* 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.
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2 h; Cooling with ice
Weighing NaH (60percent purity, 1.0g, 25 . 1mmol) is slowly added in the ice water bath in DMF (10 ml) of 50 ml round bottom bottle in, subsequently adding methyl iodide (1.3g, 11 . 04mmol) and compound phenothiazine (2g, 10.0mmol), transfer to room temperature stirring 2h, TLC monitoring after the reaction, water, for extracting DCM (50 ml x 3), magnesium sulfate drying and then concentrated dry, separate the product by silica gel column 1a (2.1g), white solid, melting point: 96 °C, yield 97percent.
97%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2 h; Cooling with ice
NaH (60percent purity, 1.0 g, 25.1 mmol) was weighed,In a 50 ml round-bottom flask containing DMF (10 ml) was slowly added in an ice-water bath,Followed by the addition of methyl iodide(1.3 g, 11.04 mmol)And the compound phenothiazine(2 g, 10.0 mmol),Transfer to room temperature for 2 h,TLC monitoring After the reaction was completed,add water,Extraction with DCM (50 mL x 3)Dried over magnesium sulfate and concentrated to dryness,The compound 1 (R is H) was isolated on a silica gel column,10-methyl-10H-phenothiazine(2.1 g),White solid,Melting point: 96 ° C, yield 97percent
96%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 4 h;
General procedure: To a solution of the phenothiazine (10 mmol, 1 equiv) in DMFwere added CH3I (20 mmol, 2 eq) and NaH (15 mmol,1.5 equiv). Themixturewas stirred at RT for 4 h. The solvent was evaporated undervacuum and the mixture was diluted with DCM and washed withNaHCO3. The organic phase was dried (MgSO4) and filtered. Thesolvent was evaporated and the crude residue was purified by silicagel column chromatography eluted with a mixture of petroleumether and ethyl acetate.10-methyl-10H-phenothiazine (1a): 2.05 g (96percent). 1H NMR(400 MHz, Acetone) δ 7.21 (td, J = 8.0, 1.5 Hz, 2H), 7.21 (dd, J 8.0,1.5 Hz, 2H), 7.14-6.93 (m, 4H), 3.39 (s, 3H).
93.9%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2 h; Cooling with ice
Weigh NaH (60percent purity, 0.5g, 12.55mmol) and slowly add DMF (10mL) in an ice water bath.In a 50 mL round bottom flask, iodomethane (0.65 g, 5.52 mmol) and the compound phenothiazine (1 g, 5.0 mmol) were added, and the mixture was transferred to room temperature and stirred for 2 h. After the reaction was completed by TLC, water was added.Extracted with DCM (50 mL x 3), dried over magnesium sulfate and evaporated.The product was isolated (1 g, 1.0 g), white solid yield 93.9percent.
87%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 0.5 h; Cooling with ice Stage #2: for 2 h;
Phenothiazine was dissolved in anhydrous THF, and 0.4 g of NaH was gradually added in an ice-water bath. The reaction was stirred at room temperature for 30 minutes. Then, methyl iodide solution was added to the reaction solution and stirred for 2 hours. After the reaction was completed, the reaction solution was quenched by the addition of deionized water and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a white solid product was obtained after purification by chromatography column in 87percent yield.
Reference：
[1] Molecular Crystals and Liquid Crystals, 2010, vol. 520, p. 36 - 43
[2] Patent: CN106045986, 2016, A, . Location in patent: Paragraph 0039; 0040; 0041
[3] Patent: CN106045987, 2016, A, . Location in patent: Paragraph 0039; 0040; 0041
[4] Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 1053 - 1056
[5] ACS Chemical Neuroscience, 2017, vol. 8, # 4, p. 798 - 806
[6] Dyes and Pigments, 2017, vol. 147, p. 130 - 140
[7] Chemistry of Heterocyclic Compounds, 1996, vol. 32, # 3, p. 365 - 370
[8] Patent: CN108191789, 2018, A, . Location in patent: Paragraph 0054; 0087; 0088
[9] Heterocyclic Communications, 2001, vol. 7, # 3, p. 277 - 282
[10] Journal of Materials Chemistry, 2012, vol. 22, # 9, p. 4040 - 4049
[11] Patent: CN107793377, 2018, A, . Location in patent: Paragraph 0062; 0063
[12] Angewandte Chemie - International Edition, 2017, vol. 56, # 48, p. 15299 - 15303[13] Angew. Chem., 2017, vol. 129, p. 15501 - 15505,5
[14] Chemical Communications, 2018, vol. 54, # 92, p. 13022 - 13025
[15] Synthesis, 1998, # 8, p. 1107 - 1109
[16] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 6, p. 1147 - 1150
[17] Journal of Physical Chemistry, 1986, vol. 90, # 11, p. 2469 - 2475
[18] Journal of Organic Chemistry, 1954, vol. 19, p. 1841,1842
[19] Journal of Organic Chemistry, 1972, vol. 37, p. 1045 - 1047
[20] J. Gen. Chem. USSR (Engl. Transl.), 1960, vol. 30, p. 1673 - 1676[21] Zhurnal Obshchei Khimii, 1960, vol. 30, p. 1680 - 1683
[22] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 63 - 71
[23] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1981, p. 852 - 859
[24] Journal of Physical Chemistry, 1995, vol. 99, # 17, p. 6530 - 6539
[25] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 17, p. 5139 - 5144
[26] Dalton Transactions, 2014, vol. 44, # 2, p. 615 - 629
[27] Dyes and Pigments, 2017, vol. 143, p. 368 - 378
[28] Dyes and Pigments, 2017, vol. 145, p. 542 - 549
[29] New Journal of Chemistry, 2018, vol. 42, # 4, p. 2520 - 2525
[30] New Journal of Chemistry, 2018, vol. 42, # 12, p. 9987 - 9999
[31] Indian Journal of Heterocyclic Chemistry, 2018, vol. 28, # 3, p. 367 - 372
2
[ 110-88-3 ]
[ 92-84-2 ]
[ 1207-72-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylsilane; trifluoroacetic acid In dichloromethane at 20℃; for 24 h; Inert atmosphere
General procedure: The N-containing substrate (1 mmol) and trioxane (270 mg, 3 mmol) were dissolved in CH2Cl2 (1.5 mL) under N2 atmosphere. To this solution were added TFA (0.75 mL) and Et3SiH (1.45 mL, 10 mmol). The reaction was monitored by TLC (eluent: see below). After 24 or 48 h (in case of incomplete conversion, after 24 h), aq 2 N NaOH (20 mL) solution was carefully added and the mixture was extracted with CH2Cl2 (3*20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and the residue was purified by flash column chromatography (FCC).
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 5422,5425
[2] Journal of the Chemical Society, 1951, p. 1834
[3] Canadian Journal of Chemistry, 1967, vol. 45, p. 745 - 749
[4] Bulletin de la Societe Chimique de France, 1960, p. 1049 - 1066
[5] Berichte der Bunsengesellschaft/Physical Chemistry Chemical Physics, 1984, vol. 88, # 10, p. 963 - 969
5
[ 74-83-9 ]
[ 92-84-2 ]
[ 1207-72-3 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 1, p. 63 - 71
[2] Dyes and Pigments, 2017, vol. 147, p. 537 - 543
6
[ 7647-01-0 ]
[ 92-84-2 ]
[ 1207-72-3 ]
Reference：
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 1886
7
[ 92-84-2 ]
[ 1207-72-3 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1947, vol. 225, p. 578
8
[ 92-84-2 ]
[ 75-36-5 ]
[ 1628-29-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 50℃; for 1 h;
19.1) 10-acetyl-10H-phenothiazine: 20 g (0.1 mol) of phenothiazine followed by 14.3 ml (2 eq.) of acetyl chloride are added to a 500 ml flask containing 200 ml of toluene. The heterogeneous reaction mixture is stirred for 1 hour at 50° C. After concentration to dryness, the precipitate is taken up in a minimum of isopentane and filtered. After drying, 24 g of a beige solid is obtained with a quantitative yield. Melting point: 210-211° C.
96%
Stage #1: With zinc(II) chloride In dichloromethane at 0℃; for 0.333333 h; Stage #2: at 0 - 20℃; for 24 h;
A mixture of zinc chloride (0.75g, 5.50mmol), acetyl chloride (0.8mL, 5.62mmol) in dichloromethane (25mL) at 0°C was stirred for 20min. Phenothiazine 16 (1.00g, 5.02mmol) was added to the solution and stirred at rt for 24h before reaction mixture was diluted with ice-cold H2O and extracted with dichloromethane (3×20 mL). The organic layers were dried with Na2SO4, filtered off and concentrated under reduced pressure. The product 17 was obtained as a green solid in 96percent (1.146g) yield; mp: 191–195°C (dichloromethane); IR (ATR diamond, cm-1) ν: 1668, 1459, 1315, 1257; 1H NMR (400MHz, CDCl3) δ: 2.20 (s, 3H, CH3), 7.22 (t, J=6Hz, 2H, H-7, H-3), 7.32 (t, J=6Hz, 2H, H-2, H-8), 7.43 (d, J=6Hz, 2H, H-4, H-6), 7.50 (d, J=6Hz, 2H, H-1, H-9); 13C NMR (100MHz, CDCl3) δ: 23.4 (CH3), 127.1 (2CH), 127.3 (2CH), 127.5 (2CH), 128.3 (2CH), 133.4 (2Cq), 139.3 (2Cq), 169.6 (Cq). HRMS (ESI): calcd for C14H12NOS [M+H]+: 242.0640 found 242.0638.
94.5%
for 0.166667 h; Microwave irradiation
General procedure: To a solution of 10H-phenothiazine (2.62 mmol) in dry toluene (5 mL) was added drop by drop the corresponding acyl chloride (0.5 mL; 6.2 mmol). The reaction was irradiate with MW (500 Watts) during 10 min, then was washed with NaOH 5percent (2 .x. 5 mL) and the organic phase was dry with anhydrous Na2SO4. Finally the solvent was remove in vacuo.
93%
for 1 h; Reflux
To 1 mmole of 10-H PTZ was added an equivalent quantity of glacial acetic acid. 10-H PTZ is stirred in solvent for 1 hr to get clear solution. To the resultant solution, 10 mL of acetyl chloride was added. During the addition of acetyl chloride, the internal temperature was maintained at 5°C. The resulting mixture was refluxed for 1 h. The mixture was kept for overnight; the formation of white crystals was taken place. Filter the residue and recrystallized from hot ethanol.[10] Yield: 93percent; m.p.: 172 °C; IR (KBr, υmax/cm−1): 2899.19 (CH3, str), 1363.51 (C-N of PTZ ring, str), 1655(C=O, str). 1H NMR (DMSO-d6, 500 MHz, δ/ppm): 8.20–8.18 (d, 2H, J= 5Hz, Ar-H), 7.42–7.40 (d, 2H, J = 5Hz, Ar-H), 7.21–7.19 (d, 2H, J = 5Hz, Ar-H), 6.50-6.48 (d, 2H, J = 5Hz, Ar-H), 3.189 (s, 3H, CH3).
Reference：
[1] Patent: US2005/222045, 2005, A1, . Location in patent: Page/Page column 13
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4113 - 4126
[3] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 101 - 105
[4] Indian Journal of Heterocyclic Chemistry, 2018, vol. 28, # 2, p. 221 - 226
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 1, p. 157 - 161
[6] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 1, p. 211 - 222
[7] Journal of the American Chemical Society, 1953, vol. 75, p. 5422,5425
[8] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1953, vol. 236, p. 1569
[9] Bulletin de la Societe Chimique de France, 1960, p. 1049 - 1066
[10] Journal of Medicinal Chemistry, 1998, vol. 41, # 2, p. 148 - 156
[11] Chemistry Letters, 2018, vol. 47, # 7, p. 825 - 828
9
[ 92-84-2 ]
[ 108-24-7 ]
[ 1628-29-1 ]
Reference：
[1] Canadian Journal of Chemistry, 2010, vol. 88, # 1, p. 42 - 49
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2568 - 2581
[3] Chemische Berichte, 1978, vol. 111, p. 1453 - 1463
[4] Journal of Pharmaceutical Sciences, 1976, vol. 65, # 11, p. 1699 - 1701
[5] Patent: WO2007/20932, 2007, A1, . Location in patent: Page/Page column 10
[6] Patent: US9198916, 2015, B1, . Location in patent: Page/Page column 12
10
[ 92-84-2 ]
[ 75-36-5 ]
[ 1628-29-1 ]
[ 6632-11-7 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 2673,2677
11
[ 92-84-2 ]
[ 591-50-4 ]
[ 7152-42-3 ]
Yield
Reaction Conditions
Operation in experiment
87.3%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate In toluene at 160℃; for 16 h; Inert atmosphere; Sealed tube
To a solution of phenothiazine (500 mg, 2.50 mmol) in dry toluene (5 mL) under nitrogen was added iodobenzene (310 mg, 2.2 mmol) sodium tert-butoxide (0.5 mL) and Pd2(dba)3 (46 mg, 0.05). The reaction mixture was stirred at 160 °C for 16 h in sealtube and was cooled to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 15 mL). The combined organic extracts were dried with Na2SO4 and rotary evaporated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20: 1) to afford 6d (600 mg, 87.3percent) as a white soild, m.p. 87-88 °C. 1H-NMR (300 MHz, Acetone-d6): δ 7.70 (t, J = 7.5, 2H), 7.57 (t, J = 7. 2, 1H), 7.44 (d, J = 7.8, 2H), 7.06 (d, J = 7.5, 2H), 6.92 (t, J = 7.2, 2H), 6.89 (t, J = 7.2, 2H), 6.23 (d, J = 8.1, 2H). 13C NMR (100 MHz, Acetone-d6): δ 144.98, 141.82, 131.64, 131.37, 129.07, 127.31, 123.37, 120.90, 116.96. ESI-HRMS m/z calcd. for C18H14NS ([M+H]+) 276.0841, found 276.0842.
78%
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 110℃;
Phenothiazine (10 g, 1 eq) and sodium tert-butoxide (14.5 g, 3 eq) were added to a three-necked flask, 100 ml adding iodobenzene of toluene was added,(20.5 g, 2 eq), tris (dibenzylideneacetone) dipalladium (1.15 g, 2 & lt; RTI ID = 0.0 & gt;0.02 eq), tri-tert-butylphosphine (1.62 g, 0.04 eq), ventilated three times, and refluxed overnight at 110 ° C. The TLC test reaction ends with an antiAfter cooling with methylene chloride (100ml), saturated NaCl washing after anhydrous magnesium sulfate drying and drying the organic phase. After the use of oilEther (100 ml) was washed twice to give 10.8 g of pale yellow 10-phenyl-10H-phenothiazine in a yield of 78percent.
37%
With 2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanol; copper(II) acetate monohydrate; sodium t-butanolate In N,N-dimethyl-formamide at 120℃; for 1 h;
General procedure: A mixture of N-unsubstituted compound 2 (1.0 mmol), aryl halide 1 (1.2 mmol), and t-BuONa (1.2 mmol) was stirred in DMF (0.3 mL) inthe presence of Cu(OAc)2·H2O (1 molpercent) and 2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanol (1 molpercent) at 120 °C for the time given inTable 2. The mixture was washed with EtOAc; after removal of thesolvent, the residue was purified by column chromatography (silicagel, petroleum ether–EtOAc).
Reference：
[1] Chinese Chemical Letters, 2015, vol. 26, # 8, p. 951 - 954
[2] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 1, p. 107 - 111
[3] Patent: CN104478870, 2016, B, . Location in patent: Paragraph 0052; 0053; 0054
[4] Journal of Materials Chemistry A, 2017, vol. 5, # 16, p. 7586 - 7594
[5] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[6] Synthesis (Germany), 2015, vol. 47, # 8, p. 1131 - 1146
[7] Journal of the American Chemical Society, 1944, vol. 66, p. 1214
[8] Journal of the American Chemical Society, 2004, vol. 126, # 5, p. 1388 - 1401
12
[ 108-86-1 ]
[ 92-84-2 ]
[ 7152-42-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In tolueneReflux; Inert atmosphere
Phenothiazine dissolved 50g (250.9mmol) and bromobenzene, 47.3g (301.1mmol), sodium t- butoxide 36.2g (376.4mmol) and tri -tert- butylphosphine 1.52g (7.53mmol) in toluene 500ml and, after inserting the Pd (dba) 2 1.44g (2.51mmol) and the mixture was stirred under reflux for 6 hours under a nitrogen atmosphere. After the reaction the organic layer was then extracted with ethyl ahseteyiteugwa dry distilled over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The product n- hexane / dichloromethane (7: 3 by volume) as a column of silica gel chromatography to obtain the objective compound of the intermediate M-2 61.7 g as a white solid (yield 89percent) .
89%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene for 6 h; Reflux; Inert atmosphere
50 g (250.9 mmol) of phenothiazine, 47.3 g (301.1 mmol) of bromobenzene, 36.2 g (376.4 mmol) of sodium t-butoxide, and 1.52 g (7.53 mmol) of tri-tert-butylphosphine were dissolved in 500 ml of toluene, 1.44 g (2.51 mmol) of Pd(dba)2 was added thereto, and the mixture was agitated for 6 hours under a nitrogen atmosphere while being refluxed. When the reaction was complete, the resultant was extracted with ethyl acetate and distilled water, an organic layer obtained therefrom was dried with magnesium sulfate and filtered, and the filtered solution was concentrated under a reduced pressure. The concentrated product was purified with n-hexane/dichloromethane (7:3 of a volume ratio) through silica gel column chromatography, obtaining 61.7 g of a white solid compound, an intermediate M-2 (89percent of a yield).
Reference：
[1] ChemCatChem, 2018, vol. 10, # 14, p. 2955 - 2961
[2] Patent: KR101531614, 2015, B1, . Location in patent: Paragraph 0792-0795
[3] Patent: KR101486562, 2015, B1, . Location in patent: Paragraph 0799-0803
[4] Chemical Communications, 2012, vol. 48, # 58, p. 7271 - 7273
[5] Physical Chemistry Chemical Physics, 2000, vol. 2, # 19, p. 4275 - 4280
[6] RSC Advances, 2017, vol. 7, # 88, p. 56144 - 56152
13
[ 92-84-2 ]
[ 108-90-7 ]
[ 7152-42-3 ]
Reference：
[1] Chemical Communications, 2015, vol. 51, # 58, p. 11705 - 11708
[2] Journal of the American Chemical Society, 2014, vol. 136, # 45, p. 16096 - 16101
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 41, p. 13433 - 13438[4] Angew. Chem., 2018, vol. 57, # 130, p. 13621 - 13626,6
[5] Journal of the American Chemical Society, 2018, vol. 140, # 1, p. 163 - 166
[6] Journal of the American Chemical Society, 2016, vol. 138, # 7, p. 2411 - 2425
14
[ 92-84-2 ]
[ 66003-78-9 ]
[ 7152-42-3 ]
Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 52, p. 13744 - 13748
15
[ 92-84-2 ]
[ 591-50-4 ]
[ 12775-96-1 ]
[ 7152-42-3 ]
Reference：
[1] Patent: US2005/95519, 2005, A1,
16
[ 92-84-2 ]
[ 637-88-7 ]
[ 7152-42-3 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1986, vol. 59, # 3, p. 803 - 808
With N-Bromosuccinimide In tetrahydrofuran at 0℃; for 16 h; Inert atmosphere
In a nitrogen-flushed 250 mL round-bottom flask with a magnetic stir bar and septum 10Hphenothiazine (7.97 g, 40.0 mmol) was dissolved in dry THF (60 mL) under nitrogen. The dark solution was deaerated by a constant stream of nitrogen through a syringe for 10 min and cooled to 0 °C (ice bath/water). N-Bromosuccinimide (7.12 g, 40.0 mmol) was slowly added to the reaction mixture under nitrogen, then stirred for 16 h and allowed to come to room tempetature. To this solution was added a saturated aqueous solution of sodium sulfite (150 mL) and the aqueous layer was extracted several times with dichloromethane. The combined organic layers were dried with anhydrous magnesium sulfate and filtered. Thesolvents were removed in vacuo and the residue was adsorbed onto celite®and purified by chromatography on silica gel (n-hexane/ethyl acetate 20:1) to give 4.95 g (45percent) of 3-bromo-10H-phenothiazine as a colorless solid, Rf (n-hexane/acetone 4:1) = 0.33. The 1H NMRspectrum was in agreement with the literature.1H NMR (CDCl3, 300 MHz): 5.89 (s, br, 1 H), 6.52 (m, 1 H), 6.61 (m, 1 H), 6.83-7.15 (m, 5 H).
Reference：
[1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2055 - 2064
[2] Journal of Materials Chemistry, 2010, vol. 20, # 39, p. 8653 - 8658
[3] Journal of Materials Chemistry C, 2014, vol. 2, # 20, p. 3942 - 3950
20
[ 92-84-2 ]
[ 3939-23-9 ]
[ 21667-32-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 10, p. 2036 - 2039
21
[ 92-84-2 ]
[ 32315-10-9 ]
[ 18956-87-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 749 - 766
22
[ 92-84-2 ]
[ 6631-94-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 2, p. 148 - 156
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 2673,2677
[3] Patent: CN105367514, 2016, A,
23
[ 92-84-2 ]
[ 75-36-5 ]
[ 6631-94-3 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1969, p. 2342 - 2355
24
[ 92-84-2 ]
[ 23503-68-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4113 - 4126
25
[ 92-84-2 ]
[ 1785-64-4 ]
Reference：
[1] Journal of Fluorine Chemistry, 1986, vol. 30, p. 399
With tri-tert-butyl phosphine; potassium-t-butoxide; palladium diacetate In toluene for 24h; Inert atmosphere; Reflux;
2.S1
S1. Under nitrogen protection, take 1.99g (10mmol) phenothiazine, 2.04g (10mmol) iodobenzene, 1.68g (15mmol) potassium tert-butoxide (t-BuOK), 0.11g (0.5mmol) palladium acetate ( Pd(OAc)2) and 0.25mL (0.25mmol) of tri-tert-butylphosphine (P(t-Bu)3) were dissolved in 90mL of toluene solution and heated to reflux for 24 hours. Cool to room temperature, heat and evaporate to remove the solvent, extract with dichloromethane three times, and add anhydrous magnesium sulfate to the organic phase for drying. The crude product is obtained by filtration, and then purified by column chromatography to obtain the product of formula (I), the mass of the obtained product is 2.6 g, and the yield is 94.5%. The specific preparation reaction formula is:
87.3%
With tris-(dibenzylideneacetone)dipalladium(0); sodium tertiary butoxide In toluene at 160℃; for 16h; Inert atmosphere; Sealed tube;
10-phenyl-10H-phenothiazine 6e
To a solution of phenothiazine (500 mg, 2.50 mmol) in dry toluene (5 mL) under nitrogen was added iodobenzene (310 mg, 2.2 mmol) sodium tert-butoxide (0.5 mL) and Pd2(dba)3 (46 mg, 0.05). The reaction mixture was stirred at 160 °C for 16 h in sealtube and was cooled to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 15 mL). The combined organic extracts were dried with Na2SO4 and rotary evaporated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20: 1) to afford 6d (600 mg, 87.3%) as a white soild, m.p. 87-88 °C. 1H-NMR (300 MHz, Acetone-d6): δ 7.70 (t, J = 7.5, 2H), 7.57 (t, J = 7. 2, 1H), 7.44 (d, J = 7.8, 2H), 7.06 (d, J = 7.5, 2H), 6.92 (t, J = 7.2, 2H), 6.89 (t, J = 7.2, 2H), 6.23 (d, J = 8.1, 2H). 13C NMR (100 MHz, Acetone-d6): δ 144.98, 141.82, 131.64, 131.37, 129.07, 127.31, 123.37, 120.90, 116.96. ESI-HRMS m/z calcd. for C18H14NS ([M+H]+) 276.0841, found 276.0842.
80%
With copper atom; anhydrous sodium carbonate In tetrahydrofuran at 190℃; for 8h; Inert atmosphere; Schlenk technique;
3.2.4 Synthesis of 10-phenyl-10H-phenothiazine
A mixture of phenothiaizine (2mmol), iodobenzene (3mmol) and anhydrous sodium carbonate (20mmol) was refluxed with a pinch of copper turnings at 190°C for 8h. Excess of iodobenzene was removed by evaporation. Then hot ethanol solution was added to the reaction mixture, filtered and solvent was removed under reduce pressure. Crude product was purified by column chromatography on silica gel (60-120 mesh size) using (Petroleum ether/Ethyl acetate=99.5:0.5) as the solvent to afford the target compound as an off-white solid (80%). 1H NMR (400MHz, CDCl3): δ 7.60 (t, J=7.6Hz, 2H), 7.47 (t, J=7.4Hz, 1H), 7.39 (d, J=7.2Hz, 2H), 7.01 (dd, J=1.6 & 7.2Hz, 2H), 6.85-6.78 (m, 4H), 6.20 (d, J=8.0Hz, 2H); 13C NMR (100MHz, CDCl3): δ 144.3, 141.0, 130.9, 130.8, 128.2, 126.9, 126.7, 122.5, 120.2, 116.1.
78%
With copper atom; potassium carbonate In N,N-dimethyl-formamide Reflux;
78%
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium tertiary butoxide In toluene at 110℃;
Preparation of 3,7-dibromo-10-phenyl-10H-phenothiazine:
Phenothiazine (10 g, 1 eq) and sodium tert-butoxide (14.5 g, 3 eq) were added to a three-necked flask, 100 ml adding iodobenzene of toluene was added,(20.5 g, 2 eq), tris (dibenzylideneacetone) dipalladium (1.15 g, 2 & lt; RTI ID = 0.0 & gt;0.02 eq), tri-tert-butylphosphine (1.62 g, 0.04 eq), ventilated three times, and refluxed overnight at 110 ° C. The TLC test reaction ends with an antiAfter cooling with methylene chloride (100ml), saturated NaCl washing after anhydrous magnesium sulfate drying and drying the organic phase. After the use of oilEther (100 ml) was washed twice to give 10.8 g of pale yellow 10-phenyl-10H-phenothiazine in a yield of 78%.
76%
With tri-tert-butyl phosphine; Palladium(0) bis(dibenzylideneacetone); sodium tertiary butoxide In toluene at 120℃; for 20h; Inert atmosphere; Schlenk technique;
72%
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); tri-tert-butyl phosphine; potassium carbonate In toluene at 110℃; for 24h; Schlenk technique; Inert atmosphere;
69%
With Cu(HOC6H3(O)CHNCH2CH2NCHC6H3(O)OH); sodium hydroxide at 120℃; for 8h;
60%
With 18-crown-6 ether; copper atom; potassium carbonate In N,N-dimethyl-formamide at 180℃; for 12h; Inert atmosphere;
1.a a) Synthesis of compound 10-phenyl-10H-phenothiazine (1)
Add phenothiazine (6g, 30mmol), copper powder (1.9g, 30mmol), potassium carbonate (8.3g, 60mmol) into a 100ml two-necked flask ) And 18-crown ether-6 (3g, 60mmol), nitrogen-purge-nitrogen cycle 3 times (10 minutes each time), then add 3.93ml of iodobenzene and 60ml of ultra-dry N,N-dimethylformamide After the reaction was heated to 180°C for 12 hours, the reaction was completed, extracted with dichloromethane/water, dried with anhydrous magnesium sulfate for 2 hours, and separated and purified by column analysis to obtain colorless crystals (4.2g) with a yield of 60%.
37%
With 2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethan-1-ol; Cu(OAc)2*H2O; sodium tertiary butoxide In N,N-dimethyl-formamide at 120℃; for 1h;
N-Substituted Compounds 3; General Procedure
General procedure: A mixture of N-unsubstituted compound 2 (1.0 mmol), aryl halide 1 (1.2 mmol), and t-BuONa (1.2 mmol) was stirred in DMF (0.3 mL) inthe presence of Cu(OAc)2·H2O (1 mol%) and 2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanol (1 mol%) at 120 °C for the time given inTable 2. The mixture was washed with EtOAc; after removal of thesolvent, the residue was purified by column chromatography (silicagel, petroleum ether-EtOAc).
With copper atom; potassium carbonate at 220℃;
With tri-tert-butyl phosphine; potassium-t-butoxide; palladium diacetate In toluene at 110 - 120℃; for 20h; Inert atmosphere;
3 Example 3: Synthesis of Compound CS-H
Under a nitrogen atmosphere, in the reaction flask, phenothiazine (1.99 g, 10 mmol),Iodobenzene (2.45 g, 12 mol), potassium t-butoxide (1.68 g, 15 mmol)And palladium acetate (0.11 g, 0.5 mmol), tri-tert-butylphosphine (0.5 mL, 0.25 mmol)Soluble in a sufficient amount of toluene solution, stirred at 110-120 ° C for 20 h,After the reaction was completed, the reaction solution was cooled to room temperature and then extracted with chloroform.The organic phase was collected, dried over anhydrous Na 2SO 4 and dried to afford crude.The petroleum ether was used as the eluent, and the crude product was separated and purified by silica gel column chromatography.The obtained product was again used in dichloromethane (90 mL).A mixture of acetic acid (45 mL) and hydrogen peroxide (2 mL) was dissolved and reacted at 70 ° C for 18 h.The reaction solution was extracted with chloroform and the organic phase was collected.It was dried over anhydrous Na 2 SO 4 and dried to give a crude product.A mixture of petroleum ether and dichloromethane (v/v, 1/1) is used as a rinse agent.The crude product is separated and purified by silica gel column chromatography.Obtained as a white solid (2.61 g, 85%).The structure was characterized by 1H NMR, 13C NMR and MS.This white solid was confirmed to be the compound CS-H.
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); tri-tert-butyl phosphine; potassium carbonate In toluene at 110℃; for 24h; Schlenk technique; Inert atmosphere;
With tris-(dibenzylideneacetone)dipalladium(0); potassium-t-butoxide; tri-tert-butylphosphonium hydrogen tetrafluoroborate In toluene for 20h; Reflux;
19.1) 10-acetyl-10H-phenothiazine: 20 g (0.1 mol) of phenothiazine followed by 14.3 ml (2 eq.) of acetyl chloride are added to a 500 ml flask containing 200 ml of toluene. The heterogeneous reaction mixture is stirred for 1 hour at 50 C. After concentration to dryness, the precipitate is taken up in a minimum of isopentane and filtered. After drying, 24 g of a beige solid is obtained with a quantitative yield. Melting point: 210-211 C.
96%
A mixture of zinc chloride (0.75g, 5.50mmol), acetyl chloride (0.8mL, 5.62mmol) in dichloromethane (25mL) at 0C was stirred for 20min. Phenothiazine 16 (1.00g, 5.02mmol) was added to the solution and stirred at rt for 24h before reaction mixture was diluted with ice-cold H2O and extracted with dichloromethane (3×20 mL). The organic layers were dried with Na2SO4, filtered off and concentrated under reduced pressure. The product 17 was obtained as a green solid in 96% (1.146g) yield; mp: 191-195C (dichloromethane); IR (ATR diamond, cm-1) nu: 1668, 1459, 1315, 1257; 1H NMR (400MHz, CDCl3) delta: 2.20 (s, 3H, CH3), 7.22 (t, J=6Hz, 2H, H-7, H-3), 7.32 (t, J=6Hz, 2H, H-2, H-8), 7.43 (d, J=6Hz, 2H, H-4, H-6), 7.50 (d, J=6Hz, 2H, H-1, H-9); 13C NMR (100MHz, CDCl3) delta: 23.4 (CH3), 127.1 (2CH), 127.3 (2CH), 127.5 (2CH), 128.3 (2CH), 133.4 (2Cq), 139.3 (2Cq), 169.6 (Cq). HRMS (ESI): calcd for C14H12NOS [M+H]+: 242.0640 found 242.0638.
94.5%
In toluene; for 0.166667h;Microwave irradiation;
General procedure: To a solution of 10H-phenothiazine (2.62 mmol) in dry toluene (5 mL) was added drop by drop the corresponding acyl chloride (0.5 mL; 6.2 mmol). The reaction was irradiate with MW (500 Watts) during 10 min, then was washed with NaOH 5% (2 × 5 mL) and the organic phase was dry with anhydrous Na2SO4. Finally the solvent was remove in vacuo.
93%
In acetic acid; for 1h;Reflux;
To 1 mmole of 10-H PTZ was added an equivalent quantity of glacial acetic acid. 10-H PTZ is stirred in solvent for 1 hr to get clear solution. To the resultant solution, 10 mL of acetyl chloride was added. During the addition of acetyl chloride, the internal temperature was maintained at 5C. The resulting mixture was refluxed for 1 h. The mixture was kept for overnight; the formation of white crystals was taken place. Filter the residue and recrystallized from hot ethanol.[10] Yield: 93%; m.p.: 172 C; IR (KBr, upsilonmax/cm-1): 2899.19 (CH3, str), 1363.51 (C-N of PTZ ring, str), 1655(C=O, str). 1H NMR (DMSO-d6, 500 MHz, delta/ppm): 8.20-8.18 (d, 2H, J= 5Hz, Ar-H), 7.42-7.40 (d, 2H, J = 5Hz, Ar-H), 7.21-7.19 (d, 2H, J = 5Hz, Ar-H), 6.50-6.48 (d, 2H, J = 5Hz, Ar-H), 3.189 (s, 3H, CH3).
In toluene; at 50℃; for 2h;Inert atmosphere;
General procedure: To a mixture of 2-(2-bromophenylthio)-3-methoxyaniline (5a) (31.0 mg, 0.100 mmol) and sodium t-butoxide(13.5 mg, 0.140 mmol, 1.4 equiv) dissolved in toluene (1.0 mL) were added RuPhos Pd G1 (3.9 mg, 5.0 mumol,5.0 mol %) and RuPhos (2.3 mg, 5.0 mumol, 5.0 mol %) at room temperature. After stirring for 24 h at 110 C, themixture was cooled to room temperature, and to this was added acetyl chloride (70.0 muL, 1.00 mmol, 10 equiv) atroom temperature. After stirring for 2 h at 50 C, the mixture was cooled to room temperature, and to this wasadded an aqueous saturated solution of sodium hydrogen carbonate (5 mL). The mixture was extracted with EtOAc(10 mL 3), and the combined organic extract was washed with brine (5 mL), dried (Na2SO4), and after filtration,the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (nhexane/EtOAc = 2/1) to give 10-acetyl-4-methoxyphenothiazine (7a) (19.0 mg, 70.0 mumol, 70.0%) as a paleyellow solid.
With C28H12Br4N12OV(4+)*4CBr3(1-); dihydrogen peroxide In water; acetonitrile at 20℃; for 12h; chemoselective reaction;
2.3. Oxidation of benzyl phenyl sulfide to benzyl phenyl sulfoxide
General procedure: A mixture of methyl phenyl sulfide (0.124 g, 1 mmol), [VO(TPPABr)]CBr3 (10 mg), and H2O2 (30 % aqueous, 6 mmol, 0.204 g,0.183 mL) in CH3CN (3 mL) was stirred for 120 min at room temperature.At the end of reaction, the catalyst was filtered and thesolvent was evaporated to afford the crude sulfoxide product.Finally, the product was purified by column chromatography usingethyl acetate/hexane (1.5:8.5) as eluent to give methyl phenyl sulfoxide as a white solid in 93% yield.
69%
With dihydrogen peroxide In acetonitrile at 60℃; for 0.333333h;
With ethanol; dihydrogen peroxide
With 3-chloro-benzenecarboperoxoic acid In acetone
With dihydrogen peroxide; oxalic acid In methanol; water at 20℃;
8%Chromat.
With oxygen; C32H38CdN8O12; ascorbic acid In 2,2,2-trifluoroethanol; water at 20℃; for 24h; Darkness;
[Practical Example 2]; The product was obtained by the same method as in Practical Example 1, except that 5 mg of a 10-acetylphenothiazine of below-given formula (5) were used instead' of the styrenated phenothiazine of formula (4). The obtained product was not gelled and maintained flowability even 20 hours after the above-described treatment.[Formula 5] EPO <DP n="11"/>[0030] The 10-acetylphenothiazine of formula (5) was synthesized by the following method. A 200-ml four-neck flask was loaded with 19.93 g (0.1 mole) of phenothiazine, 15.31 g (0.15 mole) of acetic anhydride, and 40 g of xylene, and the contents were subjected to heating under reflux conditions for 6 hours. The reaction liquid was cooled, the precipitate was separated by filtering, and the product washed with methanol. As a result, 22.6 g of 10-acetylphenothiazine having a molecular weight of 241.3 were obtained.
Heating;
The hydrochloride of 2-(methylsulfanyl)-1O-[2-(piperi-din-2-yl)ethyl]-1OH-phenothiazine was prepared in accordance with Synthetic Scheme 1. This compound had a pale blue color, a molecular weight of 365.55 g/mol, the positive ion mass [M+H] has an mlz of 357.15 and a purity of 98%.
N-[(2,4-diaminopteridin-6-yl)methyl]phenothiazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
EXAMPLE 5; Preparation of N-[(2,4-Diaminopteridin-6-yl)methyl]phenothiazine (Formula I: Ar=6-(2,4-diaminopteridine); X=N; W=CH2; Z=S; m=n=0). ;NaH (60% oil suspension containing 51 mg, 2.0 mmol) was added to a stirred solution of phenoxazine (159 mg, 0.784 mmol) in dry THF (20 mL) at 0 C. under N2. After 10 min. 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.392 mmol) was added and the reaction mixture was allowed to come to room temperature and left in stir for 2 days. The excess NaH was decomposed with MeOH (1 mL), and the mixture was concentrated to dryness by rotary evaporation. Flash chromatography on silica gel yielded the title compound, N-[(2,4-diaminopteridin-6-yl)methyl]phenothiazine, as a greenish-yellow solid; yield 20 mg (14%); mp 250 C. dec. Anal. Calcd. for C19H19N75/5CHCl3; C, 64.73, H, 4.93, Found: C, 64.55; H, 4.90.
chromium(II) acetate; at 70℃; under 7500.75 Torr; for 5.5h;
An SUS-316-made autoclave of 1 L in capacity with a stirrer was charged with 240.0 g of ethylene oxide, 0.90 g of chromium acetate (as a catalyst), and 0.45 g of phenothiazine (as a polymerization inhibitor), and then internal air of the autoclave was replaced with nitrogen gas, and then the temperature was raised to 70 C and the internal pressure was adjusted to 1.0 MPa. Next, 448 g of methacrylic acid was supplied at an almost constant rate over a period of 2 hours (during this supply, the molar ratio of ethylene oxide/methacrylic acid was set at not less than 1.05 and, after the end of the supply, this ratio was 1.05), while 70 C was kept to carry out a reaction. After the supply of the methacrylic acid had been completed, the reaction temperature was kept constant at 70 C to continue the reaction till the amount of the unreacted methacrylic acid (measured by neutralization titration) decreased to 0.10 weight %. As a result of the continuation of the reaction for 3.5 hours, the unreacted methacrylic acid decreased to 0.10 weight %, so the reaction liquid was cooled. A gas-chromatographic analysis of the resultant reaction liquid showed a hydroxyethyl methacrylate (objective product) concentration of 95 weight %, an ethylene glycol dimethacrylate (diester) concentration of 0.05 weight %, and a diethylene glycol monomethacrylate (diaddition product) concentration of 4.2 weight %. Next, the resultant reaction liquid was purified in the same way as of Example 1, thus obtaining 648 g of hydroxyethyl methacrylate. A gas-chromatographic analysis of the resultant hydroxyethyl methacrylate showed its purity of 97.8 weight % and an ethylene glycol dimethacrylate (impurity) content of 0.06 weight %, and an analysis by neutralization titration showed an acid component content of 0.03 weight %.
at 190℃; under 540.054 Torr;Product distribution / selectivity;
Using the same apparatus (Fig. 1) as in Example a1, a high boiling material having the following composition was continuously supplied from the line 1 at a rate of 580 kg/hr. High boiling (raw material) composition A decomposition reaction was carried out under a reaction pressure of 72 kPa at a decomposition temperature of 190C for a retention of 1 hours. From the line 6 at the top, a valuable substance composed mainly of acrylic acid was recovered at a rate of 449 kg/hr, while a reaction residue having the following composition was withdrawn out of the system via the line 4 at a rate of 131 kg/hr. Composition of reaction residue The bottom liquid of the decomposition reaction column was withdrawn from a 3/4B nozzle (line 2) installed at the lowest position of the bottom portion and supplied to the pump B. Via the pump B, it was withdrawn from the line 4 at a rate of 131 kg/hr, while to the line 3, it was supplied at a rate of 32000 kg/hr as a return liquid to the decomposition reaction column via the heat exchanger C for heating by a pipe having a diameter of 4B. On the other hand, the bottom liquid of the decomposition reaction column was supplied as a return liquid by the pump B from the line 5 to form the flow in a circumferential direction in the decomposition reaction column. The pipe diameter of the line 5 was 11/2(1.5)B, and the flow rate was 400 kg/hr, and the such a control was carried out by a flow rate control valve (not shown in Fig.) installed on the line 5. After carrying out a continuous operation for 6 months, the operation was stopped, and the interior of the decomposition reaction column was inspected. No accumulation was observed at the bottom of the decomposition reaction column. Further, during the operation, no clogging was observed in the transport pipe of the reaction residue.; EXAMPLES b5 to b8 Using the same apparatus as in Example b1, a decomposition reaction was carried out by supplying a high boiling material having the following composition as the raw material at a rate of 580 kg/hr. Composition of high boiling material (raw material) The conditions of the decomposition reaction were a reaction pressure of 72 kPa, a decomposition temperature of 190C and a retention time of 1 hour, and no decomposition catalyst was supplied. From the column top, a valuable substance composed mainly of acrylic acid was recovered at a rate of 449.5 kg/hr, while from the bottom, a reaction residue having the following composition was intermittently discharged at a rate of 130.5 kg/hr. Namely, the closing time and the opening time of the intermittent discharge control valve D as shown in Fig. 6, were set as shown in Table 2, and the operation was carried out. The discharged liquid was sent to the reaction residue storage tank installed in a distance of 800 m by means of a pipe having a diameter of 3/4B (inner diameter: 22.2 mm). A continuous operation was carried out for 3 months, whereby no clogging was observed in the transport pipe for the reaction residue. Further, the decomposition ratio of the acrylic acid dimer was about 72%. The results are shown in Table 2. [] Composition of the reaction residue;EXAMPLE d2 Decomposition of a high boiling liquid was carried out by using the same apparatus as in Example d1. The composition of the high boiling liquid was 5.3 wt% of acrylic acid, 10 wt% of maleic acid, 42.4 wt% of an acrylic acid dimer (acryloxypropionic acid), 1.3 wt% of hydroquinone and 1 wt% of phenothiazine, and the liquid was supplied at a rate of 580 kg/hr. The decomposition reaction was carried out under a reaction pressure of 72 kPa at a decomposition temperature of 190C for a retention time of 1 hour, whereby a decomposition gas comprising 85.1 wt% of acrylic acid, 8.7 wt% of maleic acid, 2.1 wt% of an acrylic acid dimer (acryloxypropionic acid), 0.03 wt% of hydroquinone and 4.07 wt% of others was obtained from the top of the decomposition reaction column at a rate of 449.5 kg/hr. To the heat exchanger for cooling the decomposition gas, the liquid obtained by cooling the decomposition gas was returned at a rate of 500 kg/hr. As oxygen or the like, air was supplied at a rate of 2 Nm3/hr to the column top gas line 44a as shown in Fig. 11. After carrying out a continuous operation for 3 months, the operation was stopped, and the interior of the decomposition reaction column was inspected. No polymer was observed in the interior of the decomposition reaction column or in the heat exchanger for cooling the column top gas.
EXAMPLE 4 Synthesis of Bis(trimethylsilyl)methylacrylate Bis(trimethylsilyl)chloromethane (Aldrich) 39 g, 0.2 mole), <strong>[7446-81-3]sodium acrylate</strong> (28 g, 0.3 mole), Adogen 464 (Aldrich) (6.96 g), and phenothiazine (0.10 grams) were placed in a round bottom flask equipped with a condenser, mechanical stirrer and a nitrogen inlet. The flask was charged with 100 ml of butyronitrile and heated to reflux while stirring. After 6 hours, the mixture was diluted with 150 ml hexanes and filtered to remove the solids. The solvents were removed under reduced pressure. Fractional distillation of the residue under reduced pressure gave 35.5 grams 975percent) of the desired product at 45-58° C. at 0.5 mm pressure.
EXAMPLE 4 This example shows that the entire sequence of cycloaddition, elimination and aromatization can be carried out in a single vessel with a good yield of 4-chlorophthalic anhydride. A 3-necked 50 mL flask was equipped with a pressure equalizing addition funnel, a thermocouple well with thermocouple, a water cooled condensor and a magnetic stir bar. The flask was charged with 13.2 g (0.10 mol) of a 90/10 GC area % mixture of monochloromaleic anhydride and dichloromaleic anhydride and 100 mg of phenothiazine and 0.5 g of activated carbon. The contents of the flask were heated to 80 to 130 C. and 8.8 g (0.1 mol) of chloroprene was added over 15 to 30 minutes. HCl gas was observed evolving from the reactor. After 6 hours at 130 C. the contents of the flask were sparged with oxygen for 2 hours between 130 and 150 C., filtered hot, and multiple distilled into two fractions resulting in the isolation of 13.2 g (80% of theoretical) of 4-chlorophthalic anhydride.
2,6-Di(acryloyloxymethyl)-p-cresol acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85 g (44%)
With dmap; triethylamine In tetrahydrofuran; ethyl acetate
1 2,6-Di(acryloyloxymethyl)-p-cresol acrylate (CTA)
Example 1 2,6-Di(acryloyloxymethyl)-p-cresol acrylate (CTA) A two liter, three necked flask was equipped with an overhead stirrer, nitrogen atmosphere and an addition funnel. Next, the flask was charged with 100 g of 2,6-bis(hydroxymethyl)-p-cresol (0.59 mol.), 800 ml of tetrahydrofuran, 180 g of triethylamine (1.78 mol.) 1.2 g of 4-dimethylaminopyridine and 1 g of phenothiazine. The reaction was cooled with an ice bath and 161 g of acryloyl chloride (1.78 mol.) was added slowly over 1.5 hours. Next, the reaction was warmed to room temperature and stirred for 3 hours. The triethylamine hydrochloride salt was removed by filtration. The remaining mother liquor was evaporated with a rotoevaporator to yield a light brown liquid. The liquid was dissolved in ethyl acetate and washed with HCl(10%), NaCl(aq.), NH4 OH(10%), NaCl(aq.) and dried over MgSO4. The ethyl acetate was removed with a rotoevaporator to yield 85 g (44%) of a water white liquid. The liquid became a white semi-solid upon standing. The product was confirmed by IR and 13 C NMR.
(a) 437 g of isoprene stabilized with 1.3 g of phenothiazine were added dropwise in the course of 6 hours to a solution of 832 g of 3-chloro-2-methyl-phenol, 74.4 g of 85% strength phosphoric acid and 5.8 ml of water in 1.4 liters of o-dichlorobenzene at 110 C. To complete the reaction, stirring was continued overnight at 110 C. The acid phase was separated off and the organic phase was washed until neutral. Fractional distillation gave 296 g of 7-chloro-5-hydroxy-3,3,6-trimethyl-indan; boiling point: 161-164 C./11 mm Hg; melting point: 109-109.5 C. STR8
EXAMPLE 9 Preparation of 3-(acryloyloxy)propanoic Acid (2-carboxyethyl Acryate; CEA) Acrylic acid (100 g; 1.39 mole) and phenothiazine (0.1 g) were placed in a 500 mL round bottom flask. The reaction was stirred at 92 C. for 14 hours. The excess acrylic acid was removed on a rotary evaporator at 25 C. using a mechanical vacuum pump. The amount of residue obtained was 51.3 g. The CEA (Compound 6) was used in Example 10 without purification.
EXAMPLE 7 Preparation of 3-(acryloyloxy)propanoic acid (2-carboxyethyl acrylate; CEA) Acrylic acid (100 g; 1.39 mole) and phenothiazine (0.1 g) were placed in a 500 mL round bottom flask. The reaction was stirred at 92 C. for 14 hours. The excess acrylic acid was removed on a rotary evaporator at 25 C. using a mechanical vacuum pump. The amount of residue obtained was 51.3 g. The CEA (Compound 6) was used in Example 7 without purification.
EXAMPLE 9 Preparation of 3-(acryloyloxy)propanoic acid (2-carboxyethyl acrylate; CEA) Acrylic acid (100 g; 1.39 mole) and phenothiazine (0.1 g) were placed in a 500 mL round bottom flask. The reaction was stirred at 92 C. for 14 hours. The excess acrylic acid was removed on a rotary evaporator at 25 C. using a mechanical vacuum pump. The amount of residue obtained was 51.3 g. The CEA (Compound 6) was used in Example 10 without purification.
Example 1 Synthesis of sodium 3-(phenothiazin-10-yl)propane-1-sulfonate A portion of sodium hydride (17.7 g, 0.44 moles) dispersed in mineral oil is first washed with petroleum ether (b.p. 40-60 C.) and then suspended in 200 mL dry tetrahydrofuran, in a 2 L three-neck flask. A solution of phenothiazine (80.0 g, 0.4 moles) dissolved in tetrahydrofuran (400 mL) is added under argon through a cannula. The mixture is shaken, always under argon, for one hour at room temperature and then for 30 minutes at 50 C. The mixture acquires an orange colour, following the formation of the phenothiazine anion.
Stage #1: 10H-phenothiazine; tert-butyl 4-(4-bromophenoxy) piperidine-1-carboxylate With sodium t-butanolate In toluene at 20℃; for 48h;
Stage #2: With trifluoroacetic acid In dichloromethane for 1h;
Stage #3: With sodium hydroxide In dichloromethane for 0.166667h;
7.1
To a solution of compound 7a (l . i g, 3.0 mmol) and compound 6a (776 mg, 3.9 mmol) in tolune (15 mL) was added Pd2(dba)3 (275 mg, 0.3 mmol), P(1Bu)3 (97 mg, 0.48 mmol), NaO1Bu (432 mg, 4.5 mmol). The mixture was stirred at room temperature for 48 hours, then the reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified using flash chromatography on silica (EtOAc/Hexanes, 1 :4) to provide an oil product (650 mg), which was taken up in a mixture of TFA (5 mL) and DCM (5 mL) and stirred for I hour. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in E)CM, then IN NaOH was added and the resulting solution was stirred for 10 minutes, then concentrated in vacuo to provide compound 7b (550 mg, 49%)
Example 1Synthesis of sodium 3-(phenothiazin-10-yl)propane-1-sulfonateA portion of sodium hydride (17.7 g, 0.44 moles) dispersed in mineral oil is first washed with petroleum ether (b.p. 40-60 C.) and then suspended in 200 mL dry tetrahydrofuran, in a 2 L three-neck flask. A solution of phenothiazine (80.0 g, 0.4 moles) dissolved in tetrahydrofuran (400 mL) is added under argon through a cannula. The mixture is shaken, always under argon, for one hour at room temperature and then for 30 minutes at 50 C. The mixture acquires an orange colour, following the formation of the phenothiazine anion. After the suspension has cooled to 0 C., a solution of 1,3-propanesultone (35 mL, 0.4 moles) in tetrahydrofuran is added also through a cannula. The colour of the mixture changes almost immediately to clear yellow. The mixture is stirred at 0 C. for thirty minutes after the addition of the sultone and then at room temperature for another thirty minutes.During this period, the mixture becomes almost colourless and homogeneous, with total dissolution of the material in suspension. Subsequently, the product precipitates in crystalline form. At the end of reaction, the product is separated from the solution by means of filtration and washed thoroughly first with tetrahydrofuran and then with ether. Yield: 127.6 g (92.9%). The product is already of high purity. In particular, chromatographic analysis (HPLC, lambda=254 nm) shows that the content of phenothiazine in the product is less than 0.0002 parts (mole/mole). Other impurities can be removed efficiently by recrystallization from ethanol. Molecular mass (C15H14NaO3S2): 343.40. 1H NMR 300 MHz, D2O) delta: 6.9-7.1 (m, 4H, ArH), 6.7-6.9 (m, 4H, ArH), 3.8 (t, 2H, -CH2-N, J=9.9 Hz), 2.5 (t, 2H, -CH2-S, J=11.2 Hz), 1.8-2.0 (m, 2H, -CH2-CH2-CH2). Molecular mass of the free acid (C15H15O3S2): 321.42. MS (API-ES): 322.0 [MH]+.
With N-Bromosuccinimide; In tetrahydrofuran; at 0℃; for 16h;Inert atmosphere;
In a nitrogen-flushed 250 mL round-bottom flask with a magnetic stir bar and septum 10Hphenothiazine (7.97 g, 40.0 mmol) was dissolved in dry THF (60 mL) under nitrogen. The dark solution was deaerated by a constant stream of nitrogen through a syringe for 10 min and cooled to 0 C (ice bath/water). N-Bromosuccinimide (7.12 g, 40.0 mmol) was slowly added to the reaction mixture under nitrogen, then stirred for 16 h and allowed to come to room tempetature. To this solution was added a saturated aqueous solution of sodium sulfite (150 mL) and the aqueous layer was extracted several times with dichloromethane. The combined organic layers were dried with anhydrous magnesium sulfate and filtered. Thesolvents were removed in vacuo and the residue was adsorbed onto celiteand purified by chromatography on silica gel (n-hexane/ethyl acetate 20:1) to give 4.95 g (45%) of 3-bromo-10H-phenothiazine as a colorless solid, Rf (n-hexane/acetone 4:1) = 0.33. The 1H NMRspectrum was in agreement with the literature.1H NMR (CDCl3, 300 MHz): 5.89 (s, br, 1 H), 6.52 (m, 1 H), 6.61 (m, 1 H), 6.83-7.15 (m, 5 H).
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere;
2-Bromo-4-iodo1,3-xylene (10 mmol), 5,10-phenothiazine (10 mmol), Cu (20 mmol), under a nitrogen atmosphereK2CO3 (20 mmol) and N,N-dimethylformamide (20 ml) were combined to form a solution.The above mixed solution was evacuated three times with nitrogen, and heated and stirred at 130 C for 24 h. The reaction mixture was filtered through celite and usedWash with dichloromethane (20 ml).The solvent was evaporated under reduced pressure and purified by column chromatography (hexane/dichloromethane 10:1) to give the product 10-(4-bromo-3,5-dimethylphenyl)-phenothiazine S25-1 .
With phosphorus pentoxide-methanesulfonic acid; at 60℃; for 24h;Inert atmosphere;
General procedure: Eaton?s reagent was prepared from phosphorus pentoxide (P2O5) and methanesulfonic acid (CH3SO3H) (weight ratio P2O5/CH3SO3H 1:10). The mixture was heated at 40 C under nitrogen atmosphere until complete homogeneity. Carboxylic acid (1.0 equiv) and aromatic derivative (1.1-1.5 equiv) were then added to Eaton?s reagent. The mixture was heated at 60 C under inert atmosphere for 7-43 h. After cooling to room temperature, the reaction medium was diluted with dichloromethane and carefully poured into a separatory funnel containing sodium bicarbonate aqueous solution (50% NaHCO3). The aqueous solution was extracted with dichloromethane, and the combined organic layers were dried (MgSO4). Solvent was removed under reduced pressure to give a brownish oil. The crude product was purified by column chromatography on silica gel or recrystallized to provide pure compounds.
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 9h;
To a mixture of 1-chloro-3-iodopropane (6.133 g, 0.03 mol) and NaH (3 g, 0.075 mol) in THF (25 ml) at 0C, phenothiazine (5 g, 0.025 mol) in THF (25 ml) was added. The mixture was stirred at room temperature for 9 h. After work-up, 10-(3-chloropropyl)-10H-phenothiazine was obtained in 37% yield.
8.3 g
Step 1 - Preparation of 10-(3-chloropropyl)-l OH-phenothiazine To a flask containing phenothiazine (5.45 g, 27.3 mmol) and DMF (140 mL) at 0C was added sodium hydride (60% in mineral oil, 2.19 g, 54.7 mmol). After stirring for 1 hour this mixture was added to a solution of l-chloro-3-iodopropane (8.65 mL, 82.0 mmol) in DMF (10 mL) over the course of 10 minutes and stirred overnight at room temperature. The reaction mixture was transferred to a separatory funnel, diluted with saturated sodium bicarbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0-2% ethyl acetate/hexanes to afford 8.3 grams of material that was of sufficient purity to be used in the next step. LCMS: ESI+ m/z of 276 and 278 (M+H for C135 and C137). NMR (400 MHz, CDC13) delta (ppm) = 2.24-2.30 (m, 2H), 3.68-3.71 (m, 2H), 4.10-4.13 (m, 2H), 6.92-6.99 (m, 4H), 7.18-7.22 (m, 4H).
10,10'-(sulfonylbis(4,1-phenylene))bis(10H-phenothiazine)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.7%
A mixture of 10H-phenothiazine (1.57 g, 7.87 mmol) and sodium hydride (0.38 g, 15.73 mmol) in dimethylformamide (DMF) (30 mL) was stirred at room temperature for 30 min. After stirring, bis(4-fluorophenyl) sulfone (1.00 g, 3.93 mmol) in DMF was added, and then the mixture was stirred at 60 C for 1 h followed by cooling to room temperature. The solution was extracted with dichloromethane (MC) and then the solvent was removed under vacuum. The resulting product was purified over silica gel with ethyl acetate/n-hexane as the eluent. Yield: 1.8 g (74.7%), 1H NMR (400 MHz, d-DMSO): delta 7.78 (d, 4H, J = 7.2 Hz), 7.51 (d, 4H, J = 4.2 Hz), 7.37 (t, 4H, J = 8.4 Hz), 7.3 (d, 4H, J = 4.2 Hz), 7.26 (t, 4H, J = 8.2 Hz), 7.11 (d, 4H, J = 7.2 Hz). 13C NMR (400 MHz, d-DMSO): delta 149, 141.2, 134.7, 131.8, 129.7, 129.2, 128.4, 126.8, 126.1, 117.8. MS(APCI) 613 m/z.
With oxygen; potassium carbonate; In 1,2-dichloro-benzene; at 130℃; for 6h;
General procedure: A stirred mixture of phenothiazine (100 mg, 0.5 mmol),3,5-dimethylphenol (183 mg, 1.5 mmol), and K2CO3 (69 mg,0.5 mmol) in ODCB (1.5 mL) was heated to 130 oC for 6 h under O2 balloon atmosphere. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/EtOAc, 20:1) para-3a (103 mg, 64%) and ortho-3a (34 mg, 21%) were obtained as white solids. Other compounds were synthesized similarly, and the spectroscopic data of 3a-3m and the sulfoxide of 3g are as follows.
10-(4-((4-fluorophenyl)sulfonyl)phenyl)-10H-phenothiazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.6%
A mixture of 10H-phenothiazine (3.00 g, 15.05 mmol) and sodium hydride (0.36 g, 15.05 mmol) in dimethylformamide (DMF) (50 mL) was stirred at room temperature for 30 min. After stirring, bis(4-fluorophenyl) sulfone (7.65 g, 30.11 mmol) in DMF was added, and then the mixture was stirred at 60 C for 1 h followed by cooling to room temperature. The solution was extracted with dichloromethane (MC) and then the solvent was removed under vacuum. The resulting product was purified over silica gel with ethyl acetate/n-hexane as the eluent. Yield: 4.9 g (76.6%), 1H NMR (400 MHz, d-DMSO): delta 7.98-7.95 (m, 2H, J = 7.2 Hz), 7.82 (d, 2H, J = 4.4 Hz), 7.53 (d, 2H, J = 4. Hz), 7.43 (t, 2H, J = 8.8 Hz), 7.39-7.34 (m, 4H, J = 8.8 Hz), 7.27 (t, 2H, J = 8.4 Hz), 7.1 (d, 2H, J = 6 Hz). 13C NMR (100 MHz, d-DMSO): delta 166.4, 163.9, 149.6, 140.9, 138.8, 133.2, 132.5, 130.8, 130.7, 129.9, 129.3, 128.5, 127.1, 126.7, 117.5, 117.3, 116.9. MS(APCI) 434 m/z.
Potassium hydroxide (5.13 g, 0.0913 mol) was added tophenothiazine (9.1 g, 0.0457 mol) dissolved in 20ml of DMSO. After the solutionwas heated for 30 minutes at 50 ~ 60 oC, 1- bromo -6- chloro hexan(10.2 g, 0.0502 mol) was slowly added and it was heated for 2 hours at 50 ~ 60 oC.After confirming that the reaction was complete, the salt which had beenproduced during the reaction and potassium hydroxide were removed by usingwater and chloroform. Then, the solvent was removed through a distillationunder reduced pressure. Using methylene chloride and hexane (1:5), it was alsoseparated by a chromatography to obtain a white solid (6.95g , 0.0219 mol, 48percent)
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate; In toluene; for 24h;Inert atmosphere; Reflux;
After the phenothiazine 20.0g (100.36mmol), 3-Bromo-4-nitro-pyridine 23.18 g (110.40mmol), the NaO (t-Bu)14.46 g (150.55 mmol), the Pd 2 (dba) 3 2.757 g (3.01mmmol) was suspended in the toluene 400 mL P (t-Bu)3 1.46 mL (6.02 mmol) was put and it mixed reflux under the nitrogen air current for 24 hours. It extracts in the dichloromethane and distilled water and the organic layer the silica gel is filtered. Hexane the organic solution is removed: it recrystallized as the dichloromethane and ethyl acetate and it obtained the intermediate product (C) 23.22 g (yield : 72 %) by the dichloromethane= 7 : 3 (v/v) after the silica gel column.
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate; In toluene; for 24h;Inert atmosphere; Reflux;
After the phenothiazine 20.0g (100.36mmol), 2-Bromo-3-nitro-pyridine 23.18 g (110.40mmol), the NaO (t-Bu)14.46 g (150.55 mmol), the Pd 2 (dba) 3 2.757 g (3.01mmmol) was suspended in the toluene 400 mL P (t-Bu)3 1.46 mL (6.02 mmol) was put and it mixed reflux under the nitrogen air current for 24 hours. It extracts in the dichloromethane and distilled water and the organic layer the silica gel is filtered. Hexane the organic solution is removed: it recrystallized as the dichloromethane and ethyl acetate and it obtained the intermediate product (E) 24.19 g (yield : 75 %) by the dichloromethane= 7 : 3 (v/v) after the silica gel column.
(4-(10H-phenothiazine-10-yl) phenyl)(4-bromophenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
The phenothiazine (4.00g, 20.01mmol) was added to a three-neck flask, was added successively 30mLN, N- dimethylformamide (DMF), potassium tert-butoxide (4.49g, 40.02mmol), argon gas and stirred for 20min after addition of the second intermediate (4.45g, 16.00mmol) was heated to 110 reaction 6h.The reaction was cooled to room temperature and poured into 200mL saturated saline precipitated solid was suction filtered, the resulting crude product in a volume ratio of 2: 3 mixed solution of dichloromethane and hexane as eluant purified by silica gel column chromatography, the product after vacuum drying 4.53g, 62% yield as a pale yellow powder.
4,7-diphenothiazin-N-yl-1,10-phenanthroline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
1.41 g of phenothiazine,240 mg of 70% oil dispersion of sodium hydride and.20 ml of tetrahydrofuran was added to a 50 ml single-neck round bottom flask,After refluxing under argon for 30 minutes, 0.75 g of 4,7-dichloro-1,10 phenanthroline were added., Then refluxed at 60 C for 24 hours,After cooling to room temperature, saturated saline was quenched,Dichloromethane extraction,The organic phase was dried over anhydrous sodium sulfate,Filtered, and dried.A methanol: dichloromethane volume ratio of 1:30 to obtain the product 1.38 grams. Light yellow solid, yield 80%
With tri-tert-butyl phosphine; palladium diacetate; caesium carbonate; In toluene; for 8h;Inert atmosphere; Reflux;
2, 2 '- dinitro _4, 4' - bis desert biphenyl (. 20. 0g, 49 8mmol), phenothiazines sigh (20. 0g, 100 · 4mmol), palladium acetate (1. 2g, 5. 4mmol), tri-t-butylphosphine (1. 6g, 7. 8mmol) and cesium carbonate (48. 6g, 149. 4mmol) was dissolved in toluene, under a nitrogen atmosphere, the reaction was heated at reflux for 8 hours. The solvent was evaporated in vacuo, the remaining material was stirred in pentane was added, filtered, purified by silica gel column chromatography, to obtain a solid compound 62-a (20. 4g, 64%)
10-(3-fluoro-4-methoxybenzyl)-10H-phenothiazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;Inert atmosphere;
General procedure: Under inert atmosphere, the sodium hydride (1.1 equiv.) was added to a solution of amine derivative 19-23 (1.1 equiv.) in DMF at 0 C. The benzyl bromide 15-18 (1 equiv.) was then added immediately and the reaction was stirred for 24 h. The mixture was then washed with water and extracted with methylene chloride. The organic phase was dried over MgSO4 and purified by flash chromatography (n-heptane/EtOAc, gradient from 100/0 to 0/100) to give pure compounds 5-14.
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate; In toluene; at 120℃;Inert atmosphere;
Phenothiazine (2.37 g, 11.9 mmol), 1-bromo-4-n-octyl-benzene (4.17 g, 15.4 mmol) and sodium tert-butoxide (2.3 g, 23.8 mmol) are dissolved sufficiently in 50 mL of toluene.Tri tert-butylphosphine(0.144 g, 0.7 mmol)And Pd2 (dba) 3 (0.54 g, 0.59 mmol)After sufficiently dissolving at room temperature under a nitrogen atmosphere,And the mixture is stirred at 120 C under reflux.When the reaction is complete, work-up is carried out with a 1: 1 mixture of water and chloroform.After separating the organic layer after the work-up process using the extraction method,The solvent is removed under reduced pressure.After the solvent was removed, the product was recrystallized several times with methanol to obtain a pale yellow solid product (3.5 g, 76%) was obtained.
Phenothiazine 16.20mmol 48.49mmol added sodium t-butoxide and 33ml toluene was added after the reaction flask under a nitrogen blanket. After stirring 10min, tris (dibenzylideneacetone) dipalladium 0.203mmol,Tri-tert-butylphosphine 1.295 mmol,<strong>[7321-27-9]2-bromoanthracene</strong> 24.3mmol, ventilation three times, 110 reflux overnight. After the reaction, dichloromethane 100ml extraction, evaporation of organic phase after a small amount of methylene chloride dissolved with petroleum ether precipitation products, precipitation of petroleum ether 100ml wash 3 times, ethanol100ml, washed 2 times to get 14.22mmol of light yellow product, the yield was 87.78%.
Phenothiazine 16.20mmol 48.49mmol added sodium t-butoxide and 33ml toluene was added after the reaction flask under a nitrogen blanket. After stirring 10min, tris (dibenzylideneacetone) dipalladium 0.203mmol, tri-tert-butylphosphine 1.295 mmol,<strong>[62162-97-4]2-bromophenanthrene</strong> 24.3mmol, ventilation three times, 110 reflux overnight. After the reaction, dichloromethane 100ml extraction, evaporation of organic phase after a small amount of dichloromethane dissolved with petroleum ether precipitation products, the product of petroleum ether 100ml wash 3 times, ethanol 100ml, washed 2 times to get light yellow Product 14.09 mmol, yield 86.98percent.
10-(2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecin-12-yl)-10H-phenothiazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 120℃; for 20h; Inert atmosphere; Schlenk technique;
Synthesis. Redox shuttles were synthesized by alkylation of phenothiazine with the corresponding alkyl halide. EPT was synthesized as previously described (Ergun et al., Chem. Commun., 2014, 50, 5339-5341). Phenothiazine (1.99 g, 10.0 mmol) was dissolved in DMF (20 mL). For new compounds MEPT and MEEPT dispersion of NaH in mineral oil (0.48 g, 12 mmol) was added and the reaction mixture was heated to 60 C. for 30 min. Then, <strong>[627-42-9]2-chloroethyl methyl ether</strong> (1.10 mL, 12 mmol, for MEPT) or 1-bromo-2-(2-methoxyetoxy)ethane (1.62 mL, 12 mmol, for MEEPT) was added, and the reaction was stirred at 60 C. for 12 h. The reaction was quenched by pouring it onto ice water, after which the organic components were extracted with ethyl acetate three times, and the combined extracts were washed with brine. The organic extracts were dried over MgSO4, filtered to remove solids, and concentrated by rotary evaporation. The crude product was purified by column chromatography using a gradient of 0 to 10% ethyl acetate in hexanes to afford the desired products as colorless oils. N-(2-methoxyethyl)phenothiazine (MEPT). Yield: 2.16 g (84%). 1H NMR (400 MHz, CDCl3): delta 3.38 (s, 3H), 3.74 (t, 2H, 1=6.4 Hz), 4.07 (t, 2H, 1=6.4 Hz), 6.87-6.92 (m, 4H), 7.10-7.24 (m, 4H). 13C NMR (100 MHz, CDCl3): delta 47.37, 59.09, 69.74, 115.17, 122.62, 124.67, 127.33, 127.45, 144.96. EI-MS: m/z 257 (54%), 212 (100%), 198 (20%), 180 (61%). Anal. calcd. for C15H15NOS C, 70.01; H, 5.88; N, 5.44. Found C, 69.99; H, 5.91; N, 5.39. (0043) N-[2-(2-methoxyethoxy)ethyl]phenothiazine (MEEPT). Yield: 2.22 g (74%). 1H NMR (400 MHz, CDCl3): delta 3.34 (s, 3H), 3.51-3.54 (m, 2H), 3.61-3.64 (m, 2H), 3.83 (t, 2H, 1=6.4 Hz), 4.10 (t, 2H, 1=6.4 Hz), 6.87-6.92 (m, 4H), 7.10-7.24 (m, 4H). 13C NMR (100 MHz, CDCl3): delta 47.37, 59.09, 69.74, 115.17, 122.63, 124.67, 127.33, 127.45, 144.96. EI-MS: m/z 301 (48%), 212 (100%), 198 (22%), 180 (46%). Anal. calcd. for C17H19NO2S C, 67.75; H, 6.35; N, 4.65. Found C, 67.48; H, 6.41; N, 4.88.
10-(2,2'-bipyridin-6-yl)-10H-phenothiazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With chloro(2-dicyclohexylphosphino-2?,6?-diisopropoxy-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) 2nd generation; potassium tert-butylate; In 1,4-dioxane; at 110℃; for 18h;Inert atmosphere; Sealed tube;
In a tube were added 6-bromo-2,2-bipyridine (70.5mg, 0.3mmol, 1equiv.), phenothiazine (77.7mg, 1.3equiv.), RuPhos-Pd-G2 (23.4mg, 10mol%) and t-BuOK (50.5mg, 1.5equiv). The tube was sealed, purged three times with argon and 1mL of anhydrous dioxane was added. The reaction mixture was stirred at 110C for 18h. After cooling to room temperature, 10mL of H2O were added and the aqueous layer was extracted three times with ethyl acetate (3×10 mL). The combined organic layers were dried with MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (50/50: CH2Cl2/cyclohexane) affording 51.2 mg of L1 (0.145 mmol, 48%) as an amorphous pale yellow solid. 1H NMR (300MHz, CDCl3): 8.66 (d, J=4.6 Hz, 1H); 8.25 (d, J=8.0 Hz, 1H); 8.04 (d, J=7.3 Hz, 1H); 7.91-7.71 (m, 3H); 7.63 (t, J=7.9 Hz, 1H); 7.44 (dd, J=7.7 Hz, J=1.2 Hz, 2H); 7.36 (td, J=7.7 Hz, J=1.5 Hz, 2H); 7.30-7.25 (m, 1H); 7.21 (td, J=7.6 Hz, J=1.2 Hz, 2H); 6.97 (d, J=8.3 Hz, 1H).
10-(2,2'-bipyridin-4-yl)-10H-phenothiazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With chloro(2-dicyclohexylphosphino-2?,6?-diisopropoxy-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) 2nd generation; potassium tert-butylate; In 1,4-dioxane; at 110℃; for 18h;Inert atmosphere; Sealed tube;
General procedure: In a tube were added 6-bromo-2,2-bipyridine (70.5mg, 0.3mmol, 1equiv.), phenothiazine (77.7mg, 1.3equiv.), RuPhos-Pd-G2 (23.4mg, 10mol%) and t-BuOK (50.5mg, 1.5equiv). The tube was sealed, purged three times with argon and 1mL of anhydrous dioxane was added. The reaction mixture was stirred at 110C for 18h. After cooling to room temperature, 10mL of H2O were added and the aqueous layer was extracted three times with ethyl acetate (3×10 mL). The combined organic layers were dried with MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (50/50: CH2Cl2/cyclohexane) affording 51.2 mg of L1 (0.145 mmol, 48%) as an amorphous pale yellow solid.
2,2',7,7'-tetrakis(N-phenothiazylo)-9,9'-spirobifluorene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 110℃; for 24h;Inert atmosphere;
In a reaction tube (100 mL), 2,2',7,7'-tetrabromospiropurine (3.16 g, 5 mmol), phenothiazine (4.18 g, 21 mmol), potassium t-butoxide (2.8 g, 25 mmol) , inject 50ml of dry toluene solvent, pump gas three times, under nitrogen protection,add tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol) and tri-tert-butylphosphine tetrafluoroborate (58 mg, 0.2 mmol), heated to 110 C, and reacted for 24 hours. It was naturally cooled to room temperature, extracted with dichloromethane, dried, concentrated, and then purified by column chromatography, and then purified by high-performance liquid chromatography to yield 2.35 g of light brown powder, yield 83%.
70%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 120℃; for 24h;Inert atmosphere;
General procedure: SFX1 (1.5 g, 2.3 mmol), phenothiazine (2.76 g, 13.9 mmol) and sodium tert-butoxide (1.77 g, 18.5 mmol) were added to dry toluene (30 mL) in three-necked flask. The flask was purged with nitrogen several times. Pd2(dba)3 (10 mg, 11 mmol) and [(t-Bu)3PH]BF4 (20 mg, 69 mmol) were put into the above solution. The result mixture was heated to 120 C for 24 h under the atmosphere of nitrogen. After cooling to room temperature, the solution was filtered to get residue which was washed by toluene and then stirred in a mixture of dichloromethane (500 mL), water (100 mL) and acetic acid (3 mL) until it was completely dissolved. The organic phase was collected and dried over anhydrous Na2SO4, then the solvent was removed under reduced pressure to keep it remained 10 mL. After pouring the mixture into hexane (50 mL), a large amount of solid precipitation of SFX-PT1 was obtained (3.2 g, Yield 74%).
With copper; potassium carbonate; In 1-methyl-pyrrolidin-2-one; for 48h;Inert atmosphere; Reflux;
Intermediate a (3.61 g, 9 mmol) obtained in Intermediate Preparation Example and phenothiazine (4.48 g, 22.5 mmol) were dissolved in 50 mL of NMP under nitrogen atmosphere and then catalyst copper (1.72 g, 27 mmol) Acid-binding agent and potassium carbonate (4.97g, 36mmol). The system was heated to reflux for 48 hours, naturally cooled to 20 ~ 25 ° C after adding 100mL water quenched reaction, the product was filtered to give the crude product.Silica gel column chromatography, eluent methylene chloride: n-hexane = 1: 7 (V / V), to give a white powder, the resulting powder using chemical vapor deposition system further sublimation purification, sublimation temperature of 250 ° C, to give compound C15 , Yield 58percent.
With triethyl borane; sodium hydroxide; In tert-butyl methyl ether; at 80℃; for 6h;Inert atmosphere; Sealed tube;
Under argon atmosphere,Firstly, NaOH and triethylboron are stirred to form a transparent clear solution at room temperature.The concentration is 1M/L;Then,The above triethylboron solution was successively treated with 10umol (2mol%),Amide substrate 5mmol,Triethoxysilane or polymethylhydrogensiloxane 15mmol,MTBE 2mL added to the 10mL sealed tube,It is heated and stirred in an 80C oil bath for 6 hours.The reaction is over,Exposing the reaction to air quenching,The amine product is then separated directly by column chromatography.According to the results of column chromatography separation, when using triethoxysilane or polymethylhydrogensiloxane (PMHS),The yield of the target product was:
With copper(l) iodide; 18-crown-6 ether; potassium carbonate; In 1,2-dichloro-benzene; at 185℃; for 24h;Inert atmosphere;
phenothiazine, <strong>[3740-92-9]4,6-dichloro-2-phenyl-pyrimidine</strong>, cuprous iodide, 18-crown-6 and potassium carbonate Add to single-neck round bottom flask, seal and then protect with nitrogen, then add o-dichlorobenzene dissolved and stirred at 185 °C The reaction was refluxed for 24 h. After the reaction is completed, deionized water is added to the reaction solution to quench the reaction, and then extracted with dichloromethane. The phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a white solid product was obtained after purification by chromatography column. The yield was31percent.
With copper(l) iodide; 18-crown-6 ether; potassium carbonate; In 1,2-dichloro-benzene; at 185℃; for 24h;Inert atmosphere;
Add phenothiazine,<strong>[108-70-3]1,3,5-trichlorobenzene</strong>,Cuprous iodide,18-Crown-6 and potassium carbonate were added to the single-mouth round bottom flask.Sealed then protected by nitrogen,Add o-dichlorobenzene to dissolve and stir,The reaction was refluxed at 185C for 24 h.After the reaction was completed, the reaction solution was quenched by the addition of deionized water and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, a white solid product was obtained after purification by chromatography column in 31% yield.
2,7-di(10H-phenothiazin-10-yl)-9,9'-spirobi[fluorene][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate; In tetrahydrofuran; toluene; at 110℃; for 6h;Inert atmosphere;
A mixture of <strong>[171408-84-7]2,7-dibromo-9,9'-spirobi[fluorene]</strong> (SP, 1 g, 1 equiv.), 10H-phenothiazine (2, 0.88 g,2.1 equiv.), Pd(OAc)2 (0.05 g, 0.1 equiv.), t-Bu3P (10% in toluene, 0.15 mL, 0.03 equiv.), NaOt-Bu(0.81 g, 4 equiv.), and anhydrous toluene (100 mL) were added together and stirred under a nitrogenatmosphere for 6 hours at 110 C. After completion of the reaction, the crude mixture was extractedwith dichloromethane three times. The organic layer was dried over anhydrous sodium sulphate andconcentrated through a rotary evaporation process. The residue was purified by using chloroformand n-hexane solvents through a recrystallization process to achieve SP2 as a yellow solid. Yield: 92%;1H-NMR (500 MHz, CDCl3) delta 8.12-8.14 (d, J = 10 Hz, 2H), 7.75-7.77 (d, J = 10 Hz, 2H), 7.44-7.46 (d, J =10 Hz, 2H), 7.31-7.34 (t, J = 10 Hz, 4H), 7.11-7.14 (t, J = 10 Hz, 4H), 6.87-6.94 (m, 10H), 6.81 (s, 2H),6.08-6.10 (d, 4H); 13C NMR (500 MHz, CDCl3) delta 152.66, 147.34, 141.93, 140.86, 128.34, 128.12, 126.83,126.68, 123.60, 122.21, 120.45, 115.70, 66.18; GC-MS: 710.50 for C49H30N2S2 [M+H+].
General procedure: 10H-phenothiazine (2.0 g, 2.2 equiv.), dibromide (1 equiv.),Pd2(dba)3 (1.3 g, 0.3 equiv.) and t-Bu3PHBF4 (0.7 g, 0.5 equiv.) were dissolved in dry and degassed toluene (100 mL). After the mixture wasstirred for 10 min, sodium tert-butoxide (1.0 g, 2.2 equiv.) was addedand the mixture was stirred at 110 C for 24 h. After cooling down toroom temperature, the reaction system was extracted with EtOAc(3×50 mL). The organic layer was then separated and dried over sodiumsulfate (Na2SO4). The solvent was removed under reduced pressureto give a crude product, which was purified by column chromatographywith petroleum ether/dichloromethane (5/1, v/v) as eluent toobtain the final product. 2.1.1.1. 2?,7?-di(10H-phenothiazin-10-yl)spiro[cyclopropane-1,9?-fluorene] (1). Orange yellow solid.
With sodium hydride; In toluene; mineral oil; for 24h;Inert atmosphere; Reflux;
In a 250mL single-mouth bottle,Add phenothiazine (PTZ) (5.0 g, 25.13 mmol),<strong>[357927-50-5]2-bromo-4-fluoropyridine</strong> (4.20 g, 23.87 mmol),Sodium hydride (60%) (5.02 g, 125.65 mmol) and150 mL of freshly distilled toluene, magnetic stirring, nitrogen protection, reflux reaction for 24 h.The mixture was cooled to room temperature, filtered, and the residue was washed with dichloromethane. The filtrate was collected, and the solvent was evaporated under reduced pressure. The residue was eluted with petroleum ether (PE) and dichloromethane (DCM) as eluent (PE: DCM=1: 1,V:V),Column chromatography gave 4.57 g of a pale yellow solid powder (yield: 51.4%).
With copper(l) iodide; caesium carbonate; ethylenediamine; In toluene; for 24h;Reflux;
Compound D3 (5.97 g, 30.0 mmol), <strong>[221037-98-5]3-iodobenzeneboronic acid</strong> (8.67 g, 35 mmol), cuprous iodide (2.85 g, 15.0 mmol), ethylenediamine (0.90 mg, 15.0 mmol) were sequentially added to the reaction flask. , cesium carbonate (30.0g, 92.0mmol) and toluene(200 mL), stirred under reflux for 24 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate.Concentrated under reduced pressure,The obtained crude product was subjected to column purification to yield Compound E3 (7.28 g, 76percent).
(Z)-3-(4-hydroxyphenyl)-1-(10H-phenothiazine-10-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
After thoroughly drying a 200 mL three-neck reaction flask, the reactant p-hydroxycinnamic acid was sequentially added.(16.42 g), the reaction solvent tetrahydrofuran (60 mL),After the hydroxycinnamic acid is completely dissolved,The condensing agent dicyclohexylcarbodiimide (DCC, 20.63g) was added in portions.After stirring at room temperature for 30 min, a solution of phenothiazine (17.93 g) in tetrahydrofuran (30 mL) was added dropwise at a rate of 1 drop per second, and allowed to react at room temperature for 30 h. After removing the solid by vacuum filtration under reduced pressure, the solvent was evaporated, and the crude solid was dissolved in ethyl acetate and washed three times with saturated sodium hydrogen carbonate solution, washed three times with 1.0 mol/L diluted hydrochloric acid and twice with deionized water. The organic phase was dried over anhydrous MgSO 4 to remove the solvent, and the obtained solid was dried in a vacuum oven at 40 C for 8 h to give a product.(Z)-3-(4-Hydroxyphenyl)-1-(10H-phenothiazine-10-yl)prop-2-en-1-one.
6.93 g (35 mmol) of thiazideAdd to a 250 ml three-necked flask and add 100 ml of N,N-dimethylformamide as the reaction solvent in an ice bath.Stir on a magnetic stirrer for 10 min. 0.72 g (30 mmol) of NaH was added in portions to the reaction flaskIn the middle, continue stirring for 1 h.Dissolve 2.07 g (10 mmol) of <strong>[3029-64-9]2,4,6-trichloro-5-cyanopyrimidine</strong> in 40 ml of N,N-dimethylformylThe amine solution was added dropwise to the reaction system, and after the addition was completed, the reaction was carried out at room temperature for 24 hours. After the reaction was completed, the reaction solution was poured into 200 ml of 10percent diluted hydrochloric acid, and the mixture was filtered under reduced pressure, washed with water and dried, and the crude product was obtained from petroleum ether and dichloromethane (PE: DCM=10: 1) Pass the column for the mobile phase. 4.64 g of a white solid powder was obtained in a yield of 66.7percent.
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate; In toluene; for 24h;Reflux; Inert atmosphere;
858 mg of N-63 (3 mmol), 1.3 g of PTZ-1 (6.6 mmol),1.9 g of sodium tert-butoxide (19.8 mmol), 34 mg of palladium acetate (0.15 mmol),30 mg of tri-tert-butylphosphine (0.15 mmol) and 35 mL of toluene were added to a 100 mL double-necked flask, and heated under reflux for 24 hours under the protection of nitrogen,After cooling to room temperature, the reaction solution was filtered, and 100 mL of water was added to the filtrate.Extract the organic phase with 100 mL of dichloromethane,The organic phase was separated and concentrated to 5.5 mLThe target product was obtained by column chromatography using dichloromethane and petroleum ether (volume ratio 1: 3) as eluent.Sublimation under vacuum then gave 1.3 g of yellow product 76 (86% yield).
4-phenothiazin-10-yl-2-trifluoromethylbenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
General procedure: Sixty per cent NaH in oil was washed with hexane and then added to a stirred solution of phenothiazine 5 or phenoxazine 6 derivative (10.0mmol) in dry THF (15mL) under a nitrogen atmosphere at room temperature. After stirring for 30min, 4-fluoro-2-(fluoromethyl)-benzonitrile 7 was added. (0007) The reaction mixture was quenched with water (30mL). The organic phase was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography using a mixture of hexane/ethyl acetate (3:1) as eluent.
With sodium ethanolate In N,N-dimethyl-formamide at 70 - 150℃; for 48h;
1 Example 1: Synthesis of compound 3a:
Dissolve 2,6-difluoro-benzonitrile 1a (10.0mmol, 1.39g), phenothiazine 2a (10.0mmol, 1.99g) and sodium ethoxide (30.0mmol, 2.04g) in DMF at 70 to 150°C React for 48 hours, cool to room temperature, wash with water, extract with dichloromethane, dry with anhydrous sodium sulfate, and then column chromatography to obtain 3a (4.72g, yield: 95%);
(4-(10H-phenothiazin-10-yl)phenyl)(4-fluorophenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.4%
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; ruphos; In toluene; at 120℃; for 24h;Inert atmosphere;
To a solution of compound 1 (1.00 g, 3.58 mmol) in degassed toluene (20 mL) phenothiazine (1.08 g, 5.42 mmol), K2CO3 (2.49 g, 18.02 mmol), Ruphos (0.08 g, 0.17 mmol), and Pd2(dba)3 (0.05 g, 0.087 mmol) were added. Subsequently, the reaction solution was stirred at 120 C under argon for 24 h [S7]. After cooling to room temperature, the mixture was filtered, and the solvent of the filtrate was removed by rotary evaporation. The crude product was then separated and purified by silica gel column chromatography with dichloromethane and petroleum ether (v/v=1:2) as eluent to give a gray-green powder in 73.4% yield (compound 2, 1.05 g).
Stage #1: 10H-phenothiazine With Cs2CO3 In N,N-dimethyl-formamide at 60℃; for 0.25h; Inert atmosphere;
Stage #2: 2,5-dibromo-1,3-difluorobenzene In N,N-dimethyl-formamide at 155℃; for 12h; Inert atmosphere;
4.1 1) Synthesis of intermediate (4)
First, phenothiazine (8.77 g, 44 mmol), Cs2CO3(32.50 g, 100 mmol) were sequentially added to a 250 mL two-necked round-bottomed flask, and then, under Ar atmosphere, 50 mL of ultra-dry DMF was injected through a syringe , resulting in a suspension, which was stirred at 60°C for 15 minutes.Finally, 5-bromo-2-chloro-1,3-difluorobenzene (5.44 g, 20 mmol) was added at one time from the side opening of the reaction flask, and the temperature was raised to 155° C. for 12 h.After the reaction was completed, it was lowered to room temperature, the insoluble inorganic salt was filtered off, and then the high-boiling DMF solvent was removed by vacuum concentration, and the residue was purified by a column machine, and the optimized eluent formula was DCM/PE (1:5, v/v) to obtain a powder of intermediate (4).
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