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Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 7051-34-5 * 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.
With bromine; triphenylphosphine In <i>N</i>-methyl-acetamide
Example 1 (for comparison) 1250 ml of dimethylformamide were placed into the reaction vessel, and then 280.8 g of triphenylphosphine and then 70 g of hydroxymethylcyclopropane were added, the mixture was stirred for 30 minutes at room temperature under a nitrogen atmosphere, and the solution was subsequently cooled to -10° C. Then, 158.3 g of bromine (that is to say 2 mol percent more than theoretically required) were metered in in the course of 4 hours. The reaction mixture was worked up by distillation. Bromomethylcyclopropane was obtained in a yield of 77.5percent of theory. The purity of the product was over 97percent, the open-chain halogenoalkanes amounted to 0.6percent.
73%
With triphenyl phosphite; bromine In N,N-dimethyl-formamide at -12 - 20℃; Inert atmosphere; Large scale
10062] Into a clean, dry reactor equipped with a stirrer and under nitrogen are successively loaded 4.63 kg of DMF (5.1 eqV) and then 4.53 kg of triphenylphosphite. 2.34 kg of bromine is then introduced while maintaining the temperature at less than 12° C. The stirring speed is regulated according to the fluidity of the reaction medium. When casting ends, a very thick medium with a yellow solid suspension is obtained.10063] The set point of the jacket is then adjusted to —12° C. and then 0.96 kg of cyclopropylmethanol is introduced in such a way as not to exceed a temperature of —5° C. On completion of the addition the whole is allowed to return slowly to room temperature. The set point of the jacket is then adjusted to 64° C. for distillation, which is carried out at a pressure of 13 mbar by collecting the first 24 to 30° C. fraction at the top of the colunm, then the second 30 to 40° C. fraction (partial reflux). Two fractions, Fl (1.38 kg) and F2 (293 g), are collected. The two fractions, after washing with carbonated water and then drying by means of CaC12, lead to a final product 2a (mass 1.316 kg) having a GC relative purity of 98.7percent with a yield of 73percent.
95 %Spectr.
With 1-bromo-N,N,2-trimethyl-1-propen-1-amine In dichloromethane at 0 - 20℃; for 0.5 h; Inert atmosphere
General procedure: Tetramethyl haloenamines 2a, 3 or 4 (1.1 equiv) were added at 0 °C to a solution of cyclopropyl carbinol in dry dichloromethane, then left at room temperature for 30 min. The cyclopropyl halides were quickly distilled under vacuum (bath temperature 60 °C) to avoid the formation of cyclobutyl and homoallylic halides. The halides were identical to authentic samples.
Reference：
[1] Patent: US6008420, 1999, A,
[2] Patent: US2016/355452, 2016, A1, . Location in patent: Paragraph 0062; 0063
[3] Synthetic Communications, 1996, vol. 26, # 6, p. 1109 - 1115
[4] Journal of the Chemical Society, Chemical Communications, 1982, # 18, p. 1037 - 1039
[5] European Journal of Medicinal Chemistry, 1980, vol. 15, # 6, p. 571 - 573
[6] Chem. Zentralbl., 1911, vol. 82, # I, p. 66
[7] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1914, vol. 46, p. 43[8] Chem. Zentralbl., 1914, vol. 85, # I, p. 1998
[9] Journal of the American Chemical Society, 1955, vol. 77, p. 6675
[10] Journal of the American Chemical Society, 1977, vol. 99, # 10, p. 3408 - 3414
[11] Justus Liebigs Annalen der Chemie, 1966, vol. 697, p. 100 - 110
[12] Canadian Journal of Chemistry, 1970, vol. 48, p. 3953 - 3957
[13] Justus Liebigs Annalen der Chemie, 1975, p. 2305 - 2317
[14] Journal of Organic Chemistry, 1979, vol. 44, p. 2842 - 2845
[15] Journal of Organic Chemistry, 1984, vol. 49, # 3, p. 431 - 435
[16] Canadian Journal of Chemistry, 1980, vol. 58, p. 1075 - 1079
[17] Patent: US4511566, 1985, A,
[18] Tetrahedron, 2016, vol. 72, # 3, p. 420 - 430
[19] Patent: JP5979791, 2016, B2, . Location in patent: Paragraph 0036
3
[ 2516-33-8 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Yield
Reaction Conditions
Operation in experiment
74%
With hydrogen bromide In 1,4-dioxane; chloroform at 10 - 20℃; for 2 h;
A stirrer and a thermometer were attached to a 30 mL three-necked flask, and 0.36 g (5.0 mmol) of (hydroxymethyl) cyclopropane and 5 mL of chloroform were added, followed by cooling to 10 ° C. with stirring. Next, 2.77 g (6.5 mmol) of 19percent hydrogen bromide / 1,4-dioxane solution was added dropwise, and then the reaction solution was heated to room temperature and stirring was continued for 2 hours. GC analysis was carried out on the obtained reaction solution, whereby the target compound (bromomethyl) cyclopropane was obtained in a yield of 74percent. In this reaction, bromocyclobutane as an isomer was produced in a yield of 9percent, and 4-bromo-1-butene was produced in a yield of 2percent, respectively.
Reference：
[1] Patent: JP2017/14124, 2017, A, . Location in patent: Paragraph 0033
[2] European Journal of Medicinal Chemistry, 1980, vol. 15, # 6, p. 571 - 573
[3] Patent: JP5979791, 2016, B2, . Location in patent: Paragraph 0036-0038; 0042-0052
Reference：
[1] Journal of Organometallic Chemistry, 1974, vol. 73, p. 237 - 250
11
[ 931-82-8 ]
[ 7051-34-5 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1975, vol. 45, p. 1762 - 1767[2] Zhurnal Obshchei Khimii, 1975, vol. 45, # 8, p. 1796 - 1802
12
[ 186581-53-3 ]
[ 106-95-6 ]
[ 5162-44-7 ]
[ 7051-34-5 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1987, vol. 36, # 1, p. 119 - 122[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, # 1, p. 135 - 138
13
[ 36630-46-3 ]
[ 79-15-2 ]
[ 112515-11-4 ]
[ 7051-34-5 ]
Reference：
[1] Journal of Organometallic Chemistry, 1987, vol. 326, p. 281 - 288
14
[ 75-09-2 ]
[ 594-11-6 ]
[ 82621-80-5 ]
[ 5162-44-7 ]
[ 1194-33-8 ]
[ 75-27-4 ]
[ 107-80-2 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1988, vol. 110, # 10, p. 3221 - 3225
15
[ 2516-33-8 ]
[ 10035-10-6 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2509,2515
[2] Journal of Organic Chemistry, 1950, vol. 15, p. 74,77
16
[ 74-85-1 ]
[ 75-09-2 ]
[ 594-11-6 ]
[ 82621-80-5 ]
[ 5162-44-7 ]
[ 1194-33-8 ]
[ 75-27-4 ]
[ 106-93-4 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1988, vol. 110, # 10, p. 3221 - 3225
17
[ 75-09-2 ]
[ 2516-33-8 ]
[ 7789-60-8 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2509,2515
[2] Journal of Organic Chemistry, 1950, vol. 15, p. 74,77
18
[ 75-62-7 ]
[ 104877-17-0 ]
[ 5162-44-7 ]
[ 117153-45-4 ]
[ 117135-60-1 ]
[ 7051-34-5 ]
[ 67-64-1 ]
[ 627-70-3 ]
Reference：
[1] Canadian Journal of Chemistry, 1988, vol. 66, p. 11 - 16
19
[ 157-33-5 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1982, vol. 31, # 5, p. 961 - 964[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1982, # 5, p. 1080 - 1083
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1982, vol. 31, # 5, p. 961 - 964[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1982, # 5, p. 1080 - 1083
20
[ 506-68-3 ]
[ 18773-77-8 ]
[ 7051-34-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1925, vol. 445, p. 213
21
[ 756488-62-7 ]
[ 7789-69-7 ]
[ 100-47-0 ]
[ 7051-34-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1925, vol. 445, p. 213
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 5, p. 1592 - 1600
24
[ 7051-34-5 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 18, p. 6494 - 6505
25
[ 186581-53-3 ]
[ 106-95-6 ]
[ 5162-44-7 ]
[ 7051-34-5 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1987, vol. 36, # 1, p. 119 - 122[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, # 1, p. 135 - 138
26
[ 75-09-2 ]
[ 594-11-6 ]
[ 82621-80-5 ]
[ 5162-44-7 ]
[ 1194-33-8 ]
[ 75-27-4 ]
[ 107-80-2 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1988, vol. 110, # 10, p. 3221 - 3225
27
[ 2516-33-8 ]
[ 10035-10-6 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2509,2515
[2] Journal of Organic Chemistry, 1950, vol. 15, p. 74,77
28
[ 74-85-1 ]
[ 75-09-2 ]
[ 594-11-6 ]
[ 82621-80-5 ]
[ 5162-44-7 ]
[ 1194-33-8 ]
[ 75-27-4 ]
[ 106-93-4 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1988, vol. 110, # 10, p. 3221 - 3225
29
[ 75-09-2 ]
[ 2516-33-8 ]
[ 7789-60-8 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2509,2515
[2] Journal of Organic Chemistry, 1950, vol. 15, p. 74,77
30
[ 75-62-7 ]
[ 104877-17-0 ]
[ 5162-44-7 ]
[ 117153-45-4 ]
[ 117135-60-1 ]
[ 7051-34-5 ]
[ 67-64-1 ]
[ 627-70-3 ]
Reference：
[1] Canadian Journal of Chemistry, 1988, vol. 66, p. 11 - 16
31
[ 157-33-5 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1982, vol. 31, # 5, p. 961 - 964[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1982, # 5, p. 1080 - 1083
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1982, vol. 31, # 5, p. 961 - 964[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1982, # 5, p. 1080 - 1083
32
[ 41979-39-9 ]
[ 7051-34-5 ]
[ 49682-96-4 ]
Yield
Reaction Conditions
Operation in experiment
62%
With sodium carbonate In acetonitrile at 85℃; for 16 h;
Example 192; f 5- 1-Cyclopropylmettlyl-piperidin-4-yloxy)-lH-indol-2-yll-morpholin-4-yl-methanone; a) Step 1: 1-Cyclopropylmethyl-piperidin-4-one; To a suspension of (bromomethyl)cyclopropane (500 mg, 4 mmol, 1.0 eq. ) and 4- piperidone hydrate hydrochloride (579 mg, 4 mmol, 1.0 eq. ) in acetonitrile (30 mL) was added sodium carbonate (1.148 g, 11 mmol, 3. eq. ). The reaction mixture was stirred 16 h at 85 °C. The resulting suspension was filtered and the solid was washed with acetonitrile. The filtrate was concentrated in vacuo and purified by column chromatography on silica eluting with DCM/2N NH3 in methanol 97: 3 to yield 339 mg (62 percent) of the title compound as yellow oil. MS (m/e): 154.2 (MH+, 100percent).
56%
With sodium carbonate In water; acetonitrile at 85℃;
Preparation 18: r-Cyclopropylmethyl-l,4'-bipiperidin-4-amine hydrochloride; [0130] A round bottom flask was charged with piperidin-4-one hydrochloride monohydrate (10 g, 65.1 mmol), acetonitrile (70 mL), bromomethylcyclopropane (8.79 g, 65.1 mmol), and sodium carbonate (20.7 g, 195.3 mmol). This mixture was heated overnight at 850C, then cooled, filtered and the filtrate concentrated. The product was purified by flash chromatography (16O g column, 0-7percent 2N NH3 in MeOH : DCM) to give l-(cyclopropylmethyl)piperidin-4-one as a yellow liquid (5.6 g, 56 percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.09 - 0.17 (m, 2 H) 0.52 - 0.59 (m, 2 H) 0.85 - 0.97 (m, 1 H) 2.38 (d, J=6.57 Hz, 2 H) 2.49 (t, J=6.19 Hz, 4 H) 2.84 (t, J=6.19 Hz, 4 H). MS (ES) [M+H] calculated for C30H37N9O2, 556; found 556. MS (ES) [M+H] calculated for C9Hi5NO, 154; found 154.[0131] To a solution of l-(cyclopropylmethyl)piperidin-4-one (750 mg, 4.9 mmol) and A- (BOC amino)piperidine (982 mg, 4.9 mmol) in THF (30 mL) was added AcOH (20 drops) and sodium triacetoxyborohydride (3.1 g, 14.7 mmol). This solution was allowed to stir overnight. Water (40 mL) was then added to the reaction, the layers separated, and the organic discarded. The aqueous layer was basified with sodium carbonate (10 mL sat.) and the product extracted into EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to give tert-bvXy\\ r-(cyclopropylmethyl)-l,4'-bipiperidin-4- ylcarbamate (513 mg, 31 percent yield). MS (ES) [M+H] calculated for Ci9H35N3O2, 338; found 338. tert-Butyl r-(cyclopropylmethyl)-l,4'-bipiperidin-4-ylcarbamate (513 mg, 1.52 mmol) was dissolved in MeOH (15 mL), HCl was added (2 mL cone.) and the mixture was heated to 70 0C for 3 hours. The mixture was then cooled and the product was filtered off, washed with diethyl ether, and dried to yield the title compound (530 mg, quant, yield) as a white solid. MS (ES) [M+H] found 238.
With hydrogen bromide In 1,4-dioxane; chloroform at 10 - 20℃; for 2 h;
A stirrer and a thermometer were attached to a 30 mL three-necked flask, and 0.36 g (5.0 mmol) of (hydroxymethyl) cyclopropane and 5 mL of chloroform were added, followed by cooling to 10 ° C. with stirring. Next, 2.77 g (6.5 mmol) of 19percent hydrogen bromide / 1,4-dioxane solution was added dropwise, and then the reaction solution was heated to room temperature and stirring was continued for 2 hours. GC analysis was carried out on the obtained reaction solution, whereby the target compound (bromomethyl) cyclopropane was obtained in a yield of 74percent. In this reaction, bromocyclobutane as an isomer was produced in a yield of 9percent, and 4-bromo-1-butene was produced in a yield of 2percent, respectively.
Reference：
[1] Patent: JP2017/14124, 2017, A, . Location in patent: Paragraph 0033
[2] European Journal of Medicinal Chemistry, 1980, vol. 15, # 6, p. 571 - 573
[3] Patent: JP5979791, 2016, B2, . Location in patent: Paragraph 0036-0038; 0042-0052
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 18, p. 6494 - 6505
40
[ 2516-33-8 ]
[ 10035-10-6 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2509,2515
[2] Journal of Organic Chemistry, 1950, vol. 15, p. 74,77
41
[ 75-09-2 ]
[ 2516-33-8 ]
[ 7789-60-8 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2509,2515
[2] Journal of Organic Chemistry, 1950, vol. 15, p. 74,77
42
[ 157-33-5 ]
[ 5162-44-7 ]
[ 4399-47-7 ]
[ 7051-34-5 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1982, vol. 31, # 5, p. 961 - 964[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1982, # 5, p. 1080 - 1083
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1982, vol. 31, # 5, p. 961 - 964[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1982, # 5, p. 1080 - 1083
43
[ 594-61-6 ]
[ 7051-34-5 ]
[ 19444-23-6 ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 5 - 20℃; for 1 h; Stage #2: With potassium iodide In N,N-dimethyl-formamide at 100℃; for 3 h; Microwave irradiation
To a solution of 2-hydroxy-2-methylpropanoic acid (500 mg, 4.80 mmol) in dry THF (10 ml), NaH (60percent dispersion in mineral oil, 192 mg, 4.80 mmol) was added portionwise at 5°C. The resulting mixture was stirred lh at RT. The solvent was removed, the residue was suspended in dry DMF (7 ml) and (bromomethyl)benzene (821 mg, 4.80 mmol) was added followed by a catalytic amount of KI. The reaction was heated under microwave irradiation at 100°C for 3h. After cooling the solvent was evaporated and the residue was partitioned between water and EtOAc; the organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (EtO Ac/petroleum ether = 1/1) affording benzyl 2-hydroxy-2- methylpropanoate as a yellow liquid (773 mg, 3.98 mmol, 83percent yield).
20 g (0.148 mol) of cyclopropylmethyl bromide, 39.3 g (0.15 mol) of triphenylphosphine and 30 ml of DMF were simultaneously charged into a 250 ml three-necked flask and the temperature was maintained at 100 to 110 ° C. for 6 hours The temperature was lowered to 50 ° C., After placing in 200 ml of ethyl acetate and stirring, a large amount of white solid appeared and was filtered to give 34 g of the product cyclopropylmethyltriphenylphosphine salt (2-a) as cyclopropyl bromide methyl bromide
Reference：
[1] Chemical Communications, 2017, vol. 53, # 24, p. 3497 - 3500
[2] Chemical Communications, 2017, vol. 53, # 47, p. 6327 - 6330
[3] Journal of the American Chemical Society, 2009, vol. 131, # 36, p. 12918 - 12920
[4] Liebigs Annalen der Chemie, 1993, # 3, p. 231 - 236
[5] Journal of Organic Chemistry, 1993, vol. 58, # 2, p. 438 - 443
[6] Journal of Organic Chemistry, 1968, vol. 33, # 8, p. 3082 - 3088
[7] Justus Liebigs Annalen der Chemie, 1970, vol. 732, p. 151 - 164
[8] Angewandte Chemie, 1967, vol. 79, # 12, p. 576 - 577
[9] Patent: WO2007/29587, 2007, A1, . Location in patent: Page/Page column 47-48
[10] Patent: JP2016/113440, 2016, A, . Location in patent: Paragraph 0066
45
[ 7051-34-5 ]
[ 151103-08-1 ]
[ 151103-09-2 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With potassium carbonate; potassium iodide In dimethyl sulfoxide at 70℃; for 1 h; Stage #2: at 70℃; for 4 h;
55 g of 4-(difluoromethoxy)-3-hydroxybenzaldehyde, 42.42 g of K2C03 (1.05 eq), 4.86 g of Kl (0.1 eq) and 220 mL of dimethylsulphoxide (DMSO) were loaded in a reactor. The mixture was heated at 70°C and kept for 1 h. A mixture previously prepared of 42.65 g of bromomethyl cyclopropane (1.08 eq) and 1 10 mL of DMSO was added for 1 hour. The reaction was kept for 3 h at 70°C, and then cooled at room temperature. Once the temperature was reached, 375 mL of toluene was added. The suspension was filtered to remove the remaining K2C03, and then it was cooled at 0-5°C, and 375 mL of deionised water were loaded. The phases were separated and the organic phase was washed twice with 55 mL of deionised water. The solvent was removed at reduced pressure, obtaining 70 g (yield 99percent) of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)- benzaldehyde as a viscous yellowish fluid.
98.5%
With trimethylbenzylammonium bromide; potassium carbonate; potassium iodide In tetrahydrofuran at 0℃; Reflux
The 50g (266mmol) 4- difluoromethoxy-3-hydroxybenzaldehyde was dissolved was added potassium carbonate 91.9g (665mmol) in tetrahydrofuran 500mL, potassium iodide was added 2.2g (13.3mmol) and benzyl trimethyl ammonium bromide 3.7g, was added and cooled to 0 bromomethyl cyclopropane 50.6g (375mmol) in tetrahydrofuran (150 mL) solution, stirring the reaction mixture was heated to reflux for 1-3 hours, suction filtered, the filtrate was concentrated under reduced pressure, the residue was was added 2mol / L sodium hydroxide solution to pH10, extracted twice with 500mL of dichloromethane, the solvent of the organic layers were dried over sodium sulfate and removed under reduced pressure to give 3-cyclopropyl-methoxy-4-difluoromethoxy methoxybenzaldehyde 63.5g (261mmol), a yield of 98.5percent.
97%
With potassium carbonate In tetrahydrofuran at 0℃; for 14 h; Heating / reflux
4-Difluoromethoxy-3-hydroxybenzaldehyde (10 g, 52.8 mmol) was dissolved in tetrahydrofuran (100 ml) added with potassium carbonate (44 g, 105 mmol), cooled to 0° C. and added with a solution of bromomethylcyclopropane (11 ml, 116.6 mmol) in tetrahydrofuran (50 ml). The reaction mixture was heated to reflux under stirring for 7 hrs, then fresh bromomethylcyclopropane (5.5 ml, 58.3 mmol) was added and the heating continued for further 7 hrs. The solvent was removed by vacuum distillation, then the mixture was added with 2 N sodium hydroxide (100 ml) and extracted with dichloromethane (2*100 ml). The combined organic layers were dried over sodium sulphate (5 g) and the solvent removed under reduced pressure to afford 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol, 97percent yield), that was used without further purification.
96%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 20 h;
a) 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde
4.70 g (24.98 mmol) 4-difluoromethoxy-3-hydroxybenzaldehyde are placed in 50 ml of dimethylformamide, 4.00 g (29.63 mmol) bromomethylcyclopropane and 3.50 g (25.32 mmol) potassium carbonate are added. The reaction mixture is heated to 100° C. for 20 hours, then the dimethylformamide is concentrated by evaporation. The residue is extracted with ethyl acetate and water, the organic phase is dried and evaporated to dryness. Yield: 5.83 g (96percent of theoretical)
87.7%
With 4-methyl-morpholine; zinc(II) nitrate In water; acetonitrile at 55℃;
2) Step 1) 3-hydroxy-4-fluoro-methoxybenzaldehyde (37.6g, 200mmol), bromomethyl cyclopropane(29.7g, 220mmol) and N- methylmorpholine (28.3g, 280mmol) and zinc nitrate (22.7g, 120mol)Carried out in acetonitrile mixed reaction, the reaction temperature of the mixture was 55 , after the reaction,The reaction solution was added water,Extracted with dichloromethane, concentrated, and recrystallized from methanol to give 3-cyclopropylmethoxy-4-difluoromethoxy benzaldehyde 42.5g, yield 87.7percent, purity 99.41percent.
82%
With potassium carbonate In DMF (N,N-dimethyl-formamide)
Step 1: Prepared as described for intermediate 1, using 3-hydroxy-4-25 difluoromethoxy-benzaldehyde (5 g, 26.89 mmol), anhydrous potassium carbonate (7.4 g, 53.62 mmol) and bromomethyl cyclopropane (4.5 g, 33.3 mmol) in dry DMF (50 ml). The reaction yielded 5.5 g (82 percent) of the product as viscous liquid which was used as such for step 2.
22.5 g
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 24 h;
To a solution of 4-(difluoromethoxy)-3-hydroxybenzaldehyde (18.4 g, 98 mmol) in DMF (200 ml), potassium carbonate (29.7 g, 215 mmol) and KI (16.3 g, 98 mmol) were added followed by (bromomethyl)cyclopropane (14.28 ml, 148 mmol), and the resulting suspension was stirred at RT for 24 hours. The mixture was poured into water (800 ml) and extracted with diethyl ether (3×300 ml); the combined organic layers were dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (22.5 g, 93 mmol, 94.8percent yield, MS/ESI+ 243.1 [MH]+). This product was used without purification.
22.5 g
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 24 h;
To a solution of 4-(difluoromethoxy)-3-hydroxybenzaldehyde (18.4 g, 98 mmol) in DMF (200 ml), potassium carbonate (29.7 g, 215 mmol) and KI (16.3 g, 98 mmol) were added followed by (bromomethyl)cyclopropane (14.28 ml, 148 mmol) and the resulting suspension was stirred at RT for 24h. The mixture was poured into water (800 ml) and extracted with diethyl ether (3X300 ml); the combined organic layers were dried over Na2S04 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (22.5 g, 93 mmol, 94.8percent yield, MS/ESI+ 243.1 [MH] +). This product was used without purification.
31 g
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 2 h;
Into the reaction flask added 3-hydroxy-4-difluoromethoxybenzaldehyde (21 g, 0.11 mol), cyclopropylmethyl bromide (18. 1 g, 0.13 mol), K2CO3 (18. 5 g) , then dissolved in 199. 5 g DMF and reacted at 85 ° C for 2 h with stirring. TLC monitoring until the reaction was complete. the reaction solution was filtrated , concentrated with CH2Cl2 , then for liquid extraction added CH2Cl2 , H2O into concentrated solution . The organic phase was dried and concentrated with anhydrous MgSO4 to give 31 g of a pale yellow 3-cyclopropylmethylenedioxy-4-(difluoromethoxy)benzaldehyde solution.
Reference：
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With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
N-N(Bromomethyl)cyclopropane (0.95 mg, 6.70 mmol, 0.70 mL, 95 percent) was added to a mixture of4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesium carbonate (3.49 mg, 10.72 mmol) in dry N,N-dimethylformamide (20 mL) at 0°O. After stirring for 30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to afforded 1.30 g (4.38 mmol, 85percent of theory) of the title compound. GO-MS (Method L9): R1 = 4.35 mm; mlz = 247 M1 H NMR (300 MHz, Ohloroform-d, Method M2) 6 7.81 (s, 1 H), 7.79 (s, 1 H), 3.99 (d, J = 7.1 Hz,2H), 1.32 (s, 12H), 1.27 (m, 1 H), 0.71 - 0.58 (m, 2H), 0.41 - 0.33 (m, 2H).
49%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.333333 h; Inert atmosphere Stage #2: for 24 h; Inert atmosphere
To a reaction vessel containing sodium hydride (60 wtpercent dispersion in mineral oil)(3.09 g, 77.32 mmol) was added NN-dimethylformamide (30 mL) under a stream of nitrogen followed by 4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10 g, 51.55 mmol) and the reaction mixture was stirred for 20 min at room temperature. Cyclopropylmethylbromide (8.7 g, 61.86 mmol) was then added and the reaction mixture was stirred for 24 h under an atmosphere of nitrogen. The reaction mixture was slowly poured over saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0percent-100percent EtOAc in cyclohexane) to afford 1- (cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (6.29 g, 49percent). LCMS (ESI): [M+H]+ = 249.2; lH NMR (400 MHz, CDC13) δ 7.80 (d, J= 7.4 Hz, 2H), 3.99 (d, J = 7.0 Hz, 2H), 1.32 (s, 12H), 1.29 - 1.26 (m, 1H), 0.69 - 0.60 (m, 2H), 0.41 - 0.33 (m, 2H).
48%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 14 h;
To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (8.00 g,41.2 mmol) in DMF (130 mL) was added potassium carbonate (17.1 g, 124 mmol) and(bromomethyl)cyclopropane (6.0 mL, 62 mmol). The mixture was stirred at 600 C for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 4.95 g (48 percent yield) of the titlecompound.LC-MS (Method 2): Rt = 1.12 mm; MS (ESIpos): mlz = 249 [M+H]1HNMR (400 MHz, DMSO-d6) O [ppm]: 0.314 (0.66), 0.318 (0.59), 0.325 (0.56), 0.330 (0.65),0.471 (0.53), 0.476 (0.61), 0.492 (0.62), 0.496 (0.57), 1.045 (0.78), 1.219 (1.70), 1.224 (16.00),3.295 (1.54), 3.927 (1.24), 3.946 (1.22), 7.542 (1.07), 7.544 (1.08), 7.932 (1.09).
48%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 14 h;
To a stirred solution of 4-(4, 4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (purchased from Acros, CAS 269410-08-4, 8.00 g, 41 .2 mmol) in DMF (130 mL) was added potassium carbonate (17.1 g, 124 mmol) and (bromomethyl)cyclopropane (6.0 mL, 62 mmol). The mixture was stirred at 60° C for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 4.95 g (48 percent yield) of the title compound. LC-MS (Method 2): Rt = 1.12 min; MS (ESIpos): m/z = 249 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) _ [ppm]: 0.314 (0.66), 0.318 (0.59), 0.325 (0.56), 0.330 (0.65), 0.471 (0.53), 0.476 (0.61 ), 0.492 (0.62), 0.496 (0.57), 1.045 (0.78), 1 .219 (1 .70), 1 .224 (16.00), 3.295 (1.54), 3.927 (1.24), 3.946 (1.22), 7.542 (1 .07), 7.544 (1 .08), 7.932 (1.09).
20 g (0.148 mol) of cyclopropylmethyl bromide, 39.3 g (0.15 mol) of triphenylphosphine and 30 ml of DMF were simultaneously charged into a 250 ml three-necked flask and the temperature was maintained at 100 to 110 C. for 6 hours The temperature was lowered to 50 C., After placing in 200 ml of ethyl acetate and stirring, a large amount of white solid appeared and was filtered to give 34 g of the product cyclopropylmethyltriphenylphosphine salt (2-a) as cyclopropyl bromide methyl bromide
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 6h;
Step A: tert-Butyl (3R)-1-(cyclopropylmethyl)-2-oxoazepan-3-ylcarbamate Sodium hydride (60% dispersion in mineral oil; 30 mg, 1.24 mmol) was added to a solution <strong>[106691-72-9]tert-butyl (3R)-2-oxoazepan-3-ylcarbamate</strong> (258 mg, 1.13 mmol) and cyclopropylmethyl bromide (0.27 mL, 2.83 mmol) in N,N-dimethylformamide (3 mL) at 0 C., and the mixture was allowed to warm to ambient temperature. After 6 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3*), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane?5% methanol/dichloromethane) gave the title compound (257 mg). MS 283 (M+1).
3a-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NaH; In N,N-dimethyl-formamide;
3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester A reaction flask was charged with crude 3a-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (5.5 g) in dry DMF (25 mL) under Argon. NaH (60% in oil, 0.968 g, 24.2 mmol) was added in portions and the mixture was stirred at 50 for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (3.252 g, 24.2 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (3.354 g). 1H NMR (CDCl3) d 3.98-3.94 (m, 2H), 3.44-3.40 (m, 1H), 3.05 (d, 2H), 1.96-1.88 (m, 2H), 1.79-1.62 (m, 6H), 1.29 (s, 9H), 0.88-0.79 (m, 1H), 0.35-0.30 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CDCl3) d 153.4, 78.9, 73.0, 72.5, 52.7, 34.9, 28.5, 28.1, 10.9, 2.8.
1-(cyclopropylmethyl)-4-nitro-1H-imidazole-2-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1.0h;Inert atmosphere;
15 g (81 mmol) of <strong>[865998-46-5]4-nitro-1H-imidazole-2-carboxylic acid ethyl ester</strong> is stirred under argon together with 13.13 g (97.2 mmol) of cyclopropyl methyl bromide and 22.4 g (162 mmol) of potassium carbonate in 165 ml of DMF for 1 hour at 80 C. After cooling, the reaction mixture is diluted with water and extracted four times with ethyl acetate. The combined organic phases are washed once with water and three times with saturated sodium chloride solution, dried with magnesium sulfate, and concentrated by evaporation in a vacuum. The crystalline residue is immediately reused for the next reaction. Yield: 17.59 g (70% of theory) LC-MS (Method 1): Rt=2.02 min. MS (EST+): m/z=240 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): delta=8.2 (s, 1H), 4.4 (q, 2H), 4.3 (d, 2H), 1.4 (m, 4H), 0.55 (q, 2H), 0.45 (q, 2H) ppm.
In water; N,N-dimethyl-formamide; isopropyl alcohol; toluene;
A) 2-(Cyclopropylmethyloxy)-6-methoxyacetophenone. 32.7 ml of a 50% solution of <strong>[35103-79-8]caesium hydroxide</strong> in water are added at RT to a solution of 26 g of 2-hydroxy-6-methoxyacetophenone in 400 ml of 2-propanol, and the mixture is left stirring for 15 minutes at RT. It is concentrated under vacuum, the residue is taken up with 2-propanol, the mixture is concentrated under vacuum, toluene is then added and the resulting mixture is concentrated under vacuum. The residue is dissolved in 200 ml of DMF, 25.3 g of cyclopropylmethyl bromide are added and the mixture is heated to 80 C. for 2 hours 30 minutes. It is concentrated under vacuum, the residue is taken up with water, the mixture is extracted with AcOEt, the organic phase is washed with a saturated NaCl solution and dried over Na2 SO4 and the solvent is evaporated off under vacuum. 32.7 g of the expected product are obtained.
In N-methyl-acetamide; di-isopropyl ether; Petroleum ether;
200 ml of tetrahydrofurane are introduced into a 2 liter reactor equipped with a mechanical stirrer, a dropping funnel, a reflux condenser and a thermometer and are cooled before adding 6.6 g of lithium aluminum hydride under a nitrogen atmosphere. This suspension is cooled to -5° and 80 g (0.296 mol) of ethyl p-benzoxyacetate are added dropwise thereto in such a way that the temperature does not exceed 0°. The whole is then kept at ambient temperature for 3 hours. The reaction mixture is then cooled and the excess AlLiH4 is destroyed with an excess of sodium potassium double tartrate, the mixture is filtered and the residue is evaporated. The 2-(p-benzoxyphenyl)-ethanol is caused to crystallise by trituration in isopropyl ether. 58.4 g (yield=86percent) of this product are obtained; M.p.: 86°-88°. 2.6 g (0.055 mol) of sodium hydride are suspended in 20 ml of dimethylformamide in a 250 ml flask equipped with a magnetic stirrer, a dropping funnel and a reflux condenser. 11.4 g (0.05 mol) of 2-(p-benzoxyphenyl)-ethanol dissolved in 30 ml of the same solvent are then added. The mixture is gently heated to 30° and a further 70 ml of dimethylformamide are then added. A precipitate is observed. 7.42 g (0.055 mol) of cyclopropylmethyl bromide dissolved in 20 ml of dimethylformamide are then added and the mixture is heated for 8 hours to a temperature of 60°. Progressive disappearance of the solid product is observed. The reaction mixture is poured into water and extracted with ether, and the ether solution is washed with water, dried over sodium sulphate and evaporated to dryness. The solid residue is stirred for 30 minutes in petroleum ether; the insoluble 2(p-benzoxyphenyl)-ethanol which has not reacted is then filtered off, the solvent is evaporated and the residue is rectified. 5.9 (yield=74percent) of 4-[2-(cyclopropylmethoxy)-ethyl]-1-benzoxy-benzene are thus obtained.
In N-methyl-acetamide; di-isopropyl ether; Petroleum ether;
200 ml of tetrahydrofurane are introduced into a 2 liter reactor equipped with a mechanical stirrer, a dropping funnel, a reflux condenser and a thermometer and are cooled before adding 6.6 g of lithium aluminium hydride under a nitrogen atmosphere. This suspension is cooled to -5° and 80 g (0.296 mol) of ethyl p-benzoxy-acetate are added dropwise thereto in such a way that the temperature does not exceed 0°. The whole is then kept at ambient temperature for 3 hours. The reaction mixture is then cooled and the excess AlLiH4 is destroyed with an excess of sodium potassium double tartrate, the mixture is filtered and the residue is evaporated. The 2-(p-benzoxyphenyl)-ethanol is caused to crystallise by trituration in isopropyl ether. 58.4 g (yield=86percent) of this product are obtained; M.p.: 86°-88°. 2.6 g (0.055 mol) of sodium hydride are suspended in 20 ml of dimethylformamide in a 250 ml flask equipped with a magnetic stirrer, a dropping funnel and a reflux condenser. 11.4 g (0.05 mol) of 2-(p-benzoxyphenyl)-ethanol dissolved in 30 ml of the same solvent are then added. The mixture is gently heated to 30° and a further 70 ml of dimethylformamide are then added. A precipitate is observed. 7.42 g (0.055 mol) of cyclopropylmethyl bromide dissolved in 20 ml of dimethylformamide are then added and the mixture is heated for 8 hours to a temperature of 60°. Progressive disappearance of the solid product is observed. The reaction mixture is poured into water and extracted with ether, and the ether solution is washed with water, dried over sodium sulphate and evaporated to dryness. The solid residue is stirred for 30 minutes in petroleum ether; the insoluble 2-(p-benzoxyphenyl)-ethanol which has not reacted is then filtered off, the solvent is evaporated and the residue is rectified. 5.9 g (yield=74percent) of 4-[2-(cyclopropyl-methoxy)-ethyl]-1-benzoxy-benzene are thus obtained.
N-[1-(cyclopropylmethyl)-4-piperidyl]-N-(1H-5-indazolyl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.9%
With sodium borohydrid; potassium carbonate; In titanium(IV) isopropylate; methanol; water; ethyl acetate; acetonitrile;
Example 287 N-[1-(Cyclopropylmethyl)-4-piperidyl]-N-(1H-5-indazolyl)amine 4-Piperidone hydrochloride monohydrate (1.14 g) and potassium carbonate (1.38 g) were dissolved in anhydrous acetonitrile, and (bromomethyl)cyclopropane (1 g) was added dropwise to the solution at room temperature. The reaction solution was stirred at room temperature for 18 hr. Ethyl acetate was then added to the solution, and the mixture was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure to give an intermediate. This intermediate was dissolved in titanium tetraisopropoxide (4.3 g). 5-Aminoindazole (600 mg) was added to the solution, and the mixture was stirred at room temperature for 18 hr. Methanol and sodium borohydride (170 mg) were then added to the reaction solution, and the mixture was stirred for 18 hr. The reaction solution was diluted with ethyl acetate (40 ml), and a minor amount of water was added thereto, and the mixture was then filtered under the reduced pressure. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (338 mg, yield 16.9%). 1H-NMR (CDCl3, 400 MHz): 0.11 - 0.13 (m, 2H), 0.49 - 0.57 (m, 2H), 0.86 - 0.93 (m, 1H), 1.50 - 1.59 (m, 2H), 2.11 - 2.22 (m, 4H), 2.29 - 2.31 (m, 2H), 3.04 - 3.07 (m, 2H), 3.29 - 3.35 (m, 1H), 6.79 - 6.82 (m, 2H), 7.28 - 7.31 (m, 1H), 7.88 (s, 1H) Mass spectrum (ESI-MS, m/z): 271 (M++1)
7. Preparation of Cyclopropylcarbinyl-sulfonamide Using the procedure employed for the preparation of cyclobutylcarbinyl-sulfonamide, cyclopropylcarbinyl sulfonamide was prepared from cyclopropylcarbinyl bromide (Aldrich) (see also JACS 1981, p.442-445). 1H NMR (CDCl3) delta 0.39-0.44 (m, 2H), 0.67-0.76 (m, 2H), 1.13-1.27 (m, 1H), 3.03 (d, J=7.3 Hz, 2H), 4.74 (brs, 2H); 13C NMR (CDCl3) delta 4.33, 5.61, 59.93; MS m/e 134 (M-1).
4f. Preparation of cyclopropylcarbinylsulfonamide Using the procedure employed for the preparation of cyclobutylcarbinylsulfonamide, cyclopropylcarbinylsulfonamide was prepared from cyclopropylcarbinyl bromide (Aldrich) (see also JACS 1981, p. 442-445). 1H NMR (CDCl3) delta 0.39-0.44 (m, 2H), 0.67-0.76 (m, 2H), 1.13-1.27 (m, 1H), 3.03 (d, J=7.3 Hz, 2H), 4.74 (brs, 2H); 13C NMR (CDCl3) delta 4.33, 5.61, 59.93; MS m/e 134 (M-1).
4f. Preparation of Cyclopropylcarbinylsulfonamide Using the procedure employed for the preparation of cyclobutylcarbinylsulfonamide, cyclopropylcarbinylsulfonamide was prepared from cyclopropylcarbinyl bromide (Aldrich) (see also JACS 1981, p. 442-445). 1H NMR (CDCl3) delta 0.39-0.44 (m, 2H), 0.67-0.76 (m, 2H), 1.13-1.27 (m, 1H), 3.03 (d, J=7.3 Hz, 2H), 4.74 (brs, 2H); 13C NMR (CDCl3) delta 4.33, 5.61, 59.93; MS in/c 134 (M-1).
Example 23 Preparation of cyclopropylcarbinylsulfonamide Using the procedure employed for the preparation of cyclobutylcarbinylsulfonamide, cyclopropylcarbinylsulfonamide was prepared from cyclopropylcarbinyl bromide (Aldrich) (see also JACS 1981, p. 442-445). 1H NMR (CDCl3) delta 0.39-0.44 (m, 2H), 0.67-0.76 (m, 2H), 1.13-1.27 (m, 1H), 3.03 (d, J=7.3 Hz, 2H), 4.74 (brs, 2H); 13C NMR (CDCl3) delta 4.33, 5.61, 59.93; MS m/e 134 (M-1).
3-(cyclopropylmethyl)-4,5,6,7-tetrahydro-2(3H)-benzothiazolimine Hydrobromide (15) A mixture of <strong>[2933-29-1]2-amino-4,5,6,7-tetrahydrobenzothiazole</strong> (52 mg, 0.34 mmol) and (bromomethyl)cyclopropane (47 mg, 97%, 0.34 mmol) in ethanol (5 mL) was refluxed for one day. Thereafter, the solvent was evaporated under vacuum. The residue was extracted with hot benzene, filtered and washed with benzene to gain a pale yellow solid that then was recrystallized from ethanol-ethyl ether to afford (15) (60 mg, 61%) as pale yellow crystals; mp 239-240 C.; 1H NMR (DMSO-d6): 3.88 (d, J=7.0 Hz, 2H), 2.52-2.39 (m, 4H), 1.76-1.71 (m, 4H), 1.09 (br, 1H), 0.55-0.53 (m, 2H), 0.42-0.40 (m, 2H); HER-MS m/z calcd for C11H17N2S 209.1112, found 209.1115. Anal. (C11H17BrN2S)C, H, N.
Cesium carbonate (654 mg, 2.01 mmol) was added to a solution of 6- bromoisoquinolin-l-(2H)-one (150 mg, 0.67 mmol) in DMF (2 mL) at 0 C and the reaction mixture was stirred for 30 min. (Bromomethyl)cyclopropane (0.325 mL, 3.35 mmol) was added and the mixture was stirred at 23 C for 16 h. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried over MgSC , filtered, and concentrated. The residue was purified by silica gel cliromatography, eluting with a gradient of hexanes:EtOAc, 100:0 to 75:25, to give the title compound. MS: m/z = 280.1 (M+l).
With caesium carbonate; at 50℃; for 4h;
Cesium carbonate (2.62 g), intermediate 1 (1.5 g) and (bromomethyl)cyclopropane (0.8 ml_) were stirred and heated at 50 0C for 4 hours. The mixture was allowed to cool then poured into water and extracted with ethyl acetate. The organic extracts were combined dried and evaporated under reduced pressure. The residue was triturated with ether and the sub-titled compound isolated by filtration (1.0g). MS: APCI(+ve) 277, 279 (M+H)+
) 3,5-Dichloro-4-Cyclopropylmethoxy-benzoic acid methyl ester <n="57"/>3,5-DichloiO-4-hydroxy-benzoic acid ethyl ester (1.0 g, 4.5 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.5 eq) and K2CO3 (0.98 g, 9.0 mrnol, 2.0 eq) were added ad the mixture was stirred at room temperature for 30 min. (Bromomethyl)cyclopropane (0.39 mL, 4.1 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and it was extracted with DCM and dried. The title product (0.98 g, yield 79%) was recovered and used without further purification.
b) 4-Cyclopropylmethoxy-2-methyl-benzoic acid methyl ester 4-Hydroxy~2-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.45 g, 3.0 mmol, 0.5 eq) and K2CO3 (1.66 g, 12.0 mmol, 2.0 eq) were added ad the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (0.53 mL, 5.4 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and the crude was extracted with DCM and dried. 0.42 g of title product (yield 32%) were recovered and used without further purification.C13H16O31H-NMR (CDCl3): 0.23-0.34 (2H5 m); 0.52-0.64 (2H, m); 1.15-1.24 (IH, m); 2.52 (3H, s); 3.75 (2H, d, J=7.2 Hz); 3.77 (3H, s); 6.64-6.66 (IH, m); 7.83-7.85 (2H, m).
32%
b) 4-Cyclopropylmethoxy-2-methyl-benzoic acid methyl ester; [0183] 4-Hydroxy-2-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol, 1.0 equiv.) was dissolved in acetone (14 mL), NaI (0.45 g, 3.0 mmol, 0.5 equiv.) and K2CO3 (1.66 g, 12.0 mmol, 2.0 equiv.) were added ad the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (0.53 mL, 5.4 mmol, 0.9 equiv.) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and the crude was extracted with DCM and dried. 0.42 g of title product (yield 32%) were recovered and used without further purification.C13H16O3 1H-NMR (CDCl3): 0.23-0.34 (2H, m); 0.52-0.64 (2H, m); 1.15-1.24 (1H, m); 2.52 (3H, s); 3.75(2H, d, J=7.2 Hz); 3.77 (3H, s); 6.64-6.66 (1H, m); 7.83-7.85 (2H, m).
32%
4-Hydroxy-2-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.45 g, 3.0 mmol, 0.5 eq) and K2CO3 (1.66 g, 12.0 mmol, 2.0 eq) were added ad the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (0.53 mL, 5.4 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and the crude was extracted with DCM and dried. 0.42 g of title product (yield 32%) were recovered and used without further purification. C13H16O31H-NMR (CDCl3): 0.23-0.34 (2H, m); 0.52-0.64 (2H, m); 1.15-1.24 (IH, m); 2.52 (3H, s); 3.75 (2H, d, J=7.2 Hz); 3.77 (3H, s); 6.64-6.66 (IH, m); 7.83-7.85 (2H, m).
b) 4-Cyclopropylmethoxy-3-fluoro-ben?oic acid methyl ester 3-Fluoro-4-hydroxy-benzoic acid methyl ester (1.02 g, 6.0 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.45 g, 3.0 mmol, 0.5 eq) and K2CO3 (1.66 g, 12.0 mmol, 2.0 eq) were added ad the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (0,53 mL, 5.4 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and it was extracted with DCM and dried.0.91 g of title product (yield 69%) were recovered and used without further purification.C12H13FO31H-NMR (dmso-d6): 0.34-0.37 (2PI5 m); 0.57-0.62 (2H. m); 1.22-1.26 (IH, m); 3.82 (3H, s); 3.99 (2H, d, J=6.8 Hz); 7.26 (IH, t, J=8.4 Hz); 7.67-7.77 (2H, m).
Preparation 53: 1 -Cyclopropylmethyl- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> <n="62"/>--61-Add lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.200 g, 2.08 mmol) to a suspension of sodium hydride (0.092 g, 2.29 mmol) in DMF (3 mL) at 0 0C. Stir for 20 min. at 0 0C. Add a solution of l-(bromomethyl)cyclopropane (0.295 g, 2.18 mmol) in DMF (4 mL) dropwise to the reaction mixture. Stir reaction to ambient temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, dry combined organics (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0: 100 to 60:40 ethyl acetate:hexanes) to give the title preparation (175 mg, 56percent). GC-MS: m/z = 150 [M+].
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;
Example 346; 2l4-Dibromo-1-cyclopropylmethyl-5-methyl-1 H-imidazole and 2,5-dibromo-i- cyclopropylmethyl-4-methyl-1 H-imidazole 1.65 g of sodium hydride (50% strength in mineral oil) were washed with pentane under a nitrogen atmosphere, suspended in 40 ml of DMF and cooled to 00C. 9 g of2,4-dibromo-5-methyl-1 H-imidazole were added as a solution in 35 ml of DMF. Then5.5 g of bromomethylcyclopropane were added and the mixture was stirred for 16 h at 200C. 250 ml of water and EA were added and the aqueous layer was extracted with EA. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. Flash chromatography (silica gel;EA/toluene 1 :19) of the residue yielded 5.5 g of 2,4-dibromo-1-cyclopropylmethyl-5- methyl-1 H-imidazole (oil) and 4 g of 2,5-dibromo-1-cyclopropylmethyl-4-methyl-1 H- imidazole (oil).Example 346-12,4-Dibromo-i -cyclopropylmethyl-5-methyl-i H-imidazoleTLC (EA/toluene 1 :9): Rf = 0.5Example 346-2 <n="177"/>2,5-Dibromo-1 -cyclopropylmethyM-methyM H-imidazoleTLC (ExiA/toluene 1 :9): Rf 0.36
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 1.5h;Microwave irradiation;
A mixture of <strong>[156001-68-2]methyl 3-cyano-4-hydroxybenzoate</strong> (D22; 120 mg, 0.677 mmol), (bromomethyl)cyclopropane (Aldrich; 0.099 ml, 1.016 mmol), and potassium carbonate (140 mg, 1.016 mmol) in dry N,N-dimethylformamide (DMF) (2 ml) was heated under microwave irradiation at 150 for 90mins. The cooled mixture was partitioned between water (30ml) and ethyl acetate (3x25ml), and the organic layer was washed with 50:50 brine: water and brine, dried (MgSC^) and evaporated in vacuo to give a light brown crystalline solid which was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (74 mg) MS (ES) C13H13NO3 requires 231 ; found 232 [M-H]+.
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;
N-N(Bromomethyl)cyclopropane (0.95 mg, 6.70 mmol, 0.70 mL, 95 %) was added to a mixture of4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesium carbonate (3.49 mg, 10.72 mmol) in dry N,N-dimethylformamide (20 mL) at 0O. After stirring for 30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to afforded 1.30 g (4.38 mmol, 85% of theory) of the title compound. GO-MS (Method L9): R1 = 4.35 mm; mlz = 247 M1 H NMR (300 MHz, Ohloroform-d, Method M2) 6 7.81 (s, 1 H), 7.79 (s, 1 H), 3.99 (d, J = 7.1 Hz,2H), 1.32 (s, 12H), 1.27 (m, 1 H), 0.71 - 0.58 (m, 2H), 0.41 - 0.33 (m, 2H).
49%
To a reaction vessel containing sodium hydride (60 wt% dispersion in mineral oil)(3.09 g, 77.32 mmol) was added NN-dimethylformamide (30 mL) under a stream of nitrogen followed by 4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10 g, 51.55 mmol) and the reaction mixture was stirred for 20 min at room temperature. Cyclopropylmethylbromide (8.7 g, 61.86 mmol) was then added and the reaction mixture was stirred for 24 h under an atmosphere of nitrogen. The reaction mixture was slowly poured over saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0%-100% EtOAc in cyclohexane) to afford 1- (cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (6.29 g, 49%). LCMS (ESI): [M+H]+ = 249.2; lH NMR (400 MHz, CDC13) delta 7.80 (d, J= 7.4 Hz, 2H), 3.99 (d, J = 7.0 Hz, 2H), 1.32 (s, 12H), 1.29 - 1.26 (m, 1H), 0.69 - 0.60 (m, 2H), 0.41 - 0.33 (m, 2H).
48%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 14h;
To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (8.00 g,41.2 mmol) in DMF (130 mL) was added potassium carbonate (17.1 g, 124 mmol) and(bromomethyl)cyclopropane (6.0 mL, 62 mmol). The mixture was stirred at 600 C for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 4.95 g (48 % yield) of the titlecompound.LC-MS (Method 2): Rt = 1.12 mm; MS (ESIpos): mlz = 249 [M+H]1HNMR (400 MHz, DMSO-d6) O [ppm]: 0.314 (0.66), 0.318 (0.59), 0.325 (0.56), 0.330 (0.65),0.471 (0.53), 0.476 (0.61), 0.492 (0.62), 0.496 (0.57), 1.045 (0.78), 1.219 (1.70), 1.224 (16.00),3.295 (1.54), 3.927 (1.24), 3.946 (1.22), 7.542 (1.07), 7.544 (1.08), 7.932 (1.09).
48%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 14h;
To a stirred solution of 4-(4, 4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (purchased from Acros, CAS 269410-08-4, 8.00 g, 41 .2 mmol) in DMF (130 mL) was added potassium carbonate (17.1 g, 124 mmol) and (bromomethyl)cyclopropane (6.0 mL, 62 mmol). The mixture was stirred at 60 C for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 4.95 g (48 % yield) of the title compound. LC-MS (Method 2): Rt = 1.12 min; MS (ESIpos): m/z = 249 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) _ [ppm]: 0.314 (0.66), 0.318 (0.59), 0.325 (0.56), 0.330 (0.65), 0.471 (0.53), 0.476 (0.61 ), 0.492 (0.62), 0.496 (0.57), 1.045 (0.78), 1 .219 (1 .70), 1 .224 (16.00), 3.295 (1.54), 3.927 (1.24), 3.946 (1.22), 7.542 (1 .07), 7.544 (1 .08), 7.932 (1.09).
With caesium carbonate; In acetonitrile; at 90℃;
Step 1: J- (cyclopropylmethyl)-4- (4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-lH-pyrazole; A mixture of 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.1 g, 0.5 mmol), cyclopropylmethyl bromide (60.0 uL, 0.62 mmol, Aldrich, Cat. No. 242403), and cesium carbonate (500.0 mg, 1.5 mmol) in acetonitrile (1 mL) was stirred at 90 0C overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na?SO-i. After filtration the filtrate was concentrated to yield 120 mg of the product which was directly used in the next step reaction without further purification.
Example 19; N-Cyclopentyl-3-(3-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)phenethoxy)-N-(2-(2-(5- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl)ethylamino)ethyl)propanamide Trifluoroacetic Acid Salt Step i) 1 -(Cyclopropylmethyl)-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H- pyrazole Sodium hydride (0.195 g) was washed with 2 ml of dry THF. DMF (4 mL) was added followed by portionwise addition of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (0.63 g). The mixture was stirred for 30 min and (bromomethyl)cyclopropane (0.313 mL) added. The mixture was stirred at 600C for 50 min and at rt for 16 h. The mixture was quenched with sat. ammonium chloride and ethyl acetate (70 mL). The mixture was washed with water (4x). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude l-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (717 mg) that was used in the next step without purification.MS [M+H]+ = 249 (MultiMode+) <n="115"/>1H NMR (400 MHz, CDCl3) delta 7.81 (s, IH), 7.79 (s, IH), 3.99 (d, J = 6.9 Hz, 2H), 1.32 (s, 12H), 1.31 - 1.23 (m, IH), 0.70 - 0.61 (m, 2H), 0.42 - 0.33 (m, 2H)
With potassium hydroxide; In dimethyl sulfoxide; at 10 - 30℃;
Example - 1: Preparation of 1 - [(Benzyloxy) - 4 - (2 - cyclopropyl methoxy) ethyl] benzene:In a 1.0 lit flask charged 4-benzyloxy-2-phenyl ethanol (100 gms, 0.44 moles) in dimethyl sulfoxide (300 ml). Stirred and charged powdered potassium hydroxide (61.4 gms, 1.1 moles). Stirred and cooled to 10 - 150C. Charged cyclopropyl methyl bromide (71.1 gms, 0.53 moles). Raised the temperature to 25 - 300C and maintained. After 3 hours, the reaction mass was quenched in chilled water (600 ml) maintaining temperature below 5°C. The pH of the reaction solution was adjusted with dilute (1 :4) hydrochloric acid, extracted the solution with 3 x 200 ml of toluene and distilled out toluene under vacuum below 550C. Charged petroleum ether (250 ml) to the residual mass and cooled to 00C and maintained under stirring for 2 hours. Filtered the separated solid and washed with petroleum ether. Charcoalised the filtrate for 30 minutes and filtered through hyflow bed and distilled out solvent to get the product. Wt of the product = 90 - 92 gms.
(cyclopropylmethyl)-4,5-dimethylthiazol-2(3H)-imine hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 85℃; for 16h;
Example 24C; N-r(2Z)-3-(cvclopropylmethyl)-4.5-dimethyl- 1.3-thiazol-2(3H)-ylidene1-2- ([(2S)- 1 - methylpyrrolidin-2-yl"|methoxy I -5 -(trifluoromethyl)benzamide; A mixture of 4,5-dimethylthiazol-2-amine (0.30 g, 2.3 mmol, Aldrich) and (bromomethyl)cyclopropane (0.63 g, 4.7 mmol, Aldrich) was heated at 85 0C for 16 h. The reaction mixture was cooled to room temperature and triturated with ether to obtain the crude intermediate, hydrobromide salt of (cyclopropylmethyl)-4,5-dimethylthiazol-2(3H)-imine. To a solution of the above intermediate in tetrahydrofuran (10 mL) were added Example 24B (0.71, 2.3 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (0.54, 2.8 mmol, Aldrich), 1-hydroxybenzotriazole (0.43 g, 2.8 mmol, Aldrich) and triethylamine (1.0 mL, 7.0 mmol, Aldrich). The reaction mixture was stirred at 80 0C for 2 h, cooled and then quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix Intellifiash280 (SiO2, 5-100% of triethylamine/MeOH/EtOAc (0.1/1/10) in hexanes) to afford 160 mg of the title compound. 1H NMR (300 MHz, DMSO- d6) delta ppm 0.32 - 0.69 (m, 4 H), 1.14 - 1.40 (m, 1 H), 1.48 - 1.75 (m, 3 H), 1.78 - 2.00 (m, 1 H), 2.07 - 2.22 (m, 1 H), 2.23 (s, 3 H), 2.29 (s, 3 H), 2.32 (s, 3 H), 2.53 - 2.64 (m, 1 H), 2.86 - 2.97 (m, 1 H), 3.92 - 4.07 (m, 2 H), 4.11 (d, J=IA Hz, 2 H), 7.28 (d, J=8.7 Hz, 1 H), 7.72 (dd, J=8.7, 2.4 Hz, 1 H), 7.92 (d, J=2.4 Hz, 1 H); MS (ESI+) m/z 468 (M+H)+.
With sodium hydroxide; In N,N-dimethyl-formamide; at 70℃; for 16.0h;
A mixture of crude <strong>[690264-39-2]4-bromo-2-trifluoromethoxyphenol</strong> (2.Og, 7.8 mmol), cyclopropylmethyl bromide (2.1g, 1.6 mmol), sodium hydroxide (0.624g, 1.6 mmol), and DMF (50 ml) was stirred for 16 h at 70 0C. On cooling, water was added to the reaction mixture followed by extraction with ethyl acetate twice. The organic extracts were washed with cold water followed by brine, and were dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain crude product. Purification by column chromatography (silica gel, hexane:ethyl acetate, 95:5) afforded 1.8 g (74% yield) of 4-bromo-l-cyclopropylmethoxy-2- trifluoromethoxybenzene. 1H-NMR (400 MHz, CDCl3) delta 7.260-7.366 (m, 2H), 6.838 - 6.860 (d, IH, J = 8.8 Hz), 3.848 - 3.865 (d, 2H, J = 6.8Hz), 1.233 -1.294 (m, IH), 0.594 - 0.657 (m, 2H), 0.317-0.373 (m, 2H) ppm.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g, 13.1 mmol) in N,N-dimethylformamide was treated with potassium carbonate (2.71 g, 19.6 mmol) and 1-bromomethyl-cyclopropane (1.6 ml, 15.7 mmol). The reaction mixture was stirred at 100 C. for 16 hours. For the workup, the reaction mixture was diluted with ethyl acetate, solid material was filtered, and the filtrate evaporated at reduced pressure. The residue was purified by chromatography on silica using a gradient of n-heptane and ethyl acetate=100/0 to 20/80 as the eluent to give the 5-cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester as a yellow liquid (1.69 g, 62% of theory). Mass (calculated) C11H13NO3 [207.228]; (found) [M+H]+=208.
62%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
A solution of 5-hydroxy-pyridine-2-carboxylic acid methyl ester (2.0 g, 13.1 mmol) in N5N- dimethylformamide was treated with potassium carbonate (2.71 g, 19.6 mmol) and 1- bromomethyl-cyclopropane (1.6 ml, 15.7 mmol). The reaction mixture was stirred at 100 0C for 16 hours. For the workup, the reaction mixture was diluted with ethyl acetate, solid material was filtered, and the filtrate evaporated at reduced pressure. The residue was purified by chromatography on silica using a gradient of n- heptane and ethyl acetate = 100/0 to 20/80 as the eluent to give the 5-cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester as a yellow liquid (1.69 g, 62% of theory). Mass (calculated) CHHI3NO3 [207.228]; (found) [M+H]+ = 208
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 4h;Microwave irradiation; Sealed;
Step 1 To a solution of <strong>[36953-40-9]2-bromopyridin-4-ol</strong> (1.6 g, 9.2 mmol) and (bromomethyl)cyclopropane (1.61 g, 12.0 mmol) in DMF (12 mL) in a microwave vial was added cesium carbonate (4.19 g, 12.9 mmol). The vial was sealed and heated in a microwave reactor at 120 C. for 4 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (2*). The combined organics were washed with sat'd NaCl then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20-50% EtOAc/heptane) to give 1.45 g (69%) of 2-bromo-4-cyclopropylmethoxy-pyridine as a yellow oil.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
Step 1 To a solution of <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (800 mg, 4.12 mmol) in DMF (50 mL) was added cesium carbonate (5.37 g, 16.5 mmol) and (bromomethyl)cyclopropane (1.6 mL, 16.5 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed sequentially with water, sat'd LiCl and sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/heptane) to isolate first 590 mg (58%) of 1-cyclopropylmethyl-<strong>[71759-89-2]4-iodo-1H-imidazole</strong> as a pale yellow oil followed by 227 mg (22%) of 1-cyclopropylmethyl-5-iodo-1H-imidazole as a pale yellow oil.
Step 2: tert-butyl 3-[cyclopropylmethyl(methyl)amino]pyrrolidine-l-carboxyIate (108): NaH (238 mg, 5.96 mmol) was added slowly to the solution of compound 107 (496 mg, 2.48 mmol) in dry DMF at 0 C. The reaction mixture was stirred for 1 h at room temperature and bromomethylcyclopropane (418.5 mg, 3.1 mmol) was added at 0 C and allowed to stir at room temperature for 12 h. The reaction mixture was poured into ice- water and extracted with ethyl acetate (3 x 25 mL). The combined organic solvent was washed with brine and dried over sodium sulphate, concentrated to a crude oil. The crude material was purified by column chromatography get pure desired compound 108.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4.0h;
a) 4-Bromo- 1 -(cyclopropylmethyl)- 1 H-pyrazoleTo a solution of 4-bromo-l H-pyrazole (0.1 g, 0.68 mmol) in DMF (20 ml) were added K2C03 (0.19 g, 1.36 mmol, 2 eq.) and (bromomethyl)cyclopropane (92 mg, 0.68 mmol, 1 eq.). The mixture was stirred at RT for 4 h. The mixture was quenched and extracted as in Intermediate Example 5(c). The solvent was distilled off to afford the crude product (0.15 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4.0h;
To a solution of 4-bromo-1H-pyrazole (0.1 g, 0.68 mmol) in DMF (20 ml) were added K2CO3 (0.19 g, 1.36 mmol, 2 eq.) and (bromomethyl)cyclopropane (92 mg, 0.68 mmol, 1 eq.). The mixture was stirred at RT for 4 h. The mixture was quenched and extracted as in Intermediate Example 5(c). The solvent was distilled off to afford the crude product (0.15 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;
Step 1: Synthesis of methyl 3-(cyclopropylmethoxy)-4-formylbenzoate (125) To a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (50 mg, mmol) in DMF (1 ml), cyclopropylbromide (0.5 ml, mmol) and potassium carbonate (50 mg, mmol) were added at RT. The reaction was stirred at 60 degrees for 3 hours, then poured onto water and the aqueous phase extracted with AcOEt twice. The combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure to yield 50 mg of the title compound (mmol, yield %), which was used for the next step without further purification. MS/ESI+ 180.04 [MH]+
5-Bromo-2-(cyclopropylmethylthio)pyridine To a solution of <strong>[56673-34-8]5-bromopyridine-2-thiol</strong> (3.9 g) in THF (100 mL) was added NaH (1.24 g) at 0 C. and the mixture was stirred at 0 C. for 0.5 h. Then (bromomethyl)cyclopropane (2.79 g) was added. The mixture was allowed to warm to r.t. and stirred for 6 hours. The mixture was poured into ice water (200 mL) and extracted with EA (100 mL*3). The combined organic phases were washed with brine (50 mL) and then dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by SGC (eluent: PE) to provide the subtitle compound. MS ESI+: m/z=244 [M+H]+.
To a solution of <strong>[56673-34-8]5-bromopyridine-2-thiol</strong> (3.9 g) in THF (100 ml_) was added NaH (1 .24 g) at 0C and the mixture was stirred at 0C for 0.5 h. Then (bromomethyl)cyclopropane (2.79 g) was added. The mixture was allowed to warm to r.t. and stirred for 6 hours. Themixture was poured into ice water (200 ml_) and extracted with EA (100 ml_ x 3). The combined organic phases were washed with brine (50 ml_) and then dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by SGC (eluent: PE) to provide the subtitle compound. MS ESI+: m/z = 244 [M+H]+.
To a solution of <strong>[56673-34-8]5-bromopyridine-2-thiol</strong> (3.9 g) in THE (100 mL) was added NaH (1.24 g) at 0C and the mixture was stirred at 0C for 30 minutes. Then (bromomethyl)cyclopropane (2.79 g) was added. The mixture was allowed to warm to RT and stirred for 6 hours. The mixture was poured into ice water (200 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with brine(50 mL) and then dried over Na2504. After filtration and evaporation of the solvent, the residue was purified by SGC (eluent: PE) to provide the subtitle compound. MS ESI:m/z = 244 [M+H].
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃;
A mixture of <strong>[207115-22-8]4-bromo-2-iodophenol</strong> (5.00 g, 16.7 mmol), bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate (6.54 g, 20.1 mmol) in 15 mL dimethylformamide was stirred at 50 C. overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to the provide title compound (5.84 g, 99% yield).
Sodium hydride (288 mg, 7.23 mmol) was add to <strong>[161417-28-3]4-bromopyridin-3-ol</strong> (71-1) (1.05 g, 6.03 mmol) in DMF (30 mL) at 0 C and stirred for 1 hr. (bromomethyl)cyclopropane (71-2) (701 muL, 7.23 mmol) was added and the reaction stirred overnight at room temperature. Water was added (100 mL) and the reaction extracted with EtOAc (2 x 100 mL), washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica, 0- 10% MeOH in DCM) to give 4-bromo-3-(cyclopropylmethoxy)pyridine (71-3) (.766 g, 56%) of a brown oil. LC/MS (ES+): m/z 228.0 [M + H]+
44.6%
Sodium hydride (60% w/w) (1 10 mg, 2.76 mmol) was added to <strong>[161417-28-3]4-bromopyridin-3-ol</strong> (400 mg, 2.299 mmol) in DMF (15 mL) at 0C and left stirring for 30 minutes. (Bromomethyl)cyclopropane (0.268 mL, 2.76 mmol) was added and the reaction was warmed to rt and stirred overnight. Water was added (40 mL) and the organic product was extracted with EtOAc and washed with brine, dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel column chromatography [0-5% MeOH/NH3 in DCM] and fractions containing product were combined and concentrated in vacuo to give the title compound as a brown oil (234 mg, 1.026 mmol, 44.6 % yield). LCMS (2 min, Formic Acid): Rt = 0.87 min, MH+ = 228/230.
44.6%
Sodium hydride (60 % w/w) (1 10 mg, 2.76 mmol) was added to <strong>[161417-28-3]4-bromopyridin-3-ol</strong> (400 mg, 2.299 mmol) in DMF (15 mL) at 0C and left stirring for 30 minutes. (Bromomethyl)cyclopropane (0.268 mL, 2.76 mmol) was added and the reaction was warmed to rt and stirred overnight. Water was added (40 mL) and the organic product was extracted with EtOAc and washed with brine, dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel column chromatography [0-5 % MeOH/NH3 in DCM] and fractions containing product were combined and concentrated in vacuo to give 4-bromo-3-(cyclopropylmethoxy)pyridine (234 mg, 1.026 mmol, 44.6 % yield) as a brown oil. LCMS (2 min, Formic): Rt = 0.87 min, MhT = 228/230.
A) 4-(cyclopropylmethoxy)-3-fluorobenzoic Acid To a solution of <strong>[350-29-8]3-fluoro-4-hydroxybenzoic acid</strong> (10.0 g) in methanol (200 mL) was added sulfuric acid (3.5 mL), and the mixture was heated under reflux for 1 day. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in DMF (100 mL) were added potassium carbonate (17.7 g) and (bromomethyl)cyclopropane (9.32 mL), and the mixture was stirred with heating at 70° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in a mixed solvent of THF (50 mL) and methanol (50 mL) was added 2 M aqueous sodium hydroxide solution (64 mL), and the mixture was stirred with heating at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (12.7 g). 1H NMR (300 MHz, DMSO-d6) delta 0.32-0.39 (2H, m), 0.56-0.64 (2H, m), 1.17-1.36 (1H, m), 3.98 (2H, d, J=7.2 Hz), 7.23 (1H, t, J=8.5 Hz), 7.66 (1H, dd, J=11.9, 2.1 Hz), 7.70-7.76 (1H, m), 12.90 (1H, brs).
With sodium hydroxide; In dichloromethane; water; at 20℃; for 16h;
To a stirred solution of <strong>[39903-01-0]2-amino-5-bromopyridine-3-ol</strong> (25 g, 132.9 mmol) in dichloromethane (150 mL) was added (bromomethyl)cyclopropane (35.88 g, 265.8 mmol), aliquat (7.5 g) and 40percent aqueous sodium hydroxide (150 mL) at RT, followed by stirring for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (2 x 500 mL). The combined organic layers were concentrated to dryness in vacuo and the resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 25percent ethyl acetate in hexane) affording 5-bromo-3-(cyclopropylmethoxy)pyridin-2-amine as and off white solid ( 15 g, 47percent):
47%
With sodium hydroxide; In dichloromethane; water; at 20℃; for 16h;
Preparative Example 1 Step 1: 5-bromo-3-(cyclopropylmethoxy)pyridin-2-amine To a stirred solution of <strong>[39903-01-0]2-amino-5-bromopyridine-3-ol</strong> (25 g, 132.9 mmol) in dichloromethane (150 mL) was added (bromomethyl)cyclopropane (35.88 g, 265.8 mmol), aliquat (7.5 g) and 40percent aqueous sodium hydroxide (150 mL) at RT, followed by stirring for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (2 x 500 mL). The combined organic layers were concentrated to dryness in vacuo and the resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 25percent ethyl acetate in hexane) affording 5-bromo-3- (cyclopropylmethoxy)pyridin-2-amine as and off white solid ( 15 g, 47percent): H NMR (300 MHz, DMSO-d6) delta 7.61 (s, 1H), 7.19 (s, 1H), 5.81 (s, 2H), 4 - 3.8 (m, 2H), 1.35 - 1.1 (m, 1H), 0.65 - 0.55 (m, 2H), 0.2 - 0.4 (m, 2H).
0.49 g (6.82 mmoi) cyclopropane methanol in 10 mL THF are charged with 0.42 g (11.4 mmoi) NaH and the reaction mixture is stirred at r.t. for 20 min. Then 1.00 g (5.68 mmoi) 5-bromo-2-fluoropyridine are added and the mixture is stirred at r.t. over night. The reaction is quenched by the addition of water and extracted with EtOAc. The organic layers are combined, dried over MgS04l filtered and the solvent is removed in vacuo. The crude product is purified by HPLC (MeOH/H20/FA). CgH-ioBrNO (M= 228.1 g/mol) ESI-MS: 228/229 [M+H]+ Rt (HPLC):1.14 min (method C) The following compounds are prepared analogously to example XXV.1 ; For example XXV.4 the reaction conditions are 50 C for 4 h. For examples XXV.10 - XXV.13 and XXV.19 - XXV.21 the reaction time is 2 h. For example XXV.9 no solvent is used and the reaction temperature is 95 C. For the examples XXV.4, XXV.10 - XXV.12, XXV.15 - XXV.16 and XXV.19 - XXV.21 the reaction is done in DMF. For example XXV.18 the reaction is done in DMSO at 100 C. For example XXV.21 toluene is used as solvent and the reaction conditions are 50 C for 1 h. For example XXV.22 methyltetrahydrofurane is used as solvent at 0 C for the deprotonation and 50 C for the substitution..
5-bromo-2-cyclopropylmethyl-3,4-dihydro-2H-isoquinolin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;
To a solution of <strong>[1109230-25-2]5-bromo-1,2,3,4-tetrahydroisoquinolin-1-one</strong> [CAS: 1109230-25-2] (500 mg, 2.21 mmol) in 20 mL DMF cooled to 0C is added 60% dispersion NaH in mineral oil (79.6 mg, 3.32 mmol). After gas evolution ceased bromomethylcyclopropane (299 mg, 2.21 mmol)is added and the resulting suspension is allowed to stir overnight at RT. Then another 60% dispersion NaH in mineral oil (79.6 mg, 3.32 mmol) and bromomethylcyclopropane (299 mg, 2.21 mmol) are added and the mixture is allowed to stir at RT for 3 h. The mixture is filtered and the remaining solid rinsed with DMF. The DMF is removed under reduced pressure and HV. Purification of the crude residue by HPLC (Method D) yields 209 mg (34%) of the sub-title compound as a yellow solid. LC-A: tR = 0.86 mm; [M+H] = 282.0
5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3.0h;
Potassium carbonate (1.32 g, 9.57 mmol) was added to 5-bromo-3-methyl-2-hydroxypyridine (600 mg, 3.19 mmol) and bromomethylcyclopropane (861 mg, 6.38 mmol) in DMF (6 mL). After heating at 70 C. for 3 h, EA extractive work up and silica gel chromatography (PE:EA=30:1?10:1), the title compound (510 mg, yield: 66.0%) was obtained as a white solid. 1H NMR: (CDCl3, 400 MHz) delta: 7.39 (d, J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 3.77 (d, J=6.8 Hz, 2H), 2.15 (s, 3H), 0.65-0.60 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 242.1; 244.1 (M+H)+
tert-butyl N-(4-bromo-2-pyridyl)-N-(cyclopropylmethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
To a solution of <strong>[207799-10-8]tert-butyl N-(4-bromo-2-pyridyl)carbamate</strong> (5.0 g, 18.3 mmol, synthesized via Step 1 of Intermediate CM) in DMF (50 mL) was added NaH (1.10 g, 27.5 mmol) at 0 C. for 30 minutes. Then bromomethylcyclopropane (2.97 g, 22.0 mmol) was added into the mixture. The reaction mixture was stirred at rt for 17 h. On completion, the mixture was quenched with water (40 mL) and extracted with EA (2×50 mL). The organic phase was washed with brine (60 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.7 g, 45% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.18 (d, J=5.2 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.17 (dd, J=1.6, 5.2 Hz, 1H), 3.88 (d, J=7.2 Hz, 2H), 1.55 (s, 9H), 1.22-1.15 (m, 1H), 0.47-0.40 (m, 2H), 0.28-0.23 (m, 2H).
55.2 g
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 10 - 35℃;
A) To a mixture of <strong>[207799-10-8]tert-butyl (4-bromopyridin-2-yl)carbamate</strong> (46.1 g), a sodium hydride 60% dispersion in mineral oil (10.13 g), and DMF (338 mL) was added bromomethylcyclopropane (19.64 mL). The reaction mixture was stirred overnight at room temperature, and poured into a mixture of water/ethyl acetate, and the mixture was filtered. The organic layer of the filtrate was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (55.2 g). MS (ESI+). found: 271.0.
6-bromo-1-(cyclopropylmethyl)-4-methyl-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.29 g
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 51.0h;
(Bromomethyl) cyclopropane (3.75 mmol, 0.36 mL) was added drop-wise to mixture of 6-bromo-4-methyl-lH- benzo [d] imidazole (2.5 mmol) and potassium carbonate (3.75 mmol, 0.52 g, ) in DMF (8 mL). The mixture was stirred at room temperature for 48 hours and 60°C for 3 h. The mixture was diluted with ethyl acetate and water and the organic extract was washed with brine, dried (MgS04) and concentrated under reduced pressure. Purification of the crude product by column chromatography (silica gel, gradient of 30-100percent ethyl acetate in isohexane) gave the title compound (containing ~25percent of the isomeric 5-bromo- 1- (cyclopropylmethyl) -7-methyl-lH-benzo [d] imidazole) as an off-white solid (0.29 g, 44percent).
methyl 1-(cyclopropylmethyl)-4-nitro-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;
Cyclopropylmethyl bromide (2.34g, 17.34 mmol) was slowly added to a stirred solution of methyl 4-nitro-lH-pyrazole-3-carboxylate (3g, 14.45 mmol) and potassium carbonate (2.36g, 17.34 mmol) in DMF (40mL) at 0 C. The reaction mass was stirred at room temperature for 4h. Quenched the reaction mass with ice cold water, diluted with ethyl acetate (50mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum to get a crude residue. The residue was purified by silica gel column chromatography by eluting with 0-30% ethyl acetate-hexane to afford the title compound (2.7g, 84%). ESI-MS: m/z = 226.1 (M+H)+.
1-(cyclopropylmethyl)-6-methoxy-1H-indole-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Methyl 6-methoxy-lH-indole-2-carboxylate (243 mg, 1.101 mmol) was dissolved in DMF (4 mL), to this solution, sodium hydride (44.0 mg, 1.101 mmol, 60% dispersion in mineral oil)was added. The reaction was stirred for 5 min and then (bromomethyl)cyclopropane (0.107 mL, 1.101 mmol) was added. After 40 min LCMS showed 53% starting material with 28%) of the methyl ester of the desired product. The reaction was left to stir over the weekend. LCMS showed an increase in the methyl ester of the desired product. Further (bromomethyl)cyclopropane (0.5 mL, 5.16 mmol) was added and the reaction was left stirring for a further 40 min. LCMS showed an increase in the methyl ester of the product (39%)). The reaction was left stirring for a further 3 h. LCMS showed little change. A further aliquot of sodium hydride was added and the reaction was left to stir for 1 h. A further aliquot of bromomethyl cyclopropane was added. Further sodium hydride (44.0 mg, 1.101 mmol)was added and the reaction was left stirring overnight. A further aliquot of bromomethyl cyclopropane (0.5 mL, 5.16 mmol) was added to the reaction mixture. The solution was allowed to stir for a further 2.5 h. Further sodium hydride (44.0 mg, 1.101 mmol)was added to the solution and the reaction was allowed to stir at rt overnight. A futher aliquot of bromomethyl cyclopropane (0.5 mL, 5.16 mmol) was added to the reaction mixture and the solution was left to stir for 1 h. LCMS showed 13% starting material, 33% methyl ester of the desired product and 39% desired product. A further aliquot of bromomethyl cyclopropane (0.5 mL, 5.16mmol) was added to the reaction mixture and the solution was allowed to stir for 4 h. Sodium hydride (44 mg, l . lOlmmol) was added to the reaction and the solution was left to stir for 30 min. LCMS showed 64% conversion to the desired product. NaOH (1 mL, 2 mmol, 2M) was added cautiously to the reaction, and the solution was left to stir for 1.5 h. A further aliquot of NaOH (1 mL, 2 mmol) was added to the reaction and the solution was left to stir for a further 30 min. LCMS showed 78% conversion to the desired product. The aqueous layer was acidified with H4CI (sat) and extracted with 3 x EtOAc. The organic layers were combined, passed through a hydrophobic frit and the solvent removed under vacuum to give the crude product (366 mg) a brown solid. This was used crude in the subsequent reaction.LCMS (Method B): Rt = l .Olmin, MH+ = 246.0.
benzyl (1-(cyclopropylmethyl)piperidin-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
240 mg
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 5h;Reflux;
General procedure: To a solution of compound I-7 (900 mg, 2.62 mmol) in DCM (30 mL), TFA (4.5 mL, 52.32 mmol)was added and then the reaction mixture was stirred at room temperature for 1 h and then was evaporated to give the crude product used in the next step. The mixture of the amine, DIEA (3.6mL, 20.93 mmol) and 1-bromo-3-methylbut-2-ene (1.5 mL, 13.08 mmol) in acetonitrile washeaded to reflux for 5 h and then was evaporated. Then ethyl acetate (60 mL) was added to thesolution and then the organic layer was washed with brine (20 mL × 2) and then was dried overanhydrous MgSO4. After filtration and concentration, the crude product I-8b was obtained andpurified with column chromatography (methylene chloride /methanol = 40:1 to 25:1) to givecompound I-8b light yellow oil (350 mg, 49.3%).
1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.5%
j0079J To a stirred solution of <strong>[221675-35-0]ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate</strong> (CAS 221675-35-0, 4.0 g, 21.03 mmol) in DMF (40 ml) at 0C was added NaH (60%, 0.95 g, 23.87 mmol) portion wise over 5 mm under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 45 mi (Bromomethyl)cyclopropane (2.45 ml, 25.24 mmol) was added and the reaction mixture was stirred at room temperature for 1 8h. The solvent was removed in vacuo and the residue suspended in THF (40 ml). To this mixture was added 5M aqueous sodium hydroxide (20 ml, 100 mmol) and the mixture stirred at 50 C for 18h. The solvent was removed in vacuo and the remaining material was acidified with 5M aqueous hydrochloric acid (20 ml) whilst stirring in an ice-bath. The suspension was stirred for 10 mm then the precipitate collected by vacuum filtration. The solid was washed with water (2 x 100 ml) and dried to obtain 3.48 g (76.5%) of 1-(cyclopropylmethyl)-1H-pyrrolo[2,3- b]pyridine-2-carboxylic acid EV-AQ1977-001 as a white powder. LCMS (method D):retention time 1.02mm, IVJIz = 217 (M + 1).
69.2%
To a stirred solution of ethyl 1H-pyrrolo[2,3-bjpyridine-2-carboxylate (CAS 221675-35-0, 4.40 g, 23.1 mmol) in DMF (50 ml) was added sodium hydride (60%, 1.05 g,26.3 mmol). The mixture was stirred under nitrogen at room temperature for 45 minutes and (bromomethyl)cyclopropane (CAS 7051-34-5, 2.70 ml, 27.8 mmol) was added. The mixture was stirred at room temperature for 2.5h and the solvent was removed in vacuo. The residue was suspended in THF (40 ml) and 5M aqueous sodium hydroxide (22 ml, 110 mmol) was added. The mixture was stirred at 50C for 3.5h. Additional THF (20 ml) and 5M aqueous sodium hydroxide (22 ml, 110 mmol) were added and the reaction was stirred at 50C for 16h. The reaction cmde was concentrated in vacuo and water (10 ml) and SM aqueous hydrochloric acid (100 ml) were added. The solid was filtered off, washed with water (2 x 100 ml) and dried to obtain 3.46 g (69.2%) of 1-(cyclopropylmethyl)-1H-pyrrolo[2,3- bjpyridine-2-carboxylic acid EV-AR3164-OO1 as a white powder. LCMS (method D):retention time 1.03mm, M/z = 217 (M + 1).
ethyl 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of ethyl lH-pyrrolo[2,3-b]pyridine-2-carboxylate (CAS 221675-35-0, 4.40 g, 23.1 mmol) in DMF (50 ml) was added sodium hydride (60%, 1.05 g, 26.3 mmol). The mixture was stirred under nitrogen at room temperature for 45 minutes and (bromomethyl)cyclopropane (CAS 7051-34-5, 2.70 ml, 27.8 mmol) was added. The mixture was stirred at room temperature for 2.5h and the solvent was removed in vacuo. The residue was suspended in THF (40 ml) and 5M aqueous sodium hydroxide (22 ml, 110 mmol) was added. The mixture was stirred at 50C for 3.5h. Additional THF (20 ml) and 5M aqueous sodium hydroxide (22 ml, 110 mmol) were added and the reaction was stirred at 50C for 16h. The reaction crude was concentrated in vacuo and water (10 ml) and 5M aqueous hydrochloric acid (100 ml) were added. The solid was filtered off, washed with water (2 x 100 ml) and dried in a vac oven to obtain 3.46 g (69.2%) of l-(cyclopropylmethyl)-lH- pyrrolo[2,3-b]pyridine-2-carboxylic acid EV-AR3164-001 as a white powder. LCMS (method D): retention time 1.03min, M/z = 217 (M + 1).
6-bromo-2-(cyclopropylmethyl)-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; for 1h;Cooling with ice; Inert atmosphere;
Preparation 117: 6-bromo-2-(cyclopropylmethyl)-2,3-dihydro-1 H-isoindol-1 -one (1710) (1711) A stirred solution of 6-bromo-2,3-dihydro-1 H-isoindol-1 -one (350 mg, 1.65 mmol) and cyclopropylmethyl bromide (0.198 muIota_, 1.98 mmol) in DMF (6 mL) was cooled in an ice bath under nitrogen. Then NaH (99 mg, 2.48 mmol) was added in portions. The reaction was stirred for 1 hour and then quenched with NH4CI (sat., aq.). The mixture was extracted with IPA:CHCI3 (1 :3, x3). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under vacuum to yield the title compound as a brown oil (~30 % pure) which was used crude. MS: [M+H]+ = 266/268.
methyl 5-(cyclopropylmethoxy)-1-methyl-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With caesium carbonate; In acetonitrile; at 60℃; for 2h;
Methyl 5-hydroxy-i -methyi-1f-I-pyrazoie-3-carboxyiate (0.500 g, 3.20 mrnol) was dissolved in anhydrous MeCN (15 rnL), and (bromornethyl)cyciopropane (0.519g, 3.84mmoi) and C52CO3 (1.565 g, 4.80 mrnol) were added sequentially. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with DCM, Celite was added, and the solvent was removed under reduced pressure. The residue was purified by normal phase chromatography to give methyl 5-(cyclopropyimethoxy)- 1-methyl- 1ff- pyrazole-3-carboxylate (0.651 g, 310 mmoi, 97percent yield) as a colorless oil, which solidified upon standing. MS (ES) m/z: 210.9 (M-i-H). ?H NMR (400MHz, DMSOd6) 36.15 (s, 1H), 3.96 (d, J=7.0 Hz, 2H), 3.76 (s, 3H), 3.64 (s, 3H), 1.30 1.17 (m, 1H), 0.61 -0.54 (in, 2H), 0.38 - 0.32 (rn, 2H).
2-(cyclopropylmethoxy)-2-(4-fluorophenyl)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Sodium hydride (60% dispersion in mineral oil, 5.88 g, 147 mmol) was added to a solution of 2-(4-fluorophenyl)-2-hydroxyacetic acid (10.0 g, 58.8 mmol) and in DMF (180 mL) under nitrogen and stirred for 30 minutes. (Bromomethyl)cyclopropane (14.27 mL, 147 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonatesolution. The aqueous was acidified to pH 1 with 2M HC1 and extracted with EtOAc. The combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound. 1H NMR (300 MHz, DICHLOROMETHANE-d2) 6 ppm 0.10 - 0.27 (m, 2 H), 0.45 - 0.62 (m, 2 H), 1.00 - 1.17 (m, 1 H), 3.24 - 3.46 (m, 2 H), 4.91 (s, 1 H), 6.99 - 7.14 (m, 2 H),7.39-7.50(m,2H),8.72-9.22(m, 1H)MS ES+: 223
Sodium hydride (60% dispersion in mineral oil, 5.88 g, 147 mmol) was added to a solution of 2-(4-fluorophenyl)-2-hydroxyacetic acid (10.0 g, 58.8 mmol) and in DMF (180 mL) under nitrogen and stirred for 30 minutes. (Bromomethyl)cyclopropane (14.27 mL, 147 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc and washed with saturated NaHC03solution. The aqueous was acidified to pH 1 with 2N HCl and extracted with EtOAc. The combined organics were dried (phase separator) and concentrated in vacuo to afford the title compound. 1HNMR (300 MHz, CD2Cl2) delta ppm 0.10 - 0.27 (m, 2 H), 0.45 - 0.62 (m, 2 H), 1.00 - 1.17 (m, 1 H), 3.24 - 3.46 (m, 2 H), 4.91 (s, 1 H), 6.99 - 7.14 (m, 2 H), 7.39 - 7.50 (m, 2 H), 8.72 - 9.22 (m, 1 H). MS ES-:223
benzyl (4-cyclopropylmethylene)-3-oxopiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.8%
N-Benzyloxycarbonyl-3-oxobutazine (350 mg, l. 28 mmol) was added to a three-necked flask and about 10 ml of anhydrousDMF, under nitrogen, NaH (77 mg, 1.92 mmol) was added and stirring was continued for 60 min. Bromomethylcyclopropane was added dropwise,Temperature reaction overnight. The solvent was distilled off under reduced pressure, and the aqueous solution was concentrated twice. The organic layer was concentrated to give 331 mg of an oil in a yield of 76.8%.
To a solution of 5-bromo-2-hydroxy-3-nitropyridine (14g, 63.9 mmol) in THF (200mL) at room temperature was added tBuOK (7.5g, 67.1 mmol), and stirred for 0.5 hour.(Bromomethyl)cyclopropane (8.7 mL, 92 mmol) and DMF (200mL) were added to the suspension and the resulting mixture was warmed to 85 C. The mixture was stirred overnight at 85 C. Water (600 mL) was added, and extracted with ethyl acetate (500mL*3). The organic phase was washed with water, brine, dried over Na2SO4, filtered, and evaporated in vacuum to give the crude Compound. The crude (18g) intermediate was purified by column chromatography over silica gel (eluent: Petrol ether Ethyl acetate=23). The desired fractions were evaporated in vacuum to give the product as a brown solid: 13.0 g of intermediate 75i, yield 74.5%.
1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridine-2-carbaldehyde[ No CAS ]
6-(cyclopropylmethoxy)pyridine-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%; 0.21 g
With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 16.0h;Inert atmosphere;
1-(Cyclopropylmethyl)-<strong>[358751-77-6]6-oxo-1,6-dihydropyridine-2-carbaldehyde</strong> (EV-AY2050- 001)- Step 1 6-Oxo-1,6-dihydropyridine-2-carbaldehyde (CAS 358751-77-6, 294 mg, 2.39 mmol) was dissolved in dry DMSO (10 ml) under an atmosphere of nitrogen and treated with Cs2CO3 (934 mg, 2.87 mmol) and (bromomethyl)cyclopropane (CAS 7051-34-5, 0.25 ml, 2.63 mmol). The reaction mixture was stirred at room temperature for 16h, diluted with water (20 ml) and extracted with ethyl acetate (3 x 20ml). The combined organic extracts were washed with water, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (10-100% ethyl acetate/heptane) to obtain 0.16 g (38%) of 1-(cyclopropylmethyl)-<strong>[358751-77-6]6-oxo-1,6-dihydropyridine-2-carbaldehyde</strong> (EV-AY2050- 001) as a dark green gum, LCMS (method D): retention time 0.92min, M/z = 178 (M + 1), and 0.21 g of 6-(cyclopropylmethoxy)pyridine-2-carbaldehyde (EV-AY2050-002) as a colourless oil, LCMS (method D): retention time 1.18min, M/z = 178 (M + 1).
methyl 5-bromo-1-(cyclopropylmethyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In N,N-dimethyl-formamide; at 30℃; for 8h;Inert atmosphere; Sealed tube;
Methyl 5-bromo-1-(cyclopropylmethyl)-1H-pyrrole-2-carboxylate (EV-AS5711- 002)- Step 1 To a solution of <strong>[934-07-6]methyl 5-bromo-1H-pyrrole-2-carboxylate</strong> (CAS 934-07-6, 500 mg, 2.45 mmol) in anhydrous DMF (5 ml) was added sodium hydride (60%, 150 mg, 3.75 mmol). To this solution was added (bromomethyl)cyclopropane (350 mul, 3.61 mmol) and the mixture stirred under nitrogen at 30 C in a sealed tube for 8h. The reaction mixture was concentrated, quenched with methanol and purified by flash column chromatography (0-50% ethyl acetate/heptane) to afford 566 mg (89%) of methyl 5-bromo-1-(cyclopropylmethyl)-1H-pyrrole- 2-carboxylate (EV-AS5711-002) as a yellow oil. LCMS (method D): retention time 1.44 min, M/z = 258/260 (M + 1).
ethyl 2-bromo-1-(cyclopropylmethyl)-4-methyl-1H-imidazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
Ethyl 2-bromo-1-(cyclopropylmethyl)-4-methyl-1H-imidazole-5-carboxylate (EV-AT8650-001)? Step 2 To <strong>[95470-42-1]ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate</strong> (EV-AT8648-001, 550 mg, 2.36 mmol) in DMF (10 ml), was added potassium carbonate (652 mg, 4.72 mmol) followed by (bromomethyl)cyclopropane (0.25 ml, 2.60 mmol) and the reaction mixture stirred at room temperature for 16h. Saturated aqueous ammonium chloride (150 ml) was added to the reaction mixture and the aqueous layer was extracted with ethyl acetate (2x150 ml). The combined organics were then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (0-100percent ethyl acetate/heptane) to afford 543 mg (80percent) of ethyl 2-bromo-1-(cyclopropylmethyl)-4-methyl-1H-imidazole-5-carboxylate (EV- AT8650-001) as a colourless oil. LCMS (method D): retention time 1.23 min, M/z = 287/289 (M + 1).
1-bromo-2-chloro-4-(cyclopropylmethoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
A microwave vial was charged with <strong>[13631-21-5]4-<strong>[13631-21-5]bromo-3-chlorophenol</strong></strong> (1.00 g, 4.8 mmol,), potassium carbonate (1.0 g, 7.2 mmol), DMF (15 mL) and cyclopropylmethyl bromide (0.78 g, 5.8 mmol) and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with ethyl acetate (3X50 mL). The combined organics were washed with brine and dried over MgS04. The solvents were evaporated to dryness and the residue subjected to purification by column chromatography (24 g silica, 0- 50% ethyl acetate in hexanes) to give the product as oil. NMR (300 MHz, CDCb): delta 7.47 (d, J= 8.7 Hz, 1H), 7.01 (d, J= 3.0 Hz, 1H), 6.70 (dd, J= 8.7 and 3.0 Hz, 1H), 3.78 (d, J = 7.2 Hz, 2H), 1.26 (m, 1H), 0.68-0.63 (m, 2H), 0.38-0.34 (m, 2H).
4-chloro-7-(cyclopropylmethoxy)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
NaH (44.1 mg, 1.102 mmol, 40% in oil) was added to a stirred solution of 4- chloroquinolin-7-ol (100 mg, 0.367 mmol) in DMF (1837 mu at 0 C then warmed to 25 C, after 30 min, (bromomethyl)cyclopropane (99 mg, 0.735 mmol) was added to the mixture and stirred for 16 h. Water (20 mL) was added to the reaction mixture then extracted with EtOAc (10 mL x 3). The combined organic layers was washed with saturated aqueous solution of (0598) NaCl (15 mL) then dried over Na2SC>4, filtered and concentrated. The residue was purified by p-TLC (Si02, DCM: MeOH = 50: 1) to give the title compound. MS : 234 (M + 1).
1-tert-butyl 3-methyl 2-(cyclopropylmethyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
To a solution of NaH (6.89 g, 172.22 mmol, 60percent in mineral oil) in DMF (150 mL) was added <strong>[42726-73-8]tert-butyl methyl malonate</strong> (30 g, 172.22 mmol, 29.13 mL) and the reaction mixture was stirred at 25 °C for 2 h. Bromomethylcyclopropane (27.9 g, 206.67 mmol, 19.79 mL) was added dropwise slowly and stirred for 16 h. The reaction mixture was quenched by the addition of aq. NH4CI (300 mL) at 0 °C, extracted with EtOAc (3 chi 300 mL), washed with brine (3 chi 300 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:MTBE = 100: 1 to 4: 1) to provide the title compound (29.5 g, 75percent) as a white oil.
6-bromo-5-(cyclopropylmethoxy)-1H-indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16.0h;
A mixture of <strong>[1206800-18-1]6-bromo-1H-indazol-5-ol</strong> (300 mg, 1.4 mmol, 1 eq), 1-(bromomethyl)cyclopropane(155 Jll, 1.55 mmol, 1.1 eq) and K2C03 (389 mg, 2.8 mmol, 2 eq) in DMF (1.9 mL) is stirred at 60C forapproximately 16 h. The reaction is diluted with ethyl acetate and washed with water. The aqueous layer isextracted with ethyl acetate and the combined organic layers are washed (water and brine), dried (Na2S04)and concentrated. The residue is purified by flash column chromatography (Si02, DCM/methanol 100:0 to97:3) to afford the desired product.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;
N,N-dimethylformamide, N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)-3-hydroxybenzoyl, potassium carbonate,Mix bromomethylcyclopropane,After stirring for 5 minutes,Slowly warm to 80 C, keep warm for 2 h, cool to room temperature, add ice water,The organic phase is extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated.Recrystallization from a mixed solvent of 95:5 by volume of isopropanol and water gives roflumilast.Wherein, N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)-3-hydroxybenzoyl,The molar ratio of potassium carbonate to bromomethylcyclopropane is 1:2:1.2, and the molar volume (mol/l) ratio of bromomethylcyclopropane and N,N-dimethylformamide is 0.52:3, N, N. The volume ratio of dimethylformamide to ice water is 0.3:2.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
General procedure: To a solution of 4-bromo-2-chlorophenol (Compound 27A) (5.0 g, 24.1 mmol)DMF (100 mL) was added K2C03 (10.0 g, 72.5 mmol) and 2-bromopropane (7.5 g, 61.5 mmol) and stirred at 100 C for 16 hours. The mixture was diluted with water (400 mL) and extracted with a mixture of ethyl acetate in petroleum ether (15% v/v, 300 mL x 3). The combined extracts were washed with bine (300 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (petroleum ether) to furnish Compound 27B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
General procedure: To a solution of 4-bromo-2-chlorophenol (Compound 27A) (5.0 g, 24.1 mmol)DMF (100 mL) was added K2C03 (10.0 g, 72.5 mmol) and 2-bromopropane (7.5 g, 61.5 mmol) and stirred at 100 C for 16 hours. The mixture was diluted with water (400 mL) and extracted with a mixture of ethyl acetate in petroleum ether (15% v/v, 300 mL x 3). The combined extracts were washed with bine (300 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (petroleum ether) to furnish Compound 27B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
methyl 3-(cyclopropylmethoxy)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;
(Bromomethyl)cyclopropane (588 mg, 4.36 mmol) was added to a solution of methyl 3- hydroxy-1H-pyrrole-2-carboxylate (615 mg, 4.36 mmol) and potassium carbonate (993 mg, 7.19 mmol) in DMF (5 mL) and the reaction mixture stirred at 90 C overnight. The reaction mixture was cooled to room temperature and water (100 mL) and diethyl ether (100 mL) were added. The phases were separated and the aqueous phase extracted with diethyl ether (75 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure and purified by column chromatography (silica, petroleum ether:ethyl acetate, gradient elution from 100:0 to 50:50) to give the desired product as a pale yellow oil which solidified upon standing (177 mg, 42%). (0434) 1H NMR (500 MHz, CDCl3) d 8.58 (s, 1H), 6.75 (t, J=3.0 Hz, 1H), 5.91 (t, J=3.0 Hz, 1H), 3.86 (m, 5H), 1.31 (m, 1H), 0.64-0.60 (m, 2H), 0.38-0.35 (m, 2H). (0435) LC-MS (Method B): RT = 2.61 min, m/z = 194.3 [M - H]-.
2-cyclopropylmethoxy-1-fluoro-4-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h;
Dissolve <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (500mg, 3.18mmol), potassium carbonate (878mg, 6.36mmol), cyclopropylmethyl bromide (516mg, 3.86mmol) in DMF (8mL), and stir at 50 C for 4h The raw material disappears. The reaction solution was poured into ice water to precipitate a solid, which was filtered and dried to obtain 672 mg of a yellow solid with a yield of 100% and a melting point of 68-69 C.
1-bromo-4-(cyclopropylmethoxy)-2-(trifluoromethyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.7%
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;
To a solution of <strong>[320-49-0]4-bromo-3-(trifluoromethyl)phenol</strong> (500 mg, 2.075 mmol)in DMF (2 mL) was added K2CO3 (860 mg, 6.22 mmol) and (bromomethyl)cyclopropane (402 m, 4.15 mmol) and the mixture was warmed to 50 C overnight. The reaction was cooled to room temperature and then partitioned between EtOAc (2 x 25 mL) and water (25 mL), the organics were washed with NaOH (2M, 2 x10 mL), brine (2 * 10 mL), dried over MgS04 and then concentrated in vacuo to give the crude product. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtO Ac/isohexane) to afford l-bromo-4- (cyclopropylmethoxy)-2-(trifluoromethyl)benzene (0.357 g, 1.198 mmol, 57.7 % yield) as a clear oil. Analytical data: Rl 2.86 min (Method 1); no mass observed.
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