16 mg, 0.02 mmol) were dissolved in a sealed tube in 3 ml THF. This was treated with 1.2 ml of 1M LiHMDS in THF, and the tube was purged with argon and sealed. The tube was heated at 65 o C for 4 hours. Column chromatography gave the product (155 mg, 49% yield). HRMS (ESI-TOF) [M + H] + calcd for [C 18 H 25 N 3 O 2 + H] +, 316.2025; found, 316.2031. 1 H NMR (Chloroform-d): δ 7.93 (s, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 7.4 Hz, 1H), 6.23 (s, 1H), 3.68 (t, J = 4.9 Hz, 4H), 3.18 (s, 4H), 2.47 (s, 3H), 1.52 (s, 9H)

2-Methyl-4-(piperazin-1-yl)-1H-indole (11) tert-butyl 4-(2-methyl-1H-indol-4-yl)piperazine-1-carboxylate (10) (140 mg, 0.44 mmol) was stirred in 4 ml of 4N HCl in dioxane for two hours. The solid product was collected by filtration and dried under vacuum. Yield: 91 mg of HCl salt, 82%. HRMS (ESI-TOF) [M + H] + calcd for [C 13 H 17 N 3 + H, 216.1501] + ; found, 216.1511. 13 C NMR (151 MHz, DMSO-d 6 ) δ 137.61, 134.97, 121.66, 120.80, 107.28, 106.75, 98.03, 66.77, 48.19, 43.31, 13.74. 1 H NMR (600 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 9.31 (s, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.58 (s, 1H), 6.24 (s, 1H), 3.35 (d, 8H), 2.37 (s, 3H). 7-(4-(4-(1,2-Dimethyl-1H-indol-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin- 2(1H)-one (7) 1,2-Dimethyl-4-(piperazin-1-yl)-1H-indole, trifluoroacetic acid salt (9) was converted to 7-(4-(4-(1,2-dimethyl-1H-indol-4-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one according to the procedure described for 1. Yield: 41 mg (36%) of the TFA salt. HRMS (ESI-TOF) calcd for [C 27 H 34 N 4 O 2 + H] +, 447.2760; found, 447.2762. 1 H NMR (600 MHz, Methanol-d 4 ) δ 7.14-7.01 (m, 3H), 6.64-6.57 (m, 2H), 6.49 (s, 1H), 4.07 (t, J = 5.8 Hz, 2H), 3.82 (d, J = 13.5 Hz, 2H), 3.73 (d, J = 12.0 Hz, 2H), 3.69 (s, 3H), 3.40 (t, J = 11.7 Hz, 2H), 3.36 (m, integration obscured by solvent), 3.09 (t, J = 12.4 Hz, 2H), 2.93-2.79 (m, 2H), 2.62-2.51 (m, 2H), 2.45 (d, J = 5.2 Hz, 3H), 2.03 (s, 2H), 1.92 (t, J = 7.0 Hz, 2H). 13 C NMR (151 MHz, Methanol-d4) δ 172.58, 158.27, 142.21, 138.60, 138.38, 135.84, 128.24, 120.94, 120.49, 116.04, 108.35, 106.21, 104.84, 101.73, 96.72, 66.68, 56.42, 52.23, 48.27, 30.45, 28.33, 25.94, 23.94, 20.82, 11.15. HPLC Purity: Method B, >95%, t R = 1.69 min.

2024 © sciencedocbox.com Privacy Policy | Terms of Service | Feedback