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[ CAS No. 165963-71-3 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 165963-71-3
Chemical Structure| 165963-71-3
Chemical Structure| 165963-71-3
Structure of 165963-71-3 * Storage: {[proInfo.prStorage]}
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Quality Control of [ 165963-71-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification
Alternatived Products of [ 165963-71-3 ]

Product Details of [ 165963-71-3 ]

CAS No. :165963-71-3 MDL No. :MFCD07369162
Formula : C11H22BrNO4 Boiling Point : -
Linear Structure Formula :- InChI Key :WGWDCMKAMHBDPO-UHFFFAOYSA-N
M.W : 312.20 Pubchem ID :22471886
Synonyms :

Calculated chemistry of [ 165963-71-3 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.91
Num. rotatable bonds : 11
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 69.54
TPSA : 56.79 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.22 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.05
Log Po/w (XLOGP3) : 1.39
Log Po/w (WLOGP) : 1.94
Log Po/w (MLOGP) : 1.14
Log Po/w (SILICOS-IT) : 2.0
Consensus Log Po/w : 1.9

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 1.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.93
Solubility : 3.71 mg/ml ; 0.0119 mol/l
Class : Very soluble
Log S (Ali) : -2.19
Solubility : 2.03 mg/ml ; 0.00651 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.58
Solubility : 0.0827 mg/ml ; 0.000265 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.14

Safety of [ 165963-71-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 165963-71-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 165963-71-3 ]

[ 165963-71-3 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 308085-25-8 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • [ 299931-13-8 ]
YieldReaction ConditionsOperation in experiment
96% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 60℃; for 14h; 2 EXAMPLE 2Manufacture of the Compound (4) from the Compounds (2) and (3)A mixture of the compound (2) (2.76 g, 12 mmol), the compound (3) {2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide} (4.50 g, 14.4 mmol), anhydrous potassium carbonate (1.66 g, 12 mmol), BU4NI (554 mg, 1.5 mmol) and DMF (15 ml) was stirred at 60° C. for 14 hours in an atmosphere of argon gas. After that, the solvent of the reaction mixture was evaporated under reduced pressure, water was added to the resulting residue and the mixture was extracted with ethyl acetate. The extract was washed with water, 0.1N HCl and water successively and dried over anhydrous magnesium sulfate, the solvent was evaporated therefrom under reduced pressure and the residue was purified by a silica gel column chromatography (eluting with ethyl acetate:hexane=1:1) to give 5.33 g (96%) of the compound (4) {2-[2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethoxy]-4-[3-(trifluoromethyl)-3H-diazirine-3-yl]benzaldehyde as a pale yellow oily substance.1H NMR (400 MHz, CDCl3, 25° C.): δ=10.5 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.75 (br s, 1H), 5.00 (br, 1H), 4.27 (t, J=4.8 Hz, 2H), 3.92 (t, J=4.8 Hz, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.54 (t, J=5.1 Hz, 2H), 3.3 (m, 2H), 1.43 (s, 9H); MS (FAB+): m/z (%): 484 (84) [M+Na]+, 462 (4)
91% With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12h;
70.1% With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 60℃; for 24h; Darkness;
57% With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 65℃; for 12h; Darkness;

Reference： [1]Current Patent Assignee: SEIKAGAKU CORPORATION - US6903223, 2005, B1 Location in patent: Page/Page column 12-13
[2]Hashimoto, Makoto; Hatanaka, Yasumaru; Yang, Jing; Dhesi, Jaswant; Holman, Geoffrey D. [Carbohydrate Research, 2001, vol. 331, # 2, p. 119 - 127]
[3]Li, Xin; Cao, Jian-Hua; Li, Ying; Rondard, Philippe; Zhang, Yang; Yi, Ping; Liu, Jian-Feng; Nan, Fa-Jun [Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3057 - 3060]
[4]Location in patent: scheme or table Gu, Min; Yan, Jianbin; Bai, Zhiyan; Chen, Yue-Ting; Lu, Wei; Tang, Jie; Duan, Liusheng; Xie, Daoxin; Nan, Fa-Jun [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 9, p. 3012 - 3019]
  • 2
  • [ 620-24-6 ]
  • [ 165963-71-3 ]
  • [ 819067-08-8 ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate In acetonitrile for 12h; Heating;
Reference： [1]Lakshmi; Hanshaw, Roger G.; Smith, Bradley D. [Tetrahedron, 2004, vol. 60, # 49, p. 11307 - 11315]
  • 3
  • [ 153707-56-3 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • [ 819067-00-0 ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate In acetonitrile for 24h; Heating;
Reference： [1]Lakshmi; Hanshaw, Roger G.; Smith, Bradley D. [Tetrahedron, 2004, vol. 60, # 49, p. 11307 - 11315]
  • 4
  • [ 165963-71-3 ]
  • [ 819067-09-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 89 percent / K2CO3 / acetonitrile / 12 h / Heating 2: 65 percent / CBr4; Ph3P / CH2Cl2 / 20 °C
Reference： [1]Lakshmi; Hanshaw, Roger G.; Smith, Bradley D. [Tetrahedron, 2004, vol. 60, # 49, p. 11307 - 11315]
  • 5
  • [ 165963-71-3 ]
  • [ 819067-01-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 89 percent / K2CO3 / acetonitrile / 24 h / Heating 2: 70 percent / CBr4; Ph3P / CH2Cl2 / 20 °C
Reference： [1]Lakshmi; Hanshaw, Roger G.; Smith, Bradley D. [Tetrahedron, 2004, vol. 60, # 49, p. 11307 - 11315]
  • 6
  • [ 165963-71-3 ]
  • [ 852486-86-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 89 percent / K2CO3 / acetonitrile / 12 h / Heating 2: 65 percent / CBr4; Ph3P / CH2Cl2 / 20 °C 3: 87 percent / K2CO3 / dimethylformamide / 5 h 4: TFA / CH2Cl2 / 2 h / 20 °C
Reference： [1]Lakshmi; Hanshaw, Roger G.; Smith, Bradley D. [Tetrahedron, 2004, vol. 60, # 49, p. 11307 - 11315]
  • 7
  • [ 113787-85-2 ]
  • [ 165963-71-3 ]
  • [ 891501-26-1 ]
YieldReaction ConditionsOperation in experiment
48% With potassium carbonate In N,N-dimethyl-formamide at 60℃; Inert atmosphere;
Reference： [1]Location in patent: experimental part Tomohiro, Takenori; Tachi, Norie; Azuma, Yusuke; Hatanaka, Yasumaru [Heterocycles, 2009, vol. 79, # C, p. 897 - 908]
  • 8
  • [ 79907-49-6 ]
  • [ 165963-71-3 ]
  • [ 1268259-47-7 ]
YieldReaction ConditionsOperation in experiment
584 mg With tetra-(n-butyl)ammonium iodide; potassium carbonate In butanone at 80℃; for 24h;
Reference： [1]Location in patent: experimental part Li, Xin; Li, Xiaoqi; Tang, Hong; Nan, Fajun [Chinese Journal of Chemistry, 2010, vol. 28, # 11, p. 2240 - 2244]
  • 9
  • [ 139115-92-7 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; for 3h;Inert atmosphere; tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carba-mate (0.5 g, 2.03 mmol) was dissolved in dry THF (20 ml) then Ph3P (1.06 g, 4.06 mmol, 2 eq.) was added. CBr4 (1.35 g, 4.06 mmol, 2 eq.) was slowly added to the mixture. After 3 h the solution was filtered through celite to eliminate the phosphine oxide and washed with Et2O. The solvents were removed under high vacuum. The crude product was purified by flash chromatography on silica gel (hexane/AcOEt, 4:1) to give 10 as a colorless oil (0.601 g, 95% yield)
84% With carbon tetrabromide; potassium carbonate; triphenylphosphine; In dichloromethane; at 20℃; for 24h; Compound 5 (713 mg, 2.85 mmol), CBr4 (1.23 g, 3.70 mmol), and K2CO3 (510 mg, 3.70 mmol) were dissolved in 5 mL of CH2Cl2. Ten mL of CH2Cl2 containing PPh3 (1.2 g, 4.56 mmol) was added by syringe to the solution and stirred at room temperature for 24 h. After evaporation of the reaction mixture, the resultant residue was added to n-hexane, and the insoluble material was filtered. The resultant material, which was obtained by evaporation of the filtrate, was purified by silica gel column chromatography (40 g, n-hexane-EtOAc, 1/1) to yield 6 (745 mg, 2.40 mmol, 84%) as acolorless oil. 1H NMR (270 MHz, CDCl3): 4.98 (1H,br.s), 3.76 (2H, t, J = 7.0 Hz), 3.63-3.55 (4H, m), 3.50(2H, t, J = 7.1 Hz), 3.43 (2H, t, J = 7.3 Hz), 3.25 (2H,t, J = 7.1 Hz), 1.39 (9H, s); 13C NMR (67.8 MHz,CDCl3): 155.8, 79.1, 71.0, 70.3, 70.1, 70.0, 40.2, 30.1,28.3; FI-MS m/z (rel.int.): 314 (52.5), 313 (100), 312(58.3, [M + H]+), 311 (94.8, [M]+), 57.0 (84.6); FIHR-MS m/z: calcd. for C11H22BrNO4, 311.07322,found 311.07016.
80% With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h; (1) To a solution of tert-butyl {2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamate (1.0 g) in tetrahydrofuran (20 mL),triphenylphosphine (2.1 g) and carbon tetrabromide (2.7 g) were added, and the mixture was stirred at room temperaturefor 1 day. The reaction solution was filtered through Celite(registered trademark) and then washed with diethyl ether, and then, the filtrates were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage(registered trademark) SNAP Cartridge HP-Sphere, hexane:ethylacetate = 100:0 ? 50:50) to obtain tert-butyl {2-[2-(2-bromoethoxy)ethoxy]ethyl}carbamate (1.0 g, 80%) as a colorlessoil substance. 1H NMR (300 MHz, CDCl3) delta ppm 1.45 (s, 9H), 3.28-3.36 (m, 2H), 3.45-3.51 (m, 2H), 3.53-3.58 (m, 2H), 3.62-3.69(m, 4H), 3.78-3.86 (m, 2H), 5.01 (br. s., 1H).
Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1151 - 1155
[2]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439
[3]Patent: EP3173408,2017,A1 .Location in patent: Paragraph 0341
[4]Journal of the American Chemical Society,2011,vol. 133,p. 15280 - 15283
  • 10
  • [ 107007-95-4 ]
  • [ 165963-71-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 60℃; Inert atmosphere; tert-Butyl (2-(2-(2-(3-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl) carbamoyl) -1H-indazol-1-yl)ethoxy)ethoxy)ethyl)carbamate General procedure: To a stirred solution of amide 7 (0.057 g, 0.19 mmol, 1 eq.) in DMF (2 ml), linker 10 (0.095 g, 0.3 mmol, 1.6 eq.) was added, followed by K2CO3 (0.047 g, 0.34 mmol, 1.8 eq.) and n-Bu4NI (0.007 g, 0.019 mmol, 10 mol%) at RT. After stirring overnight at 60°C, the reaction mixture was partitioned between EtOAc-water, the organic layer was washed with sat. NH4Cl, sat. NaHCO3 and brine, dried over MgSO4 and filtered. The solvent was removed in vacuo. The title compound was obtained as a white solid (0.102 g, 0.193 mmol, quantitative yield) and was used in the next step without further purification
Reference： [1]Simonin, Jonathan; Vernekar, Sanjeev Kumar V.; Thompson, Andrew J.; Hothersall, J. Daniel; Connolly, Christopher N.; Lummis, Sarah C.R.; Lochner, Martin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1151 - 1155]
  • 11
  • [ 133841-15-3 ]
  • [ 165963-71-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
70% With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide Inert atmosphere; tert-Butyl (2-(2-(2-((1-methyl-3-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)carbamoyl)-1H-indazol-7-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (35) General procedure: To a stirred solution of amide 7 (0.057 g, 0.19 mmol, 1 eq.) in DMF (2 ml), linker 10 (0.095 g, 0.3 mmol, 1.6 eq.) was added, followed by K2CO3 (0.047 g, 0.34 mmol, 1.8 eq.) and n-Bu4NI (0.007 g, 0.019 mmol, 10 mol%) at RT. After stirring overnight at 60°C, the reaction mixture was partitioned between EtOAc-water, the organic layer was washed with sat. NH4Cl, sat. NaHCO3 and brine, dried over MgSO4 and filtered. The solvent was removed in vacuo. The title compound was obtained as a white solid (0.102 g, 0.193 mmol, quantitative yield) and was used in the next step without further purification
Reference： [1]Simonin, Jonathan; Vernekar, Sanjeev Kumar V.; Thompson, Andrew J.; Hothersall, J. Daniel; Connolly, Christopher N.; Lummis, Sarah C.R.; Lochner, Martin [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1151 - 1155]
  • 12
  • [ 940289-68-9 ]
  • [ 165963-71-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate; sodium iodide In acetonitrile for 24h; Reflux;
Reference： [1]Kanoh, Naoki; Suzuki, Takahiro; Kawatani, Makoto; Katou, Yasuhiro; Osada, Hiroyuki; Iwabuchi, Yoshiharu [Bioconjugate Chemistry, 2013, vol. 24, # 1, p. 44 - 52]
  • 13
  • [ 700870-56-0 ]
  • [ 165963-71-3 ]
  • [ 1418005-95-4 ]
  • [ 1418005-96-5 ]
YieldReaction ConditionsOperation in experiment
1: 41% 2: 10% With potassium carbonate; sodium iodide In acetonitrile for 9h; Reflux;
Reference： [1]Kanoh, Naoki; Suzuki, Takahiro; Kawatani, Makoto; Katou, Yasuhiro; Osada, Hiroyuki; Iwabuchi, Yoshiharu [Bioconjugate Chemistry, 2013, vol. 24, # 1, p. 44 - 52]
  • 14
  • [ 1418005-84-1 ]
  • [ 165963-71-3 ]
  • [ 1418006-05-9 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In acetonitrile at 20℃; for 13.5h; Reflux;
Reference： [1]Kanoh, Naoki; Suzuki, Takahiro; Kawatani, Makoto; Katou, Yasuhiro; Osada, Hiroyuki; Iwabuchi, Yoshiharu [Bioconjugate Chemistry, 2013, vol. 24, # 1, p. 44 - 52]
  • 15
  • [ 1628465-88-2 ]
  • [ 165963-71-3 ]
  • [ 1628465-89-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-(4-hydroxyphenyl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide In N,N-dimethyl-formamide at 20℃; for 5h; 6 To the solution of 2-(4-hydroxyphenyl)-N-(5-methyl-4-( 1 -(2-methylbenzoyl)indolin- 5-yl)thiazol-2-yl)acetamide (0.1 g, 0.207 mmol) in DMF (1.5 ml) was added NaH(0.025 g, 0.620 mmol). The mixture was stirred at r.t. for 30 mins. tert-butyl (2-(2-(2- bromoethoxy)ethoxy)ethyl)carbamate (0.07 1 g, 0.227 mmol) was added to the reaction mixture. The reaction mixture was stirred at r.t.for 5h. H20 was added to the mixture and extracted with EtOAc (2x). The organic layer was washed with Sat. Na2504 (3X) and brine and dried over Na2 SO4, and concentrated. The residue wastaken up in DMSO and subsequently purified by reverse phase chromatography to afford COMPOUND 236.
Reference： [1]Current Patent Assignee: NATIONAL INSTITUTES OF HEALTH; THE JOHNS HOPKINS UNIVERSITY; SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE - WO2014/145642, 2014, A2 Location in patent: Page/Page column 193
  • 16
  • [ 2192-20-3 ]
  • [ 76-05-1 ]
  • [ 165963-71-3 ]
  • [ 1784701-31-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: hydroxyzine dihydrochloride With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Stage #2: 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide In N,N-dimethyl-formamide; mineral oil Stage #3: trifluoroacetic acid In water; acetonitrile A solution of 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin- 1 - yl)ethoxy)ethanol, 2 HCl (250 mg, 0.558 mmol) in DMF (5.00 mL) was treated with a 60% dispersion in mineral oil of NaH (89.0 mg, 2.23 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and room temperature for 30 min. To this mixture was added a solution of tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (174 mg, 0.558 mmol) in DMF (1.00 mL) and the resulting mixture allowed to stir overnight. The mixture was quenched with H20 and extracted with CH2CI2. The organic layer was separated, dried over MgS04, filtered and concentrated. Crude residue was purified by preparative HPLC, to give the title compound as the TFA salt. ]H NMR (400 MHz, CDC13) δ ppm 7.45 - 7.37 (m, 4H), 7.37 - 7.18 (m, 5H), 4.44 (s, 1H), 3.86 (t, J = 4.4 Hz, 2H), 3.63 - 3.48 (m, 14H), 3.29 (s, 4H), 2.91 (s, 9H), 1.43 (s, 9H). ,9F NMR (376 MHz, CDC13) δ ppm -75.78. LCMS RT (Method 1) = 5.372 min, m/z 607.7 [M+H+].
Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2015/80949, 2015, A1 Location in patent: Paragraph 0304; 0305
  • 17
  • [ CAS Unavailable ]
  • [ 76-05-1 ]
  • [ 165963-71-3 ]
  • [ 1784701-22-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-(2-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)ethoxy)ethanol trifluoroacetate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Stage #2: 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide In N,N-dimethyl-formamide; mineral oil Stage #3: trifluoroacetic acid In dichloromethane at 0 - 20℃; 14-(4-(bis(4-Chlorophenyl)methyl)piperazin- 1 -yl)-3 ,6,9,12-tetraoxatetradecan- 1 - amine. A solution of 2-(2-(4-(bis(4-chlorophenyl)methyl)piperazin- 1 -yl)ethoxy)ethanol (250 mg, 0.518 mmol) in DMF (5.00 mL) was treated with a 60% dispersion in mineral oil of NaH (83.0 mg, 2.07 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and room temperature for 30 min. To this mixture was then added a solution of tert-butyl (2-(2- (2-bromoethoxy)ethoxy)ethyl)carbamate (162 mg, 0.518 mmol) in DMF (1.00 mL) and the resulting reaction mixture allowed to stir overnight. The mixture was quenched with H20 and extracted with CH2C12. The organic layers were separated, dried over MgS04, filtered and concentrated. The residue was taken up in CH2C12 (10.0 mL) and treated with trifluoroacetic acid (5.00 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and room temperature for 30 min. The reaction mixture was concentrated and purfied by preparative HPLC to afford the title compound as the TFA salt. 1H NMR (400 MHz, OMSO-d6) δ ppm 9.54 (s, 1 H), 7.77 (s, 3H), 7.47 - 7.37 (m, 7H), 4.58 (s, 1H), 3.72 (t, J = 4.9 Hz, 2H), 3.61 - 3.43 (m, 14H), 3.45 - 3.40 (m, 2H), 3.30 (d, J = 5.1 Hz, 2H), 3.13 (d, J = 10.5 Hz, 2H), 2.97 (h, J = 5.6 Hz, 2H), 2.80 (d, J = 12.8 Hz, 2H), 2.28 (t, J = 12.4 Hz, 2H). LCMS RT (Method 1) = 4.208 min, m/z 541.5 [M+H+].
Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2015/80949, 2015, A1 Location in patent: Paragraph 0326; 0327
  • 18
  • [ 2192-20-3 ]
  • [ 76-05-1 ]
  • [ 165963-71-3 ]
  • [ 1784701-31-0 ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: hydroxyzine dihydrochloride With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.666667h; Stage #2: 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide In N,N-dimethyl-formamide; mineral oil Stage #3: trifluoroacetic acid In water; acetonitrile
Reference： [1]He, Shanshan; Xiao, Jingbo; Dulcey, Andrés E.; Lin, Billy; Rolt, Adam; Hu, Zongyi; Hu, Xin; Wang, Amy Q.; Xu, Xin; Southall, Noel; Ferrer, Marc; Zheng, Wei; Liang, T. Jake; Marugan, Juan J. [Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 841 - 853]
  • 19
  • [ 103508-78-7 ]
  • [ 165963-71-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-(2-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)ethoxy)ethanol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.666667h; Stage #2: 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide In N,N-dimethyl-formamide; mineral oil
Reference： [1]He, Shanshan; Xiao, Jingbo; Dulcey, Andrés E.; Lin, Billy; Rolt, Adam; Hu, Zongyi; Hu, Xin; Wang, Amy Q.; Xu, Xin; Southall, Noel; Ferrer, Marc; Zheng, Wei; Liang, T. Jake; Marugan, Juan J. [Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 841 - 853]
  • 20
  • [ 107-19-7 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • [ 1333880-60-6 ]
YieldReaction ConditionsOperation in experiment
20% 10 mL of dry THF was added to a flask containing 2-propyn-1-ol (560 mg, 10 mmol) and NaH (480 mg, 20 mmol) and was stirred on ice for 20 min. After the addition of 6 (488 mg, 1.6 mmol) to the solution, it was stirred for an additional 2 h. An aqueous solution of NH4Cl was added to the reaction mixture to terminate the reaction, and the solution was then extracted with 60 mL of EtOAc. The organic layer was dried over Na2SO4. The resultant matter was purified by silica gel column chromatography (40 g, n-hexane-EtOAc 3/2) to yield 7 (90 mg, 0.31 mmol, 20%) as ayellow oil. 1H NMR (270 MHz, CDCl3): 5.00 (1H, br),4.18 (2H, d, J = 3.3 Hz), 3.70-3.66 (4H, m), 3.64-3.56 (4H, m), 3.50 (2H, t, J = 7.3 Hz), 3.28 (2H, t,J = 7.2 Hz), 2.40 (1H, t, J = 3.3 Hz), 1.41 (s, 9H); 13CNMR (67.8 MHz, CDCl3): 155.9, 79.5, 79.1, 74.5,70.4, 70.3, 70.19, 70.17, 69.0, 58.3, 40.3, 28.3; FD-MSm/z (rel.int.): 288 (100, [M + H]+), 287 (19.0, [M]+),69.0 (95.7), 57.0 (91.3); FD-HR-MS m/z: calcd. forC14H26NO5, 288.18110, found 288.18038.
Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439
  • 21
  • [ CAS Unavailable ]
  • [ 165963-71-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Stage #1: C49H97NO4 With ammonia Stage #2: 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide 1 Synthesis of a Ceramide Analogue (3) A ceramide analogue was prepared in accordance with the scheme depicted in FIGS. 1a-1d.
Reference： [1]Current Patent Assignee: HYBRID SYSTEMS; PSIOXUS THERAPEUTICS LIMITED - US2017/112923, 2017, A1 Location in patent: Paragraph 0140; 0141
  • 22
  • [ 1870822-00-6 ]
  • [ 165963-71-3 ]
  • [ 1870822-01-7 ]
YieldReaction ConditionsOperation in experiment
47% With tetra-(n-butyl)ammonium iodide; potassium carbonate In 1,4-dioxane at 60℃; for 24h; 12-1.2 Reference Example 12-1 2-{2-[2-(4-{3-[(4S)-6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl}-1H-pyrazol-1-yl)ethoxy]ethoxy}ethanamine (2) A solution of (4S)-6,8-dichloro-2-methyl-4-[3-(1H-pyrazol-4-yl)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.11 g) obtained in Example 1-4 mentioned later, tert-butyl {2-[2-(2-bromoethoxy)ethoxy]ethyl}carbamate (0.15 g), potassiumcarbonate (76 mg), and tetrabutylammonium iodide (11 mg) in 1,4-dioxane (1.1 mL) was stirred at 60°C for 1 day.The reaction solution was allowed to cool, and then, water was added thereto, followed by extraction with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage(registered trademark) SNAP Cartridge KP-NH, hexane:ethyl acetate = 100:0 → 70:30) to obtain tert-butyl(2-{2-[2-(4-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl}-1H-pyrazol-1-yl)ethoxy]ethoxy}ethyl)carbamate (85 mg, 47%) as a colorless oil substance. 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (s, 9H), 2.49 (s, 3H), 2.60 (dd, J=11.5, 8.7Hz, 1H), 3.02 (dd, J=11.5, 5.9Hz,1H), 3.24-3.77 (m, 9H), 3.81-3.92 (m, 3H), 4.20-4.27 (m, 1H), 4.33 (t, J=5.4Hz, 2H), 5.02 (br. s., 1H), 6.81-6.83 (m,1H), 6.99 (d, J=7.6Hz, 1H), 7.22-7.41 (m, 4H), 7.74 (s, 1H), 7.76 (s, 1H). MS (+) : 589 [M+H]+.
Reference： [1]Current Patent Assignee: TAISHO PHARMACEUTICAL HOLDINGS CO LTD - EP3173408, 2017, A1 Location in patent: Paragraph 0341
  • 23
  • [ 71759-89-2 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • tert-butyl (2-{2-[2-(4-iodo-1H-imidazol-1-yl)ethoxy]ethoxy}ethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; (1) To a solution of <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (0.24 g) in N,N-dimethylformamide (5.0 mL), potassium carbonate (0.34 g)and tert-butyl {2-[2-(2-bromoethoxy)ethoxy]ethyl}carbamate (0.42 g) obtained in Reference Example 12-1(1) were added, and the mixture was stirred at 100C for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then,the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography(Biotage(registered trademark) SNAP Cartridge HP-Sphere, hexane:ethyl acetate = 100:0 ? 0:100) toobtain tert-butyl (2-{2-[2-(4-iodo-1H-imidazol-1-yl)ethoxy]ethoxy}ethyl)carbamate (0.34 g, 65%). LC-MS Retention Time 1.005 min LC:Agilent 1290ESI/APCI MS:Agilent 6130 Column: Waters Acquity CSH C18 1.7um, 2.1x50mm Solvent: H2O:CH3CN(0.1% Formic acid) Gradient: 0.8mL/min, 0min(95:5) ? 1.2min(50:50)1.0mL/min, ? 1.38min(3:97) MS (+) : 426 [M+H]+.
Reference： [1]Patent: EP3173408,2017,A1 .Location in patent: Paragraph 0345
  • 24
  • [ 165963-71-3 ]
  • [ 2139329-51-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium iodide; potassium carbonate / acetone / Reflux 2: dichloromethane / 2 h / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 3 steps 1: potassium carbonate; potassium iodide / acetone / Reflux 2: dichloromethane / 2 h / 20 °C 3: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 3 steps 1: potassium iodide; potassium carbonate / acetonitrile / 16 h / 80 °C / Inert atmosphere 2: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 25 °C 3: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 2 h / 25 °C
Reference： [1]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2017/185031, 2017, A1
[2]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2020/23480, 2020, A1
[3]Ahmed, Adil; Anderson, Niall A.; Benowitz, Andrew B.; Cryan, Jenni; Dai, Han; McGonagle, Grant A.; Rozier, Christine [Bioorganic and medicinal chemistry letters, 2020]
  • 25
  • [ 571190-30-2 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • tert-butyl (2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate; potassium iodide; In acetonitrile; at 80℃; for 16h;Inert atmosphere; To a solution of <strong>[571190-30-2]6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one</strong> (550 mg, 1.229 mmol) in MeCN (15 mL) was added tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (384 mg, 1.229 mmol), potassium iodide (204 mg, 1.229 mmol) and potassium carbonate (340 mg, 2.458 mmol). The reaction mixture was stirred at 80 C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to 25 C, poured into ice-water (50 mL), the resulting precipitate was isolated by filtration, washed with water (3 x 10 mL), cooled MeOH (5 mL) and EtOAc (10 mL). Further drying in vacuo afforded the title compound (750 mg, 1.106 mmol, 90%) as a yellow solid. LC-MS: [M+H]+ = 679.40 1H NMR (400 MHz, CDCl3) delta = 8.83 (s, 1H), 8.27 (br s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.36 - 7.29 (m, 1H), 5.88 (t, J = 8.9 Hz, 1H), 5.12 (br s, 1H), 3.67 (t, J = 5.6 Hz, 2H), 3.65 - 3.62 (m, 4H), 3.58 - 3.53 (m, 2H), 3.33 (br d, J = 4.9 Hz, 2H), 3.25 - 3.20 (m, 4H), 2.75 - 2.67 (m, 5H), 2.55 (s, 3H), 2.41 - 2.32 (m, 5H), 2.12 - 2.01 (m, 2H), 1.93 - 1.84 (m, 2H), 1.77 - 1.60 (m, 3H), 1.45 (s, 9H).
85% With potassium carbonate; potassium iodide; In acetone;Reflux; To a solution of 6-ace -8-cyc]opentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2- yl)arnino)pyrido[2,3-i/]pyrirnidin-7(8H)-one (Paibociclib, 2-1) (20 mg, 0.045 mmol) in acetone (0.5 mL) was added tert-butyl 2-(2-(2-bromoethoxy)ethoxy)ethylcarbamate (2-6, 21 .2 mg, 0.068 mmol), followed by K2CO3 (12.3 mg, 0.09 mmol) and KI (1 1.3mg, 0,068 mmol) and the resulting mixture was then heated to reflux and stirred overnight. The reaction mixture was diluted with EtOAc and Eta2Omicron, extracted, and washed with brine. The organic layer was dried over anhydrous Na?,S04, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give Boc protected amine 2-7 as a yellow solid (26.0 mg, 85%). LCMS: m/z 679.4 [M+1]
85% With potassium carbonate; potassium iodide; In acetone;Reflux; To a solution of <strong>[571190-30-2]6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one</strong> (Palbociclib, 2-1) (20 mg, 0.045 mmol) in acetone (0.5 mL) was added tert- butyl 2-(2-(2-bromoethoxy)ethoxy)ethylcarbamate (2-6, 21.2 mg, 0.068 mmol), followed by K2CO3; (12,3 mg, 0.09 mmol) and KI (11 3 mg, 0.068 mmol) and the resulting mixture was then heated to reflux and stirred overnight. The reaction mixture was diluted with EtOAc and H2O, extracted, and washed with brine. The organic layer was dried over anhydrous NaiSCri, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% MeOH in DCM) to give Boc protected amine 2-7 as a yellow solid (26.0 mg, 85%). LCMS: m/z 679.4 [M+l].
Reference： [1]Bioorganic and medicinal chemistry letters,2020
[2]Patent: WO2017/185031,2017,A1 .Location in patent: Page/Page column 91
[3]Patent: WO2020/23480,2020,A1 .Location in patent: Page/Page column 90-91
  • 26
  • [ 2151815-47-1 ]
  • [ 76-05-1 ]
  • [ 165963-71-3 ]
  • [ 2151815-50-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2,6-diazaspiro[3.5]nonane-5,7-dione; 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; Stage #2: trifluoroacetic acid In dichloromethane at 20℃; 1 2-(2-(2-(5,7-Dioxo-2,6-diazaspiro[3.5]nonan-2-yl)ethoxy)ethoxy)ethan-1-aminium 2,2,2- trifluoroacetate 2,6-Diazaspiro[3.5]nonane-5,7-dione is dissolved in dry N,N-dimethylformamide. Powdered potassium carbonate (3 equiv.) is added followed by tert-butyl (2-(2-(2- bromoethoxy)ethoxy)ethyl)carbamate. The reaction mixture is heated to 40 °C and allowed to stir for 12 hours. The reaction mixture is then cooled to room temperature and partitioned between ethyl acetate and brine. The organic layer is washed again with brine, dried over sodium sulfate and then concentrated under reduced pressure (U.S. Pat. Appl. Publ., 20080269234). The crude material is then dissolved in dichloromethane and a 30% solution of trifluoroacetic acid in dichloromethane is added. The mixture is allowed to stir at room temperature until the reaction is judged complete by TLC or LCMS analysis. The mixture is then concentrated under reduced pressure to give the desired trifluoroacetate salt.
Reference： [1]Current Patent Assignee: C4 THERAPEUTICS INC - WO2017/197036, 2017, A1 Location in patent: Page/Page column 195
  • 27
  • [ 2151815-52-8 ]
  • [ 76-05-1 ]
  • [ 165963-71-3 ]
  • [ 2151815-55-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-(4-hydroxyphenyl)-2,6-diazaspiro[3.5]nonane-5,7-dione; 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; Stage #2: trifluoroacetic acid In dichloromethane at 20℃; 1 2-(2-(2-(4-(5,7-Dioxo-2,6-diazaspiro[3.5]nonan-2-yl)phenoxy)ethoxy)ethoxy)ethan-1- aminium 2,2,2-trifluoroacetate: 2-(4-Hydroxyphenyl)-2,6-diazaspiro[3.5]nonane-5,7-dione is dissolved in dry N,N- dimethylformamide. Powdered potassium carbonate (3 equiv.) is added followed by tert-butyl (2- (2-(2-bromoethoxy)ethoxy)ethyl)carbamate. The reaction mixture is heated to 40 °C and allowed to stir for 12 hours. The reaction mixture is then cooled to room temperature and partitioned between ethyl acetate and brine. The organic layer is washed again with brine, dried over sodium sulfate and then concentrated under reduced pressure (U.S. Pat. Appl. Publ., 20080269234). The crude material is then dissolved in dichloromethane and a 30% solution of trifluoroacetic acid in dichloromethane is added. The mixture is allowed to stir at room temperature until the reaction is judged complete by TLC or LCMS analysis. The mixture is then concentrated under reduced pressure to give the desired trifluoroacetate salt.
Reference： [1]Current Patent Assignee: C4 THERAPEUTICS INC - WO2017/197036, 2017, A1 Location in patent: Page/Page column 197; 198
  • 28
  • [ 36725-28-7 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • C22H34N4O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere; To 130 mg of A (0.64 mmol) dissolved in 0.4 mL of Dimethylformamide (DMF) was added 100 mg of tert-butyl 2-(2-(2-bromoethoxy)ethoxy)-ethylcarbamate (Toronto Research Chemical, 0.32 mmol) and 90 mg of K2CO3 (64 mmol) and the mixture was stirred at 60 C overnight. After cooling, water was added and rinsed several times with EtOAc. The combined EtOAc layers were dried, concentrated, and chromatographed with 50-70% EtOAc to yield 81 mg of product (58%). NMR (300 MHz, CDC13) delta 9.06 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 5.15 (s, 1H), 4.53 (s, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.65 (s, 4H), 3.55 (t, J = 5.2 Hz, 2H), 3.32 (m, 5H), 2.67 (dd, J = 16.8, 6.7 Hz, 1H), 2.42 (d, J = 16.4 Hz, 1H), 1.44 (s, 9H), 1.22 (d, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDC13) delta 166.83, 155.99, 154.45, 149.64, 127.33, 123.24, 1 12.58, 79.28, 70.30, 70.26, 70.22, 69.45, 43.14, 40.39, 33.96, 28.43, 27.89, 16.40; HPLC: Rt 2.50 min (7.5 min run), purity > 95%. MS: 435 (M + 1). This product (0.19 mmol) was dissolved in 1 mL MeOH and to the solution was added acetaldehyde (50 uL, 0.89 mmol ), 10 uL HOAc (0.2 mmol) and 12 mg NaBH3CN (0.19 mmol). After 1 hour, NaHC03(aq) and CH2C12 were added, the CH2C12 was separated and the water washed twice with CH2CI2. The combined CH2CI2 was dried, concentrated, and chromatography with 60-70% EtOAc in hexane yielded 71 mg of product as a clear oil (82%). NMR (400 MHz, CDC13) delta 8.91 (s, 1H), 7.63 (d, J = 8.9 Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 5.07 (s, 1H), 3.65 (t, J = 6.0 Hz, 2H), 3.61 (s, 4H), 3.55 (dt, J = 9.9, 5.5 Hz, 4H), 3.46 (q, J = 7.0 Hz, 2H), 3.38 - 3.22 (m, 3H), 2.67 (dd, J = 16.8, 6.7 Hz, 1H), 2.43 (d, J = 16.7 Hz, 1H), 1.45 (s, 10H), 1.23 (d, J = 7.3 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDC13) delta 166.84, 155.96, 154.46, 148.89, 127.35, 121.38, 111.28, 79.22, 70.68, 70.27, 70.24, 68.74, 49.95, 45.49, 40.32, 33.97, 28.43, 27.80, 16.43, 12.14. Rt 2.99 min (7.5 min run), purity > 95%. MS: 463 (M + 1).
Reference： [1]Patent: WO2017/134231,2017,A1 .Location in patent: Page/Page column 91
  • 29
  • [ 2227215-27-0 ]
  • [ 165963-71-3 ]
  • [ 2227215-28-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; Sealed tube; 2.1 Step 1. tert-butyl (2-(2-(4-(4-((6-(3-(4-(tert-butyl)benzamido)-2-methylphenyl)-4-methyl-3- oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazin- 1-yl)ethoxy)ethyl)carbamate (2j). 4-(tert-butyl)-N-(2-methyl-3 -(4-methyl-5-oxo-6-((4-(piperazine- 1 -carbonyl)phenyl)amino)-4, 5-dihydrcpyrazin-2-yl)phenyl)benzamide trifluoroacetic acid salt (2-1, 112 mg, 0.163 mmol, 1equiv.), tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (21, 111 mg, 0.3 56 mmcl, 2equiv.), and K2C03 (113 mg, 0.815 mmol, 5 equiv.) were dissolved in anhydrous DMIF (2 mL)and then stirred at 80 °C in a sealed vial for 8 h. The reaction mixture was cooled to roomtemperature and water (3 mL) was added. The resulting mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with H20 (2 x 3 mL) and brine (1 x 3 mL), dried with NaZSO4, filtered, and concentrated to afford 2j as an oil which was carried onto the next step without further purification.
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; Sealed tube; 2.1 Step 1. tert-butyl (2-(2-(4-(4-((6-(3-(4-(tert-butyl)benzamido)-2-methylphenyl)-4-methyl-3- oxo-3,4-dihydropyrazin-2-yl)amino)benzoyl)piperazin-1-yl)ethoxy)ethyl)carbamate (2j). 4-(tert-butyl)-N-(2-methyl-3-(4-methyl-5-oxo-6-((4-(piperazine-1-carbonyl)phenyl)amino)-4,5- dihydropyrazin-2-yl)phenyl)benzamide trifluoroacetic acid salt (2-1, 112 mg, 0.163 mmol, 1 equiv.), tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (2i, 111 mg, 0.356 mmol, 2 equiv.), and K2CO3 (113 mg, 0.815 mmol, 5 equiv.) were dissolved in anhydrous DMF (2 mL) and then stirred at 80 oC in a sealed vial for 8 h. The reaction mixture was cooled to room temperature and water (3 mL) was added. The resulting mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with H2O (2 x 3 mL) and brine (1 x 3 mL), dried with Na2SO4, filtered, and concentrated to afford 2j as an oil which was carried onto the next step without further purification.
Reference： [1]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2018/98275, 2018, A1 Location in patent: Page/Page column 128; 129
[2]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2018/98288, 2018, A1 Location in patent: Page/Page column 157
  • 30
  • [ 37418-88-5 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • C19H25NO8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In N,N-dimethyl-formamide at 90℃; for 16h; 20.AA (AA): Compound X (100 mg, 0.61mmol), compound Y (256 mg, 0.92 mmol), and Et3N (430 uL, 3.06 mmol) were stirred in DMF (2 mL) at 90 °C for 16 h. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with EtOAc (20 mL) and the combined filtrate and organics were concentrated under reduced pressure to 2 mL volume. Et3N (430 uL, 3.06 mmol) and compound Z (250 mg, 0.53 mmol) were added to the concentrated filtrates and the reaction mixture heated at 90 °C for 3 h. The reaction was concentrated under reduced pressure and purified by flash chromatography to afford the title compound (270 mg, 0.57 mmol, 93%). 1H NMR (500 MHz, DMSO-c/6) δ 11.10 (s, 1H), 7.82 (dd, J = 8.5, 7.2 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.46 (d, J= 7.2 Hz, 1H), 6.77 - 6.70 (m, 1H), 5.09 (dd, J= 12.8, 5.5 Hz, 1H), 4.37 - 4.33 (m, 2H), 3.84 - 3.79 (m, 2H), 3.64 (dd, J= 5.8, 3.8 Hz, 2H), 3.54 - 3.48 (m, 4H), 3.37 (d, J= 6.2 Hz, 2H), 3.06 (q, J = 5.8 Hz, 3H), 2.60 (ddd, J= 17.0, 4.4, 2.4 Hz, 1H), 2.03 (dtd, J= 13.0, 5.3, 2.2 Hz, 1H), 1.36 (s, 9H). MS (ESI) m/z 506 (M+H)+
Reference： [1]Current Patent Assignee: MASS GENERAL BRIGHAM INC - WO2019/14429, 2019, A1 Location in patent: Paragraph 00453
  • 31
  • [ 2117-12-6 ]
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • tert-butyl (2-(2-(2-(but-3-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.6 g Stage #1: 4-(trimethylsilyl)but-3-yn-1-ol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Stage #2: 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide In N,N-dimethyl-formamide; mineral oil at 29℃; for 12h; 2.1 Step 1: 4-(Trimethysilyl)but-3-yn-l-ol (2.28 g, 16 mmol) in DMF (50 mL) was added NaH (736 mg, 18.4 mmol, 60% purity) at 0 °C and stirred at 0 °C for 15 min. Then tert-butyl (2-(2-(2- bromoethoxy)ethoxy)ethyl)carbamate (5 g, 16 mmol) was added and the mixture was stirred at 29 °C for 12 h. TLC indicated complete conversion. The reaction mixture was diluted with H20 (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated brines (100 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=20/l to 2: 1) to yield Compound 3259, tert-butyl (2-(2-(2-(but-3- yn-l-yloxy)ethoxy)ethoxy)ethyl)carbamate (2.6 g, 8.6 mmol) as a colorless oil. 1H NMR (400 Mz, CDC13) δ 3.66-3.61 (10H, m), 3.55 (2H, t), 3.33-3.31(2H, m), 2.49 (2H, td), 1.44 (9H,s).
Reference： [1]Current Patent Assignee: SIGILON THERAPEUTICS INC - WO2018/67615, 2018, A1 Location in patent: Paragraph 00544
  • 32
  • [ 1018839-94-5 ]
  • [ 165963-71-3 ]
  • [ 2301865-87-0 ]
YieldReaction ConditionsOperation in experiment
43% With N-ethyl-N,N-diisopropylamine; potassium iodide In acetonitrile at 130℃; for 48h; Sealed tube; Tert-butyl [2-(2-{2-[(6-formyl-naphthalen-2-yl)-methyl-amino]-ethoxy}-ethoxy)- ethyl]-carbamate (5) Tert-butyl {2-[2-(2-bromo-ethoxy)-ethoxy]-ethyl}-carbamate (4) was synthesized according to literature methods. To a pressure vessel were added 3 (50 mg, 0.27 mmol), 4 (168.6 mg, 0.54 mmol), KI (90mg, 0.54 mmol), /V,/V-diisopropylethylamine (105 mg, 0.81 mmol), and acetonitrile (1 mL). The pressure vessel was sealed and allowed to react at 130 °C for 2 days. Upon cooling down the mixture was purified by column (0121) chromatography (S1O2, solvent gradient: CH2CI2 to 1 : 1 EtOAc/CH Cb) to give 5 as a yellow oil (48 mg, 43%). R/(silica gel, 1 : 1 EtO Ac/Hexane) = 0.22; NMR (500 MHz, CDCb): d 10.00 (s, 1H), 8.17 (s, 1H), 7.81 (d, J= 9 Hz, 2H), 7.64 (d, J= 9 Hz, 1H), 7.19 (d, J= 9 Hz, 1H), 6.89 (s, 1H), 4.94 (s, 1H), 3.71 (s, 4H), 3.55-3.63 (m, 4H), 3.51 (t, J= 5 Hz, 2H), 3.30 (br q, j= 5 Hz, 2H), 3.15 (s, 3 H).
Reference： [1]Current Patent Assignee: UNIVERSITY OF CONNECTICUT - WO2019/140270, 2019, A1 Location in patent: Paragraph 0081
  • 33
  • [ 2227215-27-0 ]
  • [ 165963-71-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; Sealed tube; 2.1 Step 1. er-butyl (2-(2-(4-(4-((6-(3-(4-(tert-butyl)benzamido)-2-methylphenyl)-4-methyl-3- oxo-3, 4-dihydropyrazin-2-yi)ami8io)besizoyl)piperazin-l-yl)ethoxy)ethyl)carbamate (2j). 4-(tert-butyl)-N-(2-methyl-3-(4-methyl-5-oxo-6-((4-(piperazine-l- carbonyl)phenyl)amino)-4,5-dihydropyrazin-2-yl)phenyl)benzamide trifluoroacetic acid salt (2- 1, 112 mg, 0.163 mmol, 1 equiv.), tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (2i, 1 1 1 mg, 0.356 mmol, 2 equiv.), and K2CO3 (113 mg, 0.815 mmol, 5 equiv.) were dissolved in anhydrous DMF (2 mL) and then stirred at 80 °C in a sealed vial for 8 h. The reaction mixture was cooled to room temperature and water (3 mL) was added. The resulting mixture was extracted with EtOAc (4 x 10 mL). The combined organic layers were washed with H2O (2 x 3 inL) and brine (T x 3 mL), dried with NaiSOr, filtered, and concentrated to afford 2j as an oil which was carried onto the next step without further purification.
Reference： [1]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2019/148150, 2019, A1 Location in patent: Page/Page column 188; 189
  • 34
  • [ 3077-61-0 ]
  • [ 165963-71-3 ]
  • [ 2409486-57-1 ]
YieldReaction ConditionsOperation in experiment
63% With potassium carbonate In N,N-dimethyl-formamide at 20℃; 13 Example 13 : Synthesis of 3-(3-(((4-(2-(2-(2-(2-((A)-4-(4-chlorophenvn-2.3.9- trimethyl- 1diazepin-6-yl )acetamido)ethoxy)ethoxy)ethoxy)-Af-methylphenyl )sulfonamido)methyl )-4-methylphenyl )-3- (7-m ethoxy- 1 -methyl - 2.31triazol-5-yl jpropanoic acid (8) To a solution of tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate in DMF (3 mL) was added K2CO3 (146 mg, 1.06 mmol) and 4-hydroxy-N-methylbenzenesulfonamide (100 mg, 0.53 mmol). The reaction mixture was stirred overnight at room temperature and then quenched with water. The mixture was extracted with ethyl acetate (3 x 10 mL), washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by silica gel chromatography yielded tert-butyl (2-(2-(2-(4-(N- methylsulfamoyl)phenoxy)ethoxy)ethoxy)ethyl)carbamate (139 mg, 0.33 mmol, 63% yield). LC/MS m/z calculated for [M+Na]+441.2, found 441.4.
Reference： [1]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2020/18788, 2020, A1 Location in patent: Paragraph 00214; 00215; 00216
  • 35
  • 2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
  • [ 345627-80-7 ]
  • tert-butyl (2-(2-(2-(4-((5-(((5-(tert-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl)carbamoyl)piperidin-1-yl)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With potassium carbonate; In N,N-dimethyl acetamide; at 20℃; To a solution of A-(5-(((5-(/er/-butyl)oxazol-2-yl)methyl)thio)thiazol-2-yl) piperidine-4-carboxamide (100 mg, 026 mmol) in DMF (6 mL) at RT was added /er/-butyl (2-(2- (2-bromoethoxy)ethoxy)ethyl)carbamate (81.8 mg, 0.26 mmol) and K2CO3 (71.8 mg, 0.52 mmol). The mixture was stirred at RT overnight then the mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated. The residue was purified using silica gel eluting with MeOH/DCM (0% to 10%) to give /er/-butyl (2-(2-(2-(4-((5- (((5-(/c/7-butyl(oxazol-2-yl (methyl (thio(thiazol-2-yl (carbamoyl (pi peri din- 1 - yl)ethoxy)ethoxy)ethyl)carbamate (121 mg, 75% yield) as a solid. MS (ESI) m/z 612.1 [M+H]+.
Reference： [1]Patent: WO2020/23782,2020,A1 .Location in patent: Paragraph 0186
  • 36
  • [ 5054-59-1 ]
  • [ 165963-71-3 ]
  • [ 2267291-32-5 ]
YieldReaction ConditionsOperation in experiment
With potassium hydrogencarbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 12h; Inert atmosphere;
Reference： [1]Hanafi, Maha; Chen, Xinde; Neamati, Nouri [Journal of Medicinal Chemistry, 2021, vol. 64, # 3, p. 1626 - 1648]
  • 37
  • [ 2629182-44-9 ]
  • [ 165963-71-3 ]
  • [ 2629182-38-1 ]
YieldReaction ConditionsOperation in experiment
500 mg With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 16h; 4 Example 4. (S)-3-(1-((4-(((2-(2-(2-(2-(1-acryloylazetidin-3-yl)-6-(3-hydroxynaphthalen- 1 -yl)-4-oxoquinazolin-3 (4H)-yl)ethoxy)ethoxy)ethyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5 (6H)-yl)piperidine-2,6-dione 14 To a solution of 2-(1-acryloylazetidin-3-yl)-6-bromoquinazolin-4(3H)-one (300 mg, 0.9 mmol) in DMF (10 mL) were added tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (420 mg, 1.35 mmol) and cesium carbonate (590 mg, 1.8 mmol). After 16 h at 60 °C, the mixture was diluted with H2O (10 mL) and extracted with DCM/MeOH (10:1). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using silica gel eluting with EtOAc to give tert-butyl (2-(2-(2-(2-(1-acryloylazetidin-3-yl)-6-bromo-4-oxoquinazolin-3(4H)-yl)ethoxy)ethoxy)ethyl)carbamate (500 mg). MS (ESI) m/z: 565.2 [M+H]
Reference： [1]Current Patent Assignee: BIOTHERYX INC - WO2021/51034, 2021, A1 Location in patent: Paragraph 0220
  • 38
  • [ 165963-71-3 ]
  • [ 404951-55-9 ]
  • [ 2642232-19-5 ]
YieldReaction ConditionsOperation in experiment
93% With potassium carbonate; sodium iodide In acetonitrile at 60℃; for 18h; 2 Methyl (E)-3-(4-(2-(2-(1H-indol-3-yl)ethyl)-14,14-dimethyl-12-oxo-5,8,13-trioxa-2,11- diazapentadecyl)phenyl)acrylate (int-2) To a solution of int-1 (1 eq, 150 mg) and 13 (1.2 eq, 168 mg) in acetonitrile (4.5 mL, 0.1 M) was added K2CO3 (2 eq, 124 mg) and NaI (0.1 eq, 6.7 mg) in one portion. The reaction mixture was heated to 60°C and stirred for 18 h. When the starting material was consumed, the mixture was filtered through a pad of Celite and concentrated in vacuo. The resulting residue was purified using ISCO (dichloromethane/methanol, 0%-10%) to yield int-2 (237mg, 93%). UPLC-MS RT: 1.22 min (Method A), Mass m/z: (565.89, M+1).
Reference： [1]Current Patent Assignee: DANA-FARBER CANCER INSTITUTE - WO2021/92153, 2021, A1 Location in patent: Paragraph 00120; 00123; 00124
  • 39
  • [ 2378582-97-7 ]
  • [ 165963-71-3 ]
  • [ 2408026-74-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 1h; General methods for preparing some special intermediates LIN-ULM: General procedure: A 25 mL reaction flask was charged with the compound SIAIS151014 (0.69 mmol, 1 equiv), and then anhydrousN,N-dimethylformamide (6 mL) and anhydrous potassium carbonate (1.38 mmol, 2 equiv), followed by slow addition ofthe brominated substrate (0.83mmol, 1.2 equiv) under stirring at room temperature. After completion of dropping, thereaction mixture was stirred at room temperature for 1 h. After the raw materials were completely consumed, the reactionmixture was quenched by adding water, extracted with ethyl acetate, and concentrated. The crude product was separatedon a reversed-phase C18 column (eluent (v/v): acetonitrile/water = 10% -100%), the solvent was evaporated underreduced pressure, and the residue was lyophilized to obtain the intermediate compound. The intermediate compoundobtained was added to a 10 mL reaction flask, followed by adding anhydrous dichloromethane (4 mL) and trifluoroaceticacid (1 mL). The mixture was stirred at room temperature for 2 h. The reaction solvent was evaporated under reducedpressure, and the residue was treated by addition of water, and lyophilized to obtain the target compound (SIAIS213066).
Reference： [1]Current Patent Assignee: SHANGHAITECH UNIVERSITY - EP3778590, 2021, A1 Location in patent: Paragraph 0357-0358
  • 40
  • [ 2407829-65-4 ]
  • [ 165963-71-3 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 50℃;
Reference： [1]Bardeesy, Nabeel; Che, Jianwei; Donovan, Katherine A.; Du, Guangyan; Fischer, Eric S.; Gray, Nathanael S.; Henning, Nathaniel J.; Jiang, Jie; Lu, Wenchao; Wu, Qibiao; Yue, Hong; Zhang, Tinghu [Angewandte Chemie - International Edition, 2021, vol. 60, # 29, p. 15905 - 15911][Angew. Chem., 2021, vol. 133, # 29, p. 16041 - 16047]
  • 41
  • [ 202590-98-5 ]
  • [ 165963-71-3 ]
  • [ 2688070-50-8 ]
YieldReaction ConditionsOperation in experiment
81.05% With potassium carbonate In acetonitrile at 70℃; for 17h; 1D.3 Step 1: Synthesis of tert-butyl (S)-(26-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4] diazepin-6-yl)acetamido)phenoxy)-3,6,9,12,15,18,21,24- octaoxahexacosyl)carbamate General procedure: To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide (150.00 mg, 0.31 mmol, 1.00 equiv) in MeCN (4.00 mL) was added tert-butyl N-(26-bromo-3, 6, 9, 12, 15,18,21,24-octaoxahexacosan-l-yl) carbamate (175.77 mg, 0.31 mmol, 1.00 equiv) and K2CO3 (84.27 mg, 0.61 mmol, 2.00 equiv). Then the reaction mixture was stirred at 60 degrees C for 17 h. The solid was filtrated out and the filtration was concentrated. The residue was purified by silica gel column chromatography, eluted with DCM: MeOH = 10: 1. Tert-butyl (S)-(26-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetamido)phenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosyl)carbamate ( 350.00 mg, quantitative yield) as white solid. LCMS: mass calcd. For C48H67CIN6O12S: 986.42, found: 1009.60 [M+Na]+.
Reference： [1]Current Patent Assignee: DESIGN THERAPEUTICS - WO2021/158707, 2021, A1 Location in patent: Paragraph 00844; 00848; 00849; 00850; 001271; 001277; 001278
  • 42
  • [ 165963-71-3 ]
  • [ 2730031-82-8 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In 1,4-dioxane for 24h; Inert atmosphere; 4.1 Step 1. Boc-amino-PEG2-bromide 11 (32 mg, 0.103 mmol) was dissolved in 1,4-dioxane (1.0 mL), purged with Ar, then treated with 4 M HCI in 1,4-dioxane (0.26 mL, 1.029 mmol). After 1 d, the reaction was concentrated in vacuo , then dried on high vacuum for 3 h to afford crude compound 12 as a light-yellow oil.
Reference： [1]Current Patent Assignee: REGENERON PHARMACEUTICALS INC - WO2021/211984, 2021, A1 Location in patent: Paragraph 0507
  • 43
  • [ 14064-83-6 ]
  • [ 165963-71-3 ]
  • [ 2756467-57-7 ]
YieldReaction ConditionsOperation in experiment
48% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 3h; 8 A mixture of (E)-4-(4-nitrostyryl)phenol (1.0 g, 4.17 mmol), tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (1.3 g, 4.17 mmol) and K2CO3(1.15 g, 8.34 mmol) in DMF (100 mL) was stirred at 120°C for 3 hours. The mixture was diluted with water and extracted with EtOAc (100 mL x2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified through a silica gel column (eluted with EtO Ac/PE = 2/3) to give Int-11 as a white solid (950 mg, 48%).
48% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 3h; 8 A mixture of (E)-4-(4-nitrostyryl)phenol (1.0 g, 4.17 mmol), tert-butyl (2-(2-(2-bromoethoxy)ethoxy)ethyl)carbamate (1.3 g, 4.17 mmol) and K2CO3(1.15 g, 8.34 mmol) in DMF (100 mL) was stirred at 120°C for 3 hours. The mixture was diluted with water and extracted with EtOAc (100 mL x2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified through a silica gel column (eluted with EtO Ac/PE = 2/3) to give Int-11 as a white solid (950 mg, 48%).
Reference： [1]Current Patent Assignee: MASS GENERAL BRIGHAM INC; DANA-FARBER CANCER INSTITUTE - WO2021/257650, 2021, A1 Location in patent: Paragraph 00151; 00153
[2]Current Patent Assignee: MASS GENERAL BRIGHAM INC; DANA-FARBER CANCER INSTITUTE - WO2021/257650, 2021, A1 Location in patent: Paragraph 00151; 00153
  • 44
  • [ 2780378-08-5 ]
  • [ 165963-71-3 ]
  • [ 2780380-28-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 6h; 1.2 Step 2: tert-Butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate To a solution of 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (250 mg, 527.52 μmol, 86.6% purity, 1 eq) in DMF (3 mL) was added K2CO3 (145.81 mg, 1.06 mmol, 2 eq) and tert-butyl N-[2-[2-(2- bromoethoxy)ethoxy]ethyl]carbamate (280 mg, 654.71 μmol, 73% purity, 1.24 eq). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.15) to yield tert-butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (290 mg, 361.54 μmol, 68.5% yield, 80.0% purity) as a yellow gum.1H NMR (500 MHz, CDCl3) δ ppm 9.31 (t, J = 5.7 Hz, 1H), 7.95-7.87 (m, 1H), 7.58 (d, J = 6.4 Hz, 3H), 7.47 (d, J = 10.7 Hz, 2H), 6.52 (d, J = 8.9 Hz, 1H), 5.08 (s, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 4.11- 4.07 (m, 1H), 3.79 (t, J = 5.0 Hz, 2H), 3.60 (s, 4H), 3.56-3.52 (m, 2H), 3.32 (d, J = 4.6 Hz, 2H), 2.60 (d, J = 5.3 Hz, 3H), 1.39 (s, 9H); ES-LCMS m/z 642.2 [M+H]+.
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 6h; 2A.2 Step 2: tert-Butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate To a solution of 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (250 mg, 527.52 µmol, 86.6% purity, 1 eq) in DMF (3 mL) was added K2CO3 (145.81 mg, 1.06 mmol, 2 eq) and tert-butyl N-[2-[2-(2- bromoethoxy)ethoxy]ethyl]carbamate (280 mg, 654.71 µmol, 73% purity, 1.24 eq). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.15) to yield tert-butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (290 mg, 361.54 µmol, 68.5% yield, 80.0% purity) as a yellow gum.1H NMR (500 MHz, CDCl3) δ ppm 9.31 (t, J = 5.7 Hz, 1H), 7.95-7.87 (m, 1H), 7.58 (d, J = 6.4 Hz, 3H), 7.47 (d, J = 10.7 Hz, 2H), 6.52 (d, J = 8.9 Hz, 1H), 5.08 (s, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 4.11- 4.07 (m, 1H), 3.79 (t, J = 5.0 Hz, 2H), 3.60 (s, 4H), 3.56-3.52 (m, 2H), 3.32 (d, J = 4.6 Hz, 2H), 2.60 (d, J = 5.3 Hz, 3H), 1.39 (s, 9H); ES-LCMS m/z 642.2 [M+H]+.
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 6h; 1.2 Step 2: tert-Butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate To a solution of 3-(1H-imidazol-4-yl)-N-methyl-4-[[4- (trifluoromethyl)phenyl]methylamino]benzenesulfonamide (250 mg, 527.52 μmol, 86.6% purity, 1 eq) in DMF (3 mL) was added K2CO3 (145.81 mg, 1.06 mmol, 2 eq) and tert-butyl N-[2-[2-(2- bromoethoxy)ethoxy]ethyl]carbamate (280 mg, 654.71 μmol, 73% purity, 1.24 eq). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.15) to yield tert-butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (290 mg, 361.54 μmol, 68.5% yield, 80.0% purity) as a yellow gum.1H NMR (500 MHz, CDCl3) δ ppm 9.31 (t, J = 5.7 Hz, 1H), 7.95-7.87 (m, 1H), 7.58 (d, J = 6.4 Hz, 3H), 7.47 (d, J = 10.7 Hz, 2H), 6.52 (d, J = 8.9 Hz, 1H), 5.08 (s, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 4.11- 4.07 (m, 1H), 3.79 (t, J = 5.0 Hz, 2H), 3.60 (s, 4H), 3.56-3.52 (m, 2H), 3.32 (d, J = 4.6 Hz, 2H), 2.60 (d, J = 5.3 Hz, 3H), 1.39 (s, 9H); ES-LCMS m/z 642.2 [M+H]+.
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 6h; 3.2 Step 2: tert-Butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate To a solution of 3-(lH-imidazol-4-yl)-N-methyl-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (250 mg, 527.52 pmol, 86.6% purity, 1 eq) in DMF (3 mL) was added K2CO3 (145.81 mg, 1.06 mmol, 2 eq) and tert-butyl N-[2-[2-(2-bromoethoxy)ethoxy]ethyl]carbamate (280 mg, 654.71 pmol, 73% purity, 1.24 eq). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.15) to yield tert-butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (290 mg, 361.54 pmol, 68.5% yield, 80.0% purity) as a yellow gum. 1H NMR (500 MHz, CDCL) 3 ppm 9.31 (t, J = 5.7 Hz, 1H), 7.95-7.87 (m, 1H), 7.58 (d, J = 6.4 Hz, 3H), 7.47 (d, J= 10.7 Hz, 2H), 6.52 (d, J= 8.9 Hz, 1H), 5.08 (s, 1H), 4.59 (d, J= 5.8 Hz, 2H), 4.17 (t, J= 4.9 Hz, 2H), 4.11-4.07 (m, 1H), 3.79 (t, J = 5.0 Hz, 2H), 3.60 (s, 4H), 3.56-3.52 (m, 2H), 3.32 (d, J= 4.6 Hz, 2H), 2.60 (d, J= 5.3 Hz, 3H), 1.39 (s, 9H); ES-LCMS m/z 642.2 [M+H]+.
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 6h; 3.2 Step 2: tert-Butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate To a solution of 3-(lH-imidazol-4-yl)-N-methyl-4-[[4-(trifluoromethyl)phenyl]methylamino]benzenesulfonamide (250 mg, 527.52 pmol, 86.6% purity, 1 eq) in DMF (3 mL) was added K2CO3 (145.81 mg, 1.06 mmol, 2 eq) and tert-butyl N-[2-[2-(2-bromoethoxy)ethoxy]ethyl]carbamate (280 mg, 654.71 pmol, 73% purity, 1.24 eq). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.15) to yield tert-butyl N-[2-[2-[2-[4-[5-(methylsulfamoyl)-2-[[4- (trifluoromethyl)phenyl]methylamino]phenyl]imidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (290 mg, 361.54 pmol, 68.5% yield, 80.0% purity) as a yellow gum. 1H NMR (500 MHz, CDCL) 3 ppm 9.31 (t, J = 5.7 Hz, 1H), 7.95-7.87 (m, 1H), 7.58 (d, J = 6.4 Hz, 3H), 7.47 (d, J= 10.7 Hz, 2H), 6.52 (d, J= 8.9 Hz, 1H), 5.08 (s, 1H), 4.59 (d, J= 5.8 Hz, 2H), 4.17 (t, J= 4.9 Hz, 2H), 4.11-4.07 (m, 1H), 3.79 (t, J = 5.0 Hz, 2H), 3.60 (s, 4H), 3.56-3.52 (m, 2H), 3.32 (d, J= 4.6 Hz, 2H), 2.60 (d, J= 5.3 Hz, 3H), 1.39 (s, 9H); ES-LCMS m/z 642.2 [M+H]+.

Reference： [1]Current Patent Assignee: IKENA ONCOLOGY INC - WO2022/120353, 2022, A1 Location in patent: Paragraph 00534-00535
[2]Current Patent Assignee: IKENA ONCOLOGY INC - WO2022/120355, 2022, A1 Location in patent: Paragraph 00938; 001064-001065
[3]Current Patent Assignee: IKENA ONCOLOGY INC - WO2022/120353, 2022, A1 Location in patent: Paragraph 00534-00535
[4]Current Patent Assignee: IKENA ONCOLOGY INC - WO2022/159986, 2022, A1 Location in patent: Paragraph 00727
[5]Current Patent Assignee: IKENA ONCOLOGY INC - WO2022/159986, 2022, A1 Location in patent: Paragraph 00727
  • 45
  • [ CAS Unavailable ]
  • [ 165963-71-3 ]
  • [ 2787474-03-5 ]
YieldReaction ConditionsOperation in experiment
88.57% With potassium carbonate In acetonitrile at 70℃; 39.1 Step 1: Synthesis of tert-butyl N-[2-(2-{2-[benzyl(methyl)amino]ethoxy}ethoxy) ethyl]carbamate (INT102-388-1) To a solution of tert-butyl N-{2-[2-(2-bromoethoxy)ethoxy]ethyl}carbamate (1.00 g, 3.203 mmol, 1.00 equiv) in ACN (10.00 mL) was added K2CO3 (1.33 g, 9.609 mmol, 3.00 equiv) and N-methylbenzylamine (0.78 g, 6.406 mmol, 2.00 equiv) . Then the reaction was stirred at 70 degrees C overnight. The suspension was filtered and the filtrate was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (15:01) to afford tert-butyl N-[2-(2-{2-[benzyl(methyl)amino] ethoxy}ethoxy)ethyl]carbamate (1.00 g, 88.57%) as a light yellow oil. LC/MS: mass calcd. For C19H32N2O4: 352.24 found: 353.15 [M+H]+.
88.57% With potassium carbonate In acetonitrile at 70℃; 39.1 Step 1: Synthesis of tert-butyl N-[2-(2-{2-[benzyl(methyl)amino]ethoxy}ethoxy) ethyl]carbamate (INT102-388-1) To a solution of tert-butyl N-{2-[2-(2-bromoethoxy)ethoxy]ethyl}carbamate (1.00 g, 3.203 mmol, 1.00 equiv) in ACN (10.00 mL) was added K2CO3 (1.33 g, 9.609 mmol, 3.00 equiv) and N-methylbenzylamine (0.78 g, 6.406 mmol, 2.00 equiv) . Then the reaction was stirred at 70 degrees C overnight. The suspension was filtered and the filtrate was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (15:01) to afford tert-butyl N-[2-(2-{2-[benzyl(methyl)amino] ethoxy}ethoxy)ethyl]carbamate (1.00 g, 88.57%) as a light yellow oil. LC/MS: mass calcd. For C19H32N2O4: 352.24 found: 353.15 [M+H]+.
Reference： [1]Current Patent Assignee: DESIGN THERAPEUTICS - WO2022/126000, 2022, A1 Location in patent: Paragraph 001030-001033
[2]Current Patent Assignee: DESIGN THERAPEUTICS - WO2022/126000, 2022, A1 Location in patent: Paragraph 001030-001033
  • 46
  • [ 2797974-57-1 ]
  • [ 165963-71-3 ]
  • [ 2797974-66-2 ]
YieldReaction ConditionsOperation in experiment
With tripotassium phosphate tribasic; potassium iodide In N,N-dimethyl acetamide at 100℃; for 16h; 1 Step 1: Preparation of Compound C1-2 Compound A1-6 (160 mg, 0.38 mmol), C1-1 (180 mg, 0.58 mmol), potassium phosphate (246 mg, 1.16 mmol) and potassium iodide (128 mg, 0.77 mmol) were dissolved in N,N-dimethylacetamide ( 6 mL), the system was heated to 100 °C and stirred for 16 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was purified by reverse-phase silica gel column chromatography (mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 5%-95%, flow rate: 45 mL/min) to obtain Compound C1-2.
Reference： [1]Current Patent Assignee: JIANGXI JEMINCARE GROUP CO LTD; SHANGHAI JIYU PHARMACEUTICAL TECH - CN114716458, 2022, A Location in patent: Paragraph 0242-0246
  • 47
  • [ CAS Unavailable ]
  • [ 165963-71-3 ]
  • [ 2790409-44-6 ]
YieldReaction ConditionsOperation in experiment
With Cs2CO3; sodium iodide In N,N-dimethyl-formamide at 60℃; for 1h; A1.11 Step 11: Preparation of Compound A1-15 Compound A1-13 (246 mg, 0.642 mmol), A1-14 (290 mg, 0.942 mmol), cesium carbonate (416 mg, 1.280 mmol),Sodium iodide (10 mg, 0.071 mmol) was dissolved in N,N-dimethylformamide (4 mL),The system was heated to 60 °C and stirred for 1 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was purified by C18 reverse phase silica gel column chromatography (acetonitrile/0.1% aqueous ammonium bicarbonate solution (v/v)=5-65%) to obtain compound A1-15.
Reference： [1]Current Patent Assignee: JIANGXI JEMINCARE GROUP CO LTD; SHANGHAI JEMINCARE PHARMACEUTICAL; SHANGHAI JIYU PHARMACEUTICAL TECH - WO2022/127917, 2022, A1 Location in patent: Page/Page column 23-24; 26
  • 48
  • [ 2790409-49-1 ]
  • [ 165963-71-3 ]
  • [ 2790409-50-4 ]
YieldReaction ConditionsOperation in experiment
With 18-crown-6 ether; Cs2CO3 In acetonitrile at 90℃; for 10h; B1.6 Step 6: Preparation of Compound B1-7 Compound B1-6 (250 mg, 0.72 mmol), compound A1-14 (335 mg, 1.08 mmol), cesium carbonate (585 mg, 1.8 mmol), 18-crown-6 (19 mg, 0.072 mmol) were added to acetonitrile (25 ml) , the system was heated to 90 reaction 10h. The reaction solution was concentrated, water (30 mL) was added, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by C18 reverse phase silica gel column chromatography (acetonitrile/water (5% aqueous ammonium bicarbonate solution) (v/v) = 30-40%) to give compound B1-7.
Reference： [1]Current Patent Assignee: JIANGXI JEMINCARE GROUP CO LTD; SHANGHAI JEMINCARE PHARMACEUTICAL; SHANGHAI JIYU PHARMACEUTICAL TECH - WO2022/127917, 2022, A1 Location in patent: Page/Page column 27; 29
  • 49
  • [ 2790411-04-8 ]
  • [ 165963-71-3 ]
  • [ 2790409-55-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: C19H18Cl2N2O With sodium iodide In tetrahydrofuran at 25℃; for 0.5h; Inert atmosphere; Stage #2: tert-butyl N-[2-[2-(2-bromoethoxy)ethoxy]ethyl]carbamate With 18-crown-6 ether In tetrahydrofuran at 25℃; for 16h; Inert atmosphere; B3.1 Step 1: Preparation of Compound B3-7 Compound B3-6 (144 mg, 0.398 mmol) was dissolved in tetrahydrofuran (2 mL),Sodium hydride (29.6 mg, 0.74 mmol) was added under argon protection.The system was stirred at room temperature (25°C) for 0.5h.18-crown ether-6 (101.6 mg, 0.39 mmol) and compound A1-14 (186 mg, 0.589 mmol) were dissolved in tetrahydrofuran (2 mL), slowly added to the reaction solution under argon protection, and the addition was completed, the system was kept at room temperature (25°C) and stirred for 16h. The reaction solution was purified by C18 reverse phase silica gel column chromatography (acetonitrile/0.1% aqueous ammonium bicarbonate solution (v/v)=5-65%) to obtain compound B3-7.
Reference： [1]Current Patent Assignee: JIANGXI JEMINCARE GROUP CO LTD; SHANGHAI JEMINCARE PHARMACEUTICAL; SHANGHAI JIYU PHARMACEUTICAL TECH - WO2022/127917, 2022, A1 Location in patent: Page/Page column 30
  • 50
  • [ 2839318-20-4 ]
  • [ 165963-71-3 ]
  • [ 2839318-18-0 ]
YieldReaction ConditionsOperation in experiment
17% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 120℃; for 16h; Sealed tube;
Reference： [1]Divakaran, Anand; Scholtz, Cole R.; Zahid, Huda; Lin, Wenwei; Griffith, Elizabeth C.; Lee, Richard E.; Chen, Taosheng; Harki, Daniel A.; Pomerantz, William C. K. [ACS Medicinal Chemistry Letters, 2022, vol. 13, # 10, p. 1621 - 1627]
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