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Structure of 383-53-9 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 15, p. 3540 - 3546
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 10, p. 2724 - 2728
[3] Journal of Chemical Research, 2014, vol. 38, # 4, p. 208 - 210
2
[ 383-53-9 ]
[ 1891-90-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 46, p. 9889 - 9894
3
[ 313343-88-3 ]
[ 383-53-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 40℃; for 6 h; Green chemistry
General procedure: A mixture of haloalkyne (0.5 mmol), AgF (5molpercent) and water (1 equiv.) in TFA (1 mL) was stirred at 40°C for 6h, after which TFA was distilled out for reuse. The residue was separated by column chromatography to give the pure sample.
80%
With indium(III) triflate; water In acetic acid at 100℃; Sealed tube
General procedure: The reaction mixture of In(OTf)3 (16.8mg, 0.03mmol), 1-haloalkynes (0.3mmol), H2O (0.9mmol), HOAc (0.6mL), in a 5mL sealed tube was stirred at 100°C and monitored periodically by TLC. Upon completion, HOAc was removed under reduced pressure using an aspirator, and then the residue was purified by flash chromatography (PE/EA) on silica gel to afford corresponding carbonyl compounds 2a–2ad.
80%
With tetrafluoroboric acid; water In 2,2,2-trifluoroethanol at 80℃; for 2 h;
General procedure: A mixture of haloalkyne (0.2 mmol), tetrafluoroboric acid (20 molpercent, 40percent aqueous solution ) in 2,2,2-trifluoroethanol (1 mL) was stirred at 80°C for 2 or 10 h. After the reaction was finished, water (5 mL) was added and the solution was extracted with ethyl acetate (3×5 mL), the combined extract was dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by column chromatography to give the pure sample.
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 7, p. 1373 - 1375
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 1, p. 116 - 121
[3] Tetrahedron, 2016, vol. 72, # 27-28, p. 3818 - 3822
[4] Tetrahedron Letters, 2016, vol. 57, # 45, p. 4983 - 4986
[5] Chinese Journal of Chemistry, 2016, vol. 34, # 12, p. 1251 - 1254
4
[ 709-63-7 ]
[ 556110-56-6 ]
[ 383-53-9 ]
Yield
Reaction Conditions
Operation in experiment
63%
With trimethylsilyl bromide; potassium nitrate In dichloromethane at 20℃; for 16 h;
General procedure: In a Nalgene.(R). bottle, to acetophenone (2 mmol) in dichloromethane (10 mL), potassium nitrate (4 mmol) and chloro/bromotrimethylsilane (8 mmol) were added. The heterogeneous mixture was stirred vigorously at 60 °C (for chlorination) or room temperature (for bromination) until the reaction went to completion (monitored by 1H NMR spectroscopy). The reaction mixture was then filtered and solvent removed under reduced pressure. The chlorinated/brominated acetophenone derivatives were obtained upon purification by flash chromatography (silica gel) with hexane as eluent. The products were characterized by comparing their spectroscopic data with those of the authentic samples.
0.6%
With bromine; sodium hydrogencarbonate; acetic acid; sodium chloride In hexane; water; ethyl acetate
Example 41 2,2-Dibromo-1-(4-trifluoromethyl-phenyl)-ethanone. This compound was synthesised by the general procedure represented in Scheme 2, a stirred solution of 1-(4-trifluoromethyl-phenyl)-ethanone (1 g, 5.3 mmol)) and acetic acid (50 ml) was refluxed 1 h, then bromine (0.35 ml, 6.9 mmol) was added dropwise and the mixture refluxed 3 h. After cooling at room temperature, water (50 ml) was added and the mixture extracted with CH2Cl2 (50 ml), the organic layer was washed with water (50 ml), a solution of NaHCO3 saturated (50 ml) and finally with NaCl solution (50 ml), the organic layer was dried over sodium sulphate and the solvent evaporated under reduced pressure. The resulting residue was purified by column chromatography, using a mixture of ethyl acetate:hexane (1:8) as eluent giving two compounds, the titled compound 41 as a yellow solid (45percent) m.p.: 40-41° C., 1H-NMR (CDCl3): δ8.2 (d, J=8.3 Hz, 2H, Ar), 7.8 (d, J=8.3 Hz, 2H, Ar), 6.6 (s, 1H, CH); 13C-NMR (CDCl3): δ184.1 (CO), 134.7 (q, J=272.9 Hz, C-CF3), 132.7 (C-CO), 129.2 (CH), 124.8 (CH), 119.5 (q, J=33.09, CF3), 38.2 (CH); M/z (EI): 348, 346, 344 (M+, 1, 6, 1percent), 173 (M-CHBr2, 100percent); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300*3.9 mm), Purity 97percent, r.t.=9.96 min, acetonitrile/H2O (0.05percent H3PO4+0.04percent Et3N) 50/50. The second compound was identified as 2-bromo-1-(4-trifluoromethyl-phenyl)-ethanone (0,6percent), described as the example 40.
10 mmol 4-trifluoromethyl acetophenone is added to a 100 mL round bottom flaskAnd 11mmol of N-bromosuccinimide (NBS),35mL of ethyl acetate dissolved,Then add 1g of Amberlyst 15 ion exchange resin as catalyst.The reaction solution was warmed to 40°C to react. After TLC tracks the reaction,The reaction solution was filtered to remove Amberlyst 15 ion exchange resin,The filtrate was evaporated to dryness and column chromatography (eluent: petroleum ether/dichloromethane) gave white crystals.Yield 87percent.
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 20, p. 3231 - 3243
[2] Organic and Biomolecular Chemistry, 2007, vol. 5, # 16, p. 2690 - 2697
[3] Patent: CN107629022, 2018, A, . Location in patent: Paragraph 0473; 0474; 0475; 0476
[4] Journal of agricultural and food chemistry, 2002, vol. 50, # 12, p. 3486 - 3490
[5] Journal of Pharmaceutical Sciences, 2014, vol. 103, # 9, p. 2797 - 2808
[6] Tetrahedron, 2008, vol. 64, # 22, p. 5191 - 5199
[7] Journal of the American Chemical Society, 1953, vol. 75, p. 5884,5886
[8] Journal of Physical Chemistry, 1995, vol. 99, # 20, p. 8190 - 8195
[9] Journal of Medicinal Chemistry, 1996, vol. 39, # 1, p. 253 - 266
[10] Bioorganic and medicinal chemistry, 2002, vol. 10, # 3, p. 507 - 515
[11] Journal of medicinal chemistry, 1972, vol. 15, # 9, p. 989 - 994
[12] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 21, p. 3047 - 3050
[13] Tetrahedron, 2003, vol. 59, # 8, p. 1317 - 1325
[14] Journal of Medicinal Chemistry, 2007, vol. 50, # 3, p. 528 - 542
[15] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 6, p. 1746 - 1749
[16] Tetrahedron, 2008, vol. 64, # 22, p. 5191 - 5199
[17] Patent: WO2010/129665, 2010, A2, . Location in patent: Page/Page column 109
[18] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 7, p. 2316 - 2322
[19] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 70 - 81
[20] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 7, p. 2031 - 2034
[21] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 6276 - 6280
[22] Angewandte Chemie - International Edition, 2013, vol. 52, # 44, p. 11632 - 11636[23] Angew. Chem., 2013, vol. 125, # 44, p. 11846 - 11850,5
[24] Chemistry - A European Journal, 2014, vol. 20, # 20, p. 5983 - 5993
[25] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6572 - 6582
[26] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7707 - 7715
[27] Drug Design, Development and Therapy, 2016, vol. 10, p. 1807 - 1815
[28] Patent: CN105315279, 2016, A, . Location in patent: Paragraph 0112
[29] Organic Letters, 2017, vol. 19, # 8, p. 1994 - 1997
[30] Organic Letters, 2017, vol. 19, # 11, p. 2877 - 2880
[31] Organic and Biomolecular Chemistry, 2017, vol. 15, # 38, p. 8134 - 8139
[32] Patent: WO2017/198341, 2017, A1, . Location in patent: Page/Page column 868
[33] Patent: US2018/44284, 2018, A1, . Location in patent: Paragraph 0169; 0170
[34] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 310 - 319
[35] Tetrahedron Letters, 2018, vol. 59, # 33, p. 3214 - 3219
[36] Chemical Communications (Cambridge, United Kingdom), 2018, vol. 54, # 86, p. 12182 - 12185
6
[ 1616490-76-6 ]
[ 383-53-9 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 49, p. 6565 - 6568
7
[ 709-63-7 ]
[ 107-21-1 ]
[ 658680-40-1 ]
[ 556110-56-6 ]
[ 383-53-9 ]
Yield
Reaction Conditions
Operation in experiment
3.4 - 11.7 %Chromat.
With bromine In chloroform at 25 - 28℃; for 3.5 - 24 h;
2.82g (14. [99MMOL, LEQ.) OF 4APOS;-TRIFLUOROMETHYLACETOPHENONE] were dissolved in 7. [5ML] (8. 35g, 134. [53MMOL,] 8.97eq.) of ethylene glycol. While the solution was controlled to have an internal temperature [OF 25-28APOS;C,] a chloroform solution obtained by diluting 3.60g (22.53mmol, 1.50eq.) [OF BR2] with 2. [2ML] of chloroform was added to the solution, followed by stirring for 24hr with an internal temperature [OF 25-26C.] 3.5hr and 24hr after the start of the reaction, the progress of the reaction was checked by gas chromatography. The results are shown in Table 3. Table 3 Time Compound A1 C1 D 3. 5h 11. 7percent 54. 2percent 0. 3percent 24h 3. 4percent 88. 6percent 0. 8percent 1 : Compound A Compound C Compound D ouzo Br p Br bu Xf, () I CF) ()' Br L'r'3
91.09 %Chromat.
With bromine In chloroform at 28 - 32℃; for 15 h;
[106G (0. 56MOL, LEQ. ) OF 4APOS;-TRIFLUOROMETHYLACETOPHENONE WERE DISSOLVED] in [281ML] (313g, 5. [04MOL,] 9. [00EQ.)] of ethylene glycol. While the solution was controlled to have an internal temperature [OF 28-32C,] a chloroform solution obtained by diluting 108g (0. 68mol, 1.21eq.) of Br2 with [56ML] of chloroform was added to the solution, followed by stirring for [15HR] with an internal temperature of [29-32DUC.] The resulting reaction separated into an upper and lower layer. Then, the lower layer was washed with [2percent BRINE,] followed by drying with anhydrous sodium sulfate, filtration and vacuum drying, thereby obtaining 165g of a crude product of a brominated acetal represented by the following formula. The yield was 94percent. The analytical results of the crude product by gas chromatography are shown in Table 4, and [ITS 1H-NMR] spectrum was as follows. Table 4 Compound A1 C1 D1 Total Others 0. 6percent 96. 9percent 0. 9percent 1. 6percent 1 : Compound A Compound C Compound D o n o Br p Br 'bu ZIG CF3 CF CF3 3 [1H-NMR] (standard substance: TMS, solvent: [CDCL3),] [8PPM] : 3.64 (s, 2H), 3.83-3. 98 (m, 2H), 4.14-4. 30 (m, 2H), 7.64 (Ar-H, 4H). Separately, water was poured into the above-obtained upper layer, followed by extraction with ethyl acetate. The collected organic layer was dried with anhydrous sodium sulfate, followed by filtration, concentration and vacuum drying, thereby obtaining 6g of a brominated acetal of the above formula. The yield was 3percent.
[2. 82G (14. 99MMOL, LEQ. ) OF 4APOS;-TRIFLUOROMETHYLACETOPHENONE WERE] dissolved in 5. [6ML] of methanol. While the solution was controlled to have an internal temperature [OF 26-27C,] a methanol solution obtained by diluting 3.60g (22. [53MMOL,] 1.50eq.) of Br2 with [1.] [4ML] of methanol was added to the solution, followed by stirring for 24hr with an internal temperature [OF 26-28C.] 3.5hr and 24hr after the start of the reaction, the progress of the reaction was checked by gas chromatography. The results are shown in Table 2. Table 2 Time Compound A1 B1 D 3. 5h 29. 2percent 53. 8percent 9. 5percent 24h 26. 0percent 45. 3percent 25. 3percent : Compound A Compound B Compound D 0 CH30 OCH3 0 Br I Br Br / CF) () CF3 CF-Br 3 3
General procedure: Ammonium carbonate (0.29 g, 3 mmol) was added to the appropriate aliphatic carboxylic acid (1 mL) and the mixture was stirred at 100 C for 30 minutes. The appropriate 1-aryl-2-bromoethanone (1 mmol) was added to the solution. Then the mixture was stirred for 15 minutes. The reaction was extracted with CH2Cl2, and the combined organic extracts were dried, filtered and concentrated under reduced pressure to give 2-alkyl-4(5)-aryl-1H-imidazoles.
With sodium hydroxide In ethanol; lithium hydroxide monohydrate at 20℃; for 0.583333h;
I-11.A
Intermediate 1-11Step A: To compound 1-11-1 (48.1 g, 180.1 mmol) and malonitrile (29.7mg, 450.0 mmol) was added ethanol (180 mL), and the reaction was stirred until dissolution. To the reaction solution was added an aqueous solution of NaOH (1 N, 180.1 mL). The reaction was vigorously stirred for 30 min under ambient conditions. To the completed reaction was added ethanol (180 mL), and the suspension was stirred for 5 min. The resulting solid was isolated by vacuum filtration and washed with a cold 50% EtOHZH2O solution to yield compound 1-11-2 as a white solid.
With sodium hydroxide In ethanol; lithium hydroxide monohydrate at 20℃; for 0.5h;
I11.A
To compound I-11-1 (48.1 g, 180.1 mmol) and malonitrile (29.7 mg, 450.0 mmol) was added ethanol (180 mL), and the reaction was stirred until dissolution. To the reaction solution was added an aqueous solution of NaOH (1 N, 180.1 mL). The reaction was vigorously stirred for 30 min under ambient conditions. To the completed reaction was added ethanol (180 mL), and the suspension was stirred for 5 min. The resulting solid was isolated by vacuum filtration and washed with a cold 50% EtOH/H2O solution to yield compound I-11-2 as a white solid.
With sodium hydroxide In ethanol
With sodium hydroxide In ethanol; lithium hydroxide monohydrate at 0℃; for 0.5h;
Example 156 (2S)-1-({2-[4-(4-Trifluoromethyl-phenyl)-thiazol-2-ylamino]-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile This compound was prepared in analogy to example 47, steps A] to C] starting from (2-thioureido-ethyl)-carbamic acid tert-butyl ester [CAS 331779-96-5], 4-(trifluoromethyl)phenacyl bromide and IIA. It was isolated as its free amine, as a white foam. MS (ISP): 424.4 (MH+).
5-chloro-1-(4-trifluoromethylphenacyl)pyrimidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; water; triethylamine;
EXAMPLE 14 5-Chloro-1-(4-trifluoromethylphenacyl)pyrimidin-2-one A suspension of <strong>[54326-16-8]5-chloropyrimidin-2-one</strong> (408 mg). and 2-bromo-4'-trifluoromethyl-acetophenone (824 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 45 mins. Water (100 ml) was added and the precipitate was collected. This solid was crystallized from acetone to give the title pyrimidinone (571 mg,); m.p. 243-245; lambdamaxEtOH 235.5 nm (epsilon 20040), 282 nm (epsilon 1880), 333.5 nm (epsilon 1860), lambdainf 287.5 nm (epsilon 1790).
Intermediate 11: 4-(4-Trifiuoromethyl-phenyl)-thiazol-2-ylamine.[0070] 2-Bromo-l-(4-trifluoromethyl-phenyl)-ethanone (10 g, 37.4 mmol) and thiourea (2.85 g, 37.4 mmol) are dissolved in dry acetone (100 mL) and heated at reflux for 2 h. The solution is cooled and stirred at rt for 2 h, then filtered and washed with acetone to give 4-(4-trifluoromethyl-phenyl)-thiazol-2-ylamine 11 (9.35 g, 100%) as white crystals. 1H-NMR (400 MHz, DMSOd6) δ = 8.30 (br. s, 2H), 7.98 (d, J = 8.0 Hz5 2H), 7.84 (d, J = 8.0 Hz, 2H)5 7.42 (s, IH). MS calcd. for Ci0H8F3N2S (M+H+) 245.0, found 245.1.
100%
In propan-2-one at 20℃; for 4h; Heating / reflux;
1
Intermediate 1; 4-(4-Trifluoromethyl-phenyl)-thiazol-2-ylamine; 2-Bromo-l-(4-trifluoromethyl-phenyl)-ethanone (10 g, 37.4 mmol) and thiourea (2.85 g, 37.4 mmol) are dissolved in dry acetone (100 mL) and heated at reflux for 2 h. The solution is cooled and stirred at rt for 2 h, then filtered and washed with acetone to give 4-(4- trifluoromethyl-phenyl)-thiazol-2-ylamine 1 (9.35 g, 100%) as white crystals. 1H-NMR (400 MHz, DMSOd6) δ = 8.30 (br. s, 2H), 7.98 (d, J= 8.0 Hz, 2H), 7.84 (d, J= 8.0 Hz, 2H), 7.42 (s, IH). MS calcd. for C10H8F3N2S (M+H+) 245.0, found 245.1.
97%
In ethanol for 2h; Reflux;
95%
In methanol at 20℃; for 3h;
91%
In ethanol for 12h; Reflux;
4 2.3 General procedure B for the synthesis of 4′-substituted-4-aryl-2-aminothiazoles (3a-g)
General procedure: A mixture of 4′-substituted-2-bromo acetophenones 2a-g (1 mmol) and thiourea (1.2 mmol, 0.0912 g) was refluxed in ethanol for 12h. Then, the reaction mixture was cooled and poured slowly into ice-cold water with constant stirring. The precipitate obtained was filtered, washed and dried. The crude product was recrystallized from ethanol to afford 4′-substituted 2-aminothiazoles 3a-g. The completion of reaction was monitored by TLC.
91.7%
In ethanol at 80℃; for 3h;
1.1. Chemistry experimental procedure A of intermediates 3a-j
General procedure: Some of the intermediates 3a-j were commercially unavailable or expensive, so the compounds were obtained by the following chemistry experimental procedure A. To a solution of bromoacetophenone analogue (1 mmol) in anhydrous ethanol (30 mL), thiourea (1 mmol) was added, and the mixture solution was stirred at 80 °C for 3 h. The completion of the reaction was monitored by TLC. The mixed solution was concentrated under reduced pressure to remove the solvent, and the saturated NaHCO3 solution was added to adjust the pH to 8~9. Large amounts of solids were observed to precipitate out of the solution. The solid was collected by suction filtration, washed with anhydrous ethanol and dried in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography eluting with a gradient of ethyl acetate/petroleum ether mixture to afford pure intermediates 3a-j
91.7%
In ethanol at 80℃; for 3h;
1.1. Chemistry experimental procedure A of intermediates 3a-j
General procedure: Some of the intermediates 3a-j were commercially unavailable or expensive, so the compounds were obtained by the following chemistry experimental procedure A. To a solution of bromoacetophenone analogue (1 mmol) in anhydrous ethanol (30 mL), thiourea (1 mmol) was added, and the mixture solution was stirred at 80 °C for 3 h. The completion of the reaction was monitored by TLC. The mixed solution was concentrated under reduced pressure to remove the solvent, and the saturated NaHCO3 solution was added to adjust the pH to 8~9. Large amounts of solids were observed to precipitate out of the solution. The solid was collected by suction filtration, washed with anhydrous ethanol and dried in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography eluting with a gradient of ethyl acetate/petroleum ether mixture to afford pure intermediates 3a-j
In ethanol for 2h; Reflux;
5.1.2. General procedure for the synthesis of 4-(2-chlorophenyl)thiazol-2-amine
General procedure: The crude 2-bromo-1-(2-chlorophenyl)ethanone (0.64 mL, 4.28 mmol) was dissolved in anhydrous ethanol (10 mL) and treated with thiourea (344 mg, 4.51 mmol). After heating at reflux for 2 h, the reaction mixture was cooled to room temperature, with a yellow precipitation. The solid obtained was filtered, washed with water and ethanol and vacuum dried to afford 4b as a yellow solid (884 mg, 98.0%).
With copper (II) bromide In ethanol for 2h; Reflux;
3-[4-({(5,6,7,8-tetrahydronaphthalen-2-yl)-[4-(4-trifluoromethylphenyl)thiazol-2-yl]amino}methyl)benzoylamino]propionic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: Fmoc-β-Ala-Wang resin With piperidine In 1-methyl-pyrrolidin-2-one for 0.666667h; solid phase reaction;
Stage #2: 4-Carboxybenzaldehyde With benzotriazol-1-ol; diisopropyl-carbodiimide In 1-methyl-pyrrolidin-2-one; acetonitrile at 20℃; for 16h; solid phase reaction;
Stage #3: 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone; 6-amino-1,2,3,4-tetrahydronaphthalene; 9-fluorenylmethoxycarbonyl isothiocyanate Further stages;
With diethylamino-sulfur trifluoride for 168h; Neat (no solvent);
4
Scheme 5 (above) depicts the synthesis of fluorinated PYT compound E-12.E-6 was halogenated (using, e.g., n-bromosuccinimide (NBS)) in the presence of a catalyst (e.g., PTSA) to provide alpha-halo compound E-7. Exposure of E-7 to a suitable fluorinating reagent (e.g., diethylaminosulfur trifluoride (DAST)) afforded gem-difluoro compound E-8. The alpha halide moiety of E-8 could then be displaced using an azide salt (e.g., sodium azide) to afford compound E-9. Reduction of the azide group of E-9 using a suitable reducing agent (e.g., Pd(OH)2/C) under acidic conditions provided the corresponding amine salt E-IO. Addition of a suitably activated carbonate (e.g., bis(trichloromethyl)carbonate) to amine E-IO under basic conditions produced urea E-Il, which could then react with malonic acid, or a derivative thereof, to generate PYT compound E-12
Preparation 50 2-amino-1-[4-(trifluoromethyl)phenyl]ethan-1-one hydrochloride 2-bromo-1-[4-(trifluoromethyl)phenyl]ethan-1-one (2.7 g, 10.11 mmol) was dissolved in acetonitrile (45 mL), then Sodium diformylamide (1.105 g, 11.62 mmol) was added one pot. The mixture was stirred ar RT for 2 hrs, then at 70 C. for 2 hrs. The solvent was removed and EtOH (35 mL) was added, followed by conc. HCl 37% (5.9 mL) and the reaction was stirred at reflux for 1.5 hr. The precipitate was filtered and dried to give 2-amino-1-[4-(trifluoromethyl)phenyl]ethan-1-one hydrochloride (p50, 2.3 g, y=95%) as white solid. MS (m/z): 204.1 [MH]+.
A mixture of 4'-(trifluoromethyl)phenacyl bromide (1.50 g, 5.62 mmol) and ethylmalonate monoamide (1.84 g, 14.05 mmol) was heated at 130C for 2 h. Water was added and the mixture was washed with EtOAc (3 x 100 mL). The combined organic layers were washed with water and brine, dried over a2S04, filtered and concentrated in vacuo. The crude residue was purified by silica chromatography (2% EtOAc/hexane) to afford ethyl 2-(4-(4-(trifluoromethyl)phenyl)oxazol-2-yl)acetate (0.73 g, 43%).
With sodium hydrogencarbonate In ethanol for 8h; Reflux;
4
General procedure: To a solution of 2-aminoheteroarene (10mmol) in ethanol (50mL), phenacyl bromide (10mmol) and NaHCO3 (30mmol) were added at rt and the reaction mixture was refluxed for 8h. On removal of solvent, the residue was dissolved with ethyl acetate (100mL) and washed with water (50mL), brine (50mL), and dried over sodium sulfate. The solvent was evaporated to give crude product, which was purified by combiflash chromatography (1-20% EtOAc/PE) to give the desired product 3-(4-bromophenyl)-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b]thiazole (4f) Isolated yield 41%; Rf (1:4 EtOAc/PE) 0.71; off white solid: mp 192-194 °C; 1H NMR (300 MHz, CDCl3) δ (ppm): 6.86 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.94 (s, 1H), 7.96 (d, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ (ppm): 108.1, 109.4, 122.5, 124.0, 125.3 (*2C), 125.8 (q), 128.4, 128.6, 129.0, 129.5, 131.5, 132.7, 137.4, 146.5, 150.5; HRMS (ESI): m/z [M+H]+ calcd for C18H11BrF3N2S: 422.9773, found 422.9768; HPLC: 99.2%.
4-(4-(trifluoromethyl)phenyl)-N-(4-methlphenlyl)thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In ethanol; at 70℃;
General procedure: The properly substituted bromoacetophenone 4, 6-15, 17-19 (1 equiv) and thioureas a-n (1 equiv) were solubilized in dry ethanol (5mLmmol-1 of bromoacetophenone) and reacted at 70C until consumption of the starting materials as indicated by TLC. After cooling, the solvent was evaporated and the residue obtained was washed with diethyl ether (3×10mL) to give the title compounds as a powder in good overall yields. In some cases, the crude material was purified by flash column chromatography. Yields, purification methods and purity are reported in details in the SI. Analytical data for compounds n, 6a, 8a, 15a, matched the data published previously [27,33,32,31].
5-bromo-1-[2-oxo-2-(4-trifluoromethylphenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
A solution of 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone (160 mg, 0.59 mmol), 2-bromo-1-(4-(trifluoromethyl)phenyl)ethanone (160 mg, 0.59 mmol,) and potassiumcarbonate (100 mg, 0.72 mmol,) in N,N-dimethylformamide (3 mL) was stirred at room temperature overnight. The reaction mixture was quenched with water and was extracted with diethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The remaining brown oil was purified by flash chromatography (12 g column, 0-15%) ethyl acetate/hexanes) to afford 5-bromo- 1 -[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (125 mg, 64%) as light yellow solid. 1H NMR (chloroform-d) oe ppm 8.13 (d, J= 8.0 Hz, 2H), 7.82 (d, J= 8.3 Hz, 2H), 7.05 (d, J 1.8 Hz, 1H), 6.87 (d, J 1.8 Hz, 1H), 5.73 (s, 2H), 3.75 (s, 3H).
In toluene; at 150℃; for 0.5h;Microwave irradiation;
To Cbz-Gly-NH2 (0.98 g, 4.7 mmol) and 4-trifluoromethylphenacylbromide (0.50 g, 1.9 mmol) was added toluene (3.7 mL), and the mixture was stirred with heating in a microwave reactor at 150 C. for 30 min. Ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration. Ethanol (3 mL) and a catalytic amount of 10%-palladium/carbon were added to the obtained solid, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL). 4 mol/L Hydrochloric acid/1,4-dioxane solution (1.5 mL) was added, and the mixture was concentrated under reduced pressure. 1,4-Dioxane and diethyl ether were added to the obtained residue, and the mixture was cooled at 0 C. for 3 hr. The precipitated solid was collected by filtration to give the title compound as a gray powder (99 mg, 0.36 mmol, 19%)
{5-[4-(trifluoromethyl)phenyl]imidazol-2-yl}methylcarbamic acid phenylmethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: N-(Benzyloxycarbonyl)glycine With caesium carbonate In 1-methyl-pyrrolidin-2-one at 20℃; for 1h;
Stage #2: 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone In 1-methyl-pyrrolidin-2-one at 20℃; for 0.5h;
Stage #3: With ammonium acetate In 1-methyl-pyrrolidin-2-one at 120℃; for 4h;
R.8.1 Synthesis of {5-[4-(trifluoromethyl)phenyl]imidazol-2-yl}methylcarbamic acid phenylmethyl ester
To Cbz-Gly-OH (0.15 g, 0.72 mmol) and cesium carbonate (0.12 g, 0.36 mmol) was added N-methylpyrrolidinone, and the mixture was stirred at room temperature for 1 hr. 4-Trifluoromethylphenacylbromide (0.19 g, 0.72 mmol) was added, and the mixture was stirred at room temperature for 30 min. Thereafter, xylene (3.2 mL) and ammonium acetate (1.2 g, 16 mmol) were added, and the mixture was stirred at 120° C. for 4 hr. After allowing to cool to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was washed twice with saturated aqueous sodium carbonate solution. The obtained organic layer was dried over sodium sulfate. The desiccant was filtered off, the solvent was evaporated, and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound as an orange powder (0.23 g, 0.61 mmol, 86%). MS (ESI) m/z 376 (M+H)+
2-amino-6-(4-trifluoromethylphenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With triethylamine; In 1,4-dioxane; for 24h;Reflux; Inert atmosphere;
General procedure: The starting materials 1 and 2 (10 mmol each) were mixed with 40 ml of 1, 4-dioxane. Et3N (10 mmol), was added all at once at room temperature. The reaction was stirred vigorously to ensuremixing, and subsequently refluxed at high heat. Note: Thick slurry might form initially at the bottom of theflask. Regardless, continue heating at reflux for the indicated amount of time, to ensure completion of the reaction. The reaction mixture was removed from the heat and allowed to reach room temperature. It was evaporated under vacuum to remove the solvent. The residue was quenched with 50 ml of cold water, andmaintained at room temperature for one hour. Subsequently, it was stirred vigorously until a fine precipitate was formed. The precipitate was filtered under vacuum, washed well with 3 x 50 ml of water, and dried under vacuum overnight. In most cases, this procedure gives a product that is pure for all practical synthetic and analytical purposes. Procedures for 3k and 3l required chromatographic purification, and are described indetails.
Multi-step reaction with 4 steps
1.1: hexamethylenetetramine / chloroform / 16 h / 20 °C
1.2: 12 h / 20 °C
2.1: sodium tetrahydroborate / methanol / 0.5 h / 0 °C
3.1: triethylamine / dichloromethane / 1 h / 0 °C
4.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / 0 - 20 °C
Multi-step reaction with 4 steps
1.1: sodium diformamide / acetonitrile / 4 h / 20 - 70 °C
1.2: 1.5 h / Reflux
2.1: sodium tetrahydroborate; methanol / 0.5 h / 0 °C
3.1: sodium hydroxide / water; dichloromethane / 2.5 h / 0 - 20 °C
4.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 - 20 °C
Multi-step reaction with 4 steps
1: sodium tetrahydroborate; methanol / 1 h / Inert atmosphere; Cooling with ice
2: ammonia / methanol / 48 h / 20 °C / Inert atmosphere
3: triethylamine / dichloromethane / 17 h / 20 °C / Inert atmosphere; Cooling with ice
4: potassium carbonate / N,N-dimethyl-formamide / 36 h / 20 - 60 °C / Inert atmosphere
7-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethoxy)-4-(trifluoromethyl)-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With triethylamine; In tetrahydrofuran; at 20℃; for 24h;
General procedure: The appropriate bromoketone (6a-o) (1.7 mmol) and triethylamine (1.6 mmol) were added to as olution of either7-hydroxy-4-methyl-2H-chromen-2-one 4 (1.4 mmol)or <strong>[575-03-1]7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one</strong> 5 (1.4 mmol) in THF (20 mL). The mixture was stirred at room temperature for 24h, filtered and the solvent was evaporated under reduced pressure.The solid residue was purified by column chromatography eluting with DCM/MeOH 9:1 to afford (7a-n) and (8a-o).
8-bromo-3-[4-(trifluoromethyl)phenyl]-2H-1,4-benzoxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate In dichloromethane; water at 20℃;
A Step A: 8-bromo-2-(4-(trifluoromethyl)phenyl)-2H-benzo[b][l,4]oxazine
Step A: 8-bromo-2-(4-(trifluoromethyl)phenyl)-2H-benzo[b][l,4]oxazine Into a 3-L 3-necked round-bottom flask were placed a solution of 2-amino-6- bromophenol (56.3 g, 299.43 mmol, 1.00 equiv) in dichloromethane (600 mL), BU4NSO4H (5 g, 1.05 equiv), aq K2CO3 (207 mL, 1.00 equiv, 20%). This was followed by the addition of a solution of 2-bromo-l-[4-(trifluoromethyl)phenyl]ethan-l-one (80 g, 299.58 mmol, 1.00 equiv) in dichloromethane (200 mL) dropwise with stirring at room temperature. The resulting solution was stirred overnight at room temperature. Then it was diluted with 500 mL of water and extracted with 3x500 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The crude product was re-crystallized from EA/Hexane (1 : 10) to give 8-bromo-3-[4-(trifluoromethyl)phenyl]-2H-l,4-benzoxazine as a solid.
6-bromo-3-(4-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]thiazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate In dichloromethane; water at 20℃; for 20h;
99.A Step A: 6-bromo-3 -(4-(trifluoromethyl)phenyl)-2H-benzo [b] [ 1 ,4]thiazine
Step A: 6-bromo-3 -(4-(trifluoromethyl)phenyl)-2H-benzo [b] [ 1 ,4]thiazine To a solution of 2-amino-4-bromobenzenethiol (1 g, 4.90 mmol) in DCM (20 mL) were added K2CO3 (15 mL, 4.45 mmol) in water (15 mL) and tetrabutylammonium hydrogen sulfate (0.015 g, 0.045 mmol), then 2-bromo- 1 -(4-(trifluoromethyl)phenyl)ethanone (1.190 g, 4.45 mmol) in DCM (5 mL) was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature for 20 h. LCMS showed the desired compound was formed, then the mixture was extracted with DCM (100 mL*3). The combined organic layers were washed with brine (100 mL*3), dried over Na2S04, filtered and concentrated in vacuo to give 6-bromo-3-(4- (trifluoromethyl)phenyl)-2H-benzo[b][l,4]thiazine as an oil, which was used in the next step directly. LC/MS (m/z): 373 (M+H)+.
5-bromo-3-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoxaline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; In methanol; at 20℃;
Step B: 5-bromo-3-(4-(trifluoromethyl)phenyl)-l,2-dihydroquinoxaline To a solution of 3-bromobenzene-l, 2-diamine (370 mg, 1.978 mmol) in MeOH (15 mL) was added sodium acetate (162 mg, 1.978 mmol), then 2-bromo-l-(4- (trifluoromethyl)phenyl)ethanone (528 mg, 1.978 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. TLC (Petroleum ether: EtOAc =5: 1) showed that the reaction was complete. The reaction mixture was diluted by water (20 mL) and extracted by EtOAc (3*20 mL). The organic layers were dried over Na2S04 and evaporated under reduced pressure to give 5-bromo-3-(4-(trifluoromethyl)phenyl)-l,2-dihydroquinoxaline as a solid, which was directly used in the next step.
8-fluoro-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium hydrogencarbonate; In toluene; for 12h;Reflux;
General procedure: A mixture of appropriately substituted pyridin-2-amine (10 mmol), 2-bromoacetophenone (10 mmol), and sodium bicarbonate (15 mmol) in anhydrous toluene (25 mL) was stirred for 12 h under reflux. After removal of toluene under vacuum, dichloromethane was added to the residue and any insoluble was removed by filtration. The crude products were crystallized from methanol or purified by silica gel chromatography using hexane/ethylacetate, 7:3 (v/v) as eluent.
2-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroimidazo[2,1-b]benzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
In ethanol; at 150℃; for 0.333333h;Microwave irradiation;
30 mg (0.19 mmol) of 4,5,6,7-tetrahydrobenzo [d] thiazol-2-amine and (2-Bromo-4-trifluoromethylacetophenone(50 mg, 0.19 mmol) was added to a solution of dissolved in 3 ml of ethanol and stirred in a microwave reactor at 150 C for 20 minutes. The residue was concentrated under reduced pressure and subjected to column chromatography (EtOAc: Hex = 1: 4) to obtain Compound 2e (15 mg, 24%).
2-methyl-7-[4-(trifluoromethyl)phenyl]-8H-pyrrolo[2,3-e]benzoxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With <i>N</i>,<i>N</i>-dimethyl-aniline In 5,5-dimethyl-1,3-cyclohexadiene at 170℃; for 17h;
46.c c) 2-Methyl-7-[4-(trifluoromethyl)phenyl]-8H-pyrrolo[2,3-e]benzoxazole
A solution of the compound obtained in h) (5.25 g, 35.43 mmol), and 4-trifluoromethylphenacyl bromide (9.46 g, 35.43 mmol) in N,N-dimethylaniline (20 mL) and xylene (40 mL) was stirred at 170° C. for 17 hours. After the reaction mixture was left to cool, 2 N hydrochloric acid was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting crystals were washed with methanol, and collected by filtration to obtain crystals of the title compound (1.95 g, yield 17%). 1H-NMR (CDCl3) δ: 2.69 (3H, s), 7.03 (1H, d, J=2.3 Hz), 7.32 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=8.9 Hz), 7.70 (2H, d, J=8.9 Hz), 7.77 (2H, d, J=8.6 Hz), 9.25 (1H, br)
3-(pyridin-4-yl)-4-[4-(trifluoromethyl)phenyl]-2,5-dihydrofuran-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
45% yield. White amorphous solid. 113 4-pyridylacetic acid hydrochloride (1mmol) was dissolved in dry 114 methanol (10mL), and 115 potassium tert-butoxide (2mmol) was added. The resultant mixture was stirred for 15min under Ar atmosphere. The solvent was then removed, and the remaining solid redissolved in dry 116 DMF (10mL). 98 4-(Trifluoromethyl)phenacyl bromide (1mmol) was added to the solution, and the reaction mixture was stirred for 1h. The mixture was extracted with ethyl acetate (50mL) and water (100mL). The organic layer was dried over sodium sulfate, and the solvent removed. The product was purified by silica gel column chromatography using 117 hexane: 118 ethyl acetate 40:60 as a mobile phase. 1H NMR (500MHz, CDCl3) delta 8.71-8.59 (m, 2H), 7.75-7.60 (m, 2H), 7.46-7.39 (m, 2H), 7.36-7.32 (m, 2H), 5.19 (s, 2H); 13C NMR (125MHz, CDCl3) delta 171.4, 157.2, 150.4, 137.8, 133.8, 133.5, 133.2, 132.9, 132.7, 129.1, 127.9, 126.7, 126.4, 126.4, 126.4, 126.3, 125.9, 124.5, 123.5, 122.4, 70.7; HRMS (TOF-ESI+) m/z calcd for C16H10F3NO2+ 306,0736; found 306,0742; LRMS (APCI+): m/z (relative intensity) 306.4 [M+H]+; Anal. Calc. for C16H10F3NO2: C, 50.03; H, 2.36; N, 3.65; found: C, 50.04; H, 2.39, N, 3.57.
7-(4-(trifluoromethyl)phenyl)imidazo[2,1-c][1,2,4]triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate; In ethanol; for 4h;Inert atmosphere; Reflux;
General procedure: Under an argon atmosphere, <strong>[1120-99-6]3-amino-1,2,4-triazine</strong> (100mg, 1,04mmol) and K2CO3 (173mg, 1,25mmol) were added to a solution of 2-bromo(substituted)acetophenone (1,14mmol) in EtOH (2mL). The resulting solution was heated to reflux for 4h and then cooled down to r.t. After concentration under reduced pressure, the residue was diluted with CH2Cl2 (10mL), the CH2Cl2 layer was washed with H2O (2×10mL), and dried (MgSO4). After filtration and concentration under reduced pressure, the crude was purified by flash chromatography on silica gel (EtOAc-PE, 1:9 to 4:6).
ethyl 6-chloro-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
In N,N-dimethyl-formamide; at 60.0℃; for 4.0h;
Ethyl 3-amino-6-chloropyridazine-4-carboxylate (270 mg, 1.339 mmol) was added to 2- bromo-l-(4-(trifluoromethyl)phenyl)ethanone (358 mg, 1.339 mmol) in DMF (6 mL). The solution was heated at 60 C for 4 h. The resulting orange liquid was partitioned between ether (30 mL) and saturated aq. NaHCC solution (20 mL). The organic layer was washed with water (20 mL) and saturated aq. NaCl solution (20 mL), dried over MgS04, filtered and concentrated. The residue was purified by column chromatography on silica gel (5? 20% ethyl acetate in hexanes; 40 g column) to afford ethyl 6-chloro-2-(4-(trifluoromethyl)phenyl)imidazo[l,2-)]pyridazine-8-carboxylate (190 mg, 0.514 mmol, 38% yield) as a yellow solid: NMR (400MHz, DMSO-de) delta 9.23 (s, IH), 8.31 (d, J=8.0 Hz, 2H), 7.89 (d, J=8.0 Hz, 2H), 7.79 (s, IH), 4.49 (q, J=7.1Hz, 2H), 1.42 (t, J=7.2 Hz, 3H); LCMS (ESI) m/e 370.0 [(M+H) + , calcd for C16H12N3O2F3CI 370.1].
2,9,10-trimethoxy-3-p-trifloromethylphenylformylmethylenoxyprotoberberine chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: To a stirred solution of JTH (100 mg, 0.29 mmol) in anhydrous CH3CN or DMF, K2CO3 (122 mg,0.88 mmol) was added and heated to 70 °C. Then R1Br or benzyl chloroformate (2?4 eq) was added andstirred for 5?6 h. The mixture was cooled to precipitate completely, filtrated and washed by CH2Cl2 toafford compounds 5a?g.
2-(4-chlorophenyl)-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
In ethanol for 18h; Reflux;
General procedure for the synthesis of 6-(4-substituted phenyl)-2-(4-substituted phenyl)imidazo[2,1-b][1,3,4]thiadiazole 5a-l
General procedure: To a solution of 5-(4-substituted phenyl)-1,3,4-thiadiazole-2-amine 3a-l (0.01 mol) in 10 mLabsolute ethanol, the corresponding phenacyl bromide was added (0.02 mol). The mixture wasrefluxed for 18 h or more, depending of the reaction progress, monitored by TLC. After the reactionwas complete, the mixture was filtered and the solid hydrobromide was collected. The precipitatewas neutralized by aqueous sodium carbonate solution, filtered and purified by recrystallization or bycolumn chromatography to remove unwanted products. The purification method is indicated belowfor each individual compound.
2-(4-methoxyphenyl)-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
In ethanol; for 18h;Reflux;
General procedure: To a solution of 5-(4-substituted phenyl)-1,3,4-thiadiazole-2-amine 3a-l (0.01 mol) in 10 mLabsolute ethanol, the corresponding phenacyl bromide was added (0.02 mol). The mixture wasrefluxed for 18 h or more, depending of the reaction progress, monitored by TLC. After the reactionwas complete, the mixture was filtered and the solid hydrobromide was collected. The precipitatewas neutralized by aqueous sodium carbonate solution, filtered and purified by recrystallization or bycolumn chromatography to remove unwanted products. The purification method is indicated belowfor each individual compound.
General procedure: Hantasch condensation reaction of 4-trifluoromethylbromoacetophenone (A) with N-Boc-piperidine 4-thioamide (B) in protic solvent ethanol to form thiazole ring intermediate (C );Then, the Boc group is removed under strong acid TFA conditions to obtain a compound (D) and a reductive amination reaction with 5-nitrofurfural (C) to obtain a final product F.
3-(4-hydroxy-3-(hydroxymethyl)butyl)-6-(4-(trifluoromethyl)phenyl)-3,5-dihydro-9H-imidazo[1,2-a]purin-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
General procedure: To a suspension of penciclovir (6) or hydroxybutylguanine (7)(0.2 g, 0.8 mmol or 0.9 mmol, respectively) in dry dimethylformamide(16 mL), sodium hydride (60% suspension in mineral oil, 1.2 eq.) wasadded and the reaction stirred at room temperature (21 C) for 1.5 h.Bromoketone (8) (1.3 eq.) was then added and the reaction stirred for6 h. Aqueous ammonia (25% solution 5 mL) was added to quench thereaction, which was concentrated under reduced pressure and the residualoil purified by flash column chromatography using gradientelution (CH2Cl2-MeOH). The obtained products were recrystallisedfrom a mixture of CH2Cl2 and MeOH.
With sodium hydroxide In dimethyl sulfoxide at 20℃;
II-1 [Production Example II-1] Preparation of Compound II-f1
After dissolving 4-(trifluoromethyl)phenylacetic acid in anhydrous DMSO and sodium hydroxide, it was reacted with 2-bromo-4'-trifluoromethylacetophenone at room temperature.Compound II-f1 was obtained (83%).
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 3h; Inert atmosphere;
General Procedure A: Synthesis of Starting Material
General procedure: Phenacyl bromide and Fluorobenzoic acid (1.1 equiv.) was dissolved in MeCN (0.1 M). To the solution was added N,N-diisopropylethylamine (DIPEA, 2 equiv.) dropwise with stirring. The solution was stirred for 3 h (monitored by TLC) at room temperature and then evaporated. The residue was purified by column chromatography to afford the desired ester 1
2-(bromomethyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With toluene-4-sulfonic acid In toluene Reflux;
24.1 1) Synthesis of 2-(bromomethyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxane (II):
When equipped with a condenser,Add 2-bromo-4'-trifluoromethylacetophenone (10.0mmol),2-methyl-1,3-propanediol (12.0mmol),P-toluenesulfonic acid (0.20g, 1.16mmol), toluene (13mL) as the solvent, heating to reflux, TLC (VEA/VPE=1/10) to follow the reaction, after the completion of the reaction, transfer the reaction solution to a separatory funnel, wash with water , The organic phase is dried with anhydrous sodium sulfate, filtered,Spin dry toluene to obtain 2-(bromomethyl)-5-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxane;
2-(bromomethyl)-(4S)-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With toluene-4-sulfonic acid In toluene Reflux;
22.1 1) Synthesis of 2-(bromomethyl)-4S-methyl-2-(4-trifluoromethylphenyl)-1,3-dioxolane (II):
When equipped with a condenser,Add 2-bromo-4'-trifluoromethylacetophenone (10.0mmol),(S)-1-methyl-1,2-ethylene glycol (11.0mmol),P-toluenesulfonic acid (0.20g, 1.16mmol), toluene (13mL) as the solvent, heating to reflux, TLC (VEA/VPE=1/10) to follow the reaction, after the completion of the reaction, transfer the reaction solution to a separatory funnel, wash with water , The organic phase is dried with anhydrous sodium sulfate, filtered,Spin dry toluene to obtain 2-(bromomethyl)-4S-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxolane;
With potassium carbonate In propan-2-one at 60℃; for 6h;
1.4 (4) Synthesis of compound (R)-4
K2CO3(2.20g, 16.0 mmol), (R)-3 (0.68 g, 2.0 mmol), 2-bromo-4'-(trifluoromethyl)acetophenone (0.91 g, 4.8 mmol) and 30 ml acetone were added to a 100 ml monoglycerical flask. After 60 °C heating and stirring for 6h, it is cooled to room temperature. Distillation to remove solvents under reduced pressure, add 50 mL of water, extract with ethyl acetate (3×50 mL), combine the organic phase, add saturated brine (3×50 mL) to wash the organic phase, anhydrousNa2SO4dry, reduce pressure distillation to remove the solvent. The yellow powder was separated by 300~400 mesh silica gel and PE:DCM=1:1 eluent column chromatography, and then recrystallized by EA to obtain a yellow needle-like solid of 0.8g ((R)-4), with a yield of 59%.
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