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Structure of 1514-87-0 * 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.
Synthesis of methyl chlorodifluoroacetate (CH3O(CO)CF2Cl) from 1-chloro-1,1,2,2-tetrafluoro-2-methoxyethane (CH3OCF2CF2Cl): The reaction was carried out in the same manner as in Example 3, except that CH3OCF2CF2Cl was used as a starting material, to obtain 1.34 mmol (67percent) of CH3O(CO)CF2Cl.
Reference：
[1] Tetrahedron Letters, 1991, vol. 32, # 52, p. 7689 - 7690
[2] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 247
19
[ 1514-87-0 ]
[ 609-73-4 ]
[ 384-22-5 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 55, # 2, p. 225 - 228
20
[ 1514-87-0 ]
[ 121-17-5 ]
[ 320-88-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 1994, vol. 66, # 2, p. 167 - 170
21
[ 1514-87-0 ]
[ 139-85-5 ]
[ 127842-54-0 ]
[ 151103-08-1 ]
Yield
Reaction Conditions
Operation in experiment
13%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h;
Methyl chlorodifluoroacetate (15.3 mL, 145 mmol) was added to a suspension of 3,4- dihydroxybenzaldehyde (5.0 g, 36 mmol) and potassium carbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 0C for 16 h and then diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCOs, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH (400 MHz, CDCI3) 6.60 (t, J = 72 Hz, 1 H, OCHF2), 6.64 (t, J = 72 Hz, 1 H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.76-7.78 (m, 2H, HZ, H6), 9.96 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.2 (t, J = 259 Hz), 1 15.4 (t, J = 259 Hz), 121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; vmax 794, 1038, 1381 , 1509, 1698, cm"1. Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21 percent) as a colourless crystalline solid; mp 94-95 0C (recrystallized from EtOAc); δH (500 MHz, CDCI3) 5.82 (s, 1 H, OH), 6.65 (t, J = 72.0 Hz, 1 H, CHF2), 7.27 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1 H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1 H, HZ), 9.92 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.6 (t, J = 259 Hz), 117.1 , 119.2, 123.1 , 134.6, 142.9, 147.8, 190.9; vmax 1087, 1237, 1508, 1592, 1686, 2859, 3313 cm"1.
13%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h;
Methyl chlorodifluoroacetate (15.3 mL, 145mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (5.0 g, 36 mmol) and potassiumcarbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 °C for 16 h and then diluted with water. The aqueous phase wasextracted with EtOAc and the combined organic fractions were washed withsaturated aqueous NaHCO3, water, brine, dried and concentrated. Theresidue was purified by column chromatography, eluting with 10percent EtOAc/petrol togive 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH(400 MHz, CDCl3) 6.60 (t, J= 72 Hz, 1H, OCHF2), 6.64(t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1H, H5), 7.76–7.78 (m, 2H, H2, H6),9.96 (s, 1H, CHO); δC (125MHz, CDCl3) 115.2 (t, J =259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm–1.Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21percent)as a colourless crystalline solid; mp 94–95 °C (recrystallized from EtOAc); δH (500 MHz, CDCl3)5.82 (s, 1H, OH), 6.65 (t, J = 72.0 Hz, 1H, CHF2), 7.27 (d, J5,6= 8.0 Hz, 1H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1H, H2),9.92 (s, 1H, CHO); δC (125MHz, CDCl3) 115.6 (t, J =259 Hz), 117.1, 119.2, 123.1, 134.6, 142.9, 147.8, 190.9; nmax 1087, 1237, 1508, 1592, 1686,2859, 3313 cm–1.
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 7673 - 7688
[2] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 35
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
22
[ 1514-87-0 ]
[ 139-85-5 ]
[ 127842-54-0 ]
Reference：
[1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 11, p. 1457 - 1461
23
[ 1514-87-0 ]
[ 151103-08-1 ]
[ 127842-54-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 16, p. 2149 - 2152
24
[ 1514-87-0 ]
[ 139-85-5 ]
[ 151103-08-1 ]
Yield
Reaction Conditions
Operation in experiment
79.4%
at 60 - 65℃; for 3 h;
The 138.1g (1mol) 3,4- dihydroxybenzaldehyde was added to a concentration of 1L 7mol / L sodium hydroxide solution was added phase transfer catalyst tetrabutylammonium 16.6 g Ammonium, chloro-difluoro-acetic acid methyl ester 180.5g (1.3mol), stirred, solution was reacted at 60 -65 3 hours the reaction is complete, diluted with 1L of water and twice with 500mL ethyl acetate, the aqueous layer was collected, concentrated hydrochloric add was adjusted to pH 2 with 1.5L extracted three times with ethyl acetate, ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to dryness and the residue with petroleum ether - ethyl acetate (3: l) recrystallization, white crystals 149.4g, yield 79.4percent, 99.45percent purity.,
57%
With caesium carbonate In N,N-dimethyl-formamide at 20 - 90℃; for 0.5 h; Microwave irradiation; Green chemistry
Method (a): A suspension of 3,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) in an. DMF (15 mL) was stirred under nitrogen atmosphere for 10 min. Then, Cs2CO3 (3.26 g, 10 mmol) and methyl chlorodifluoroacetate (1.73 g, 12 mmol) were added. The mixture was stirred at 60-70 °C for 6 h. After cooling to room temperature, the solution was poured into water (30 mL) and extracted with ethylacetate (3 * 20 mL), washed with brine (3 * 10 mL), dried (MgSO4) and concentrated under reduced pressure. The obtained oil was purified by Silicagel (100-200 mesh) column chromatography using a mixture of ethylacetate/exane (15:85) as the eluent. The pure product was obtained as a white solid. Yield: 39percent (lit.:15-30percent). 27 Mp: 86-88 °C. Method (b): The 4-(difluoromethoxy)-3-hydroxybenzaldehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3,4-dihydroxybenzaldehyde (0.415 g, 3 mmol)in an. DMF (5 mL), Cs2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate(0.520 g, 3.6 mmol) were added; then the mixturewas irradiated with microwaves, under pressure, increasing theemitted power until 300W in 2 min and at the same time coolingby compressed air to avoid the temperature increasing over 90 C; the irradiation was carried on for further 3 min and then the mixturewas cooled to room temperature, with compressed air, in1 min. The cycle was repeated five times for a total reaction timeof 30 min. The mixture was poured into water (100 mL) andextracted with ethyl acetate (3 20 mL); the organic phase waswashed with water (20 mL), brine (20 mL), dried (MgSO4) and concentratedunder reduced pressure, yielding a brown oil which waspurified by Silicagel (100–200 mesh) column chromatographyeluting with an ethylacetate/exane mixture (15:85). The pureproduct was obtained as a light gray solid. Yield: 57percent (lit. 15–30percent).27 Mp: 86–88 C. 1H NMR (CDCl3): d 6.05 (br s, 1H, OH, 1H disappearswith D2O), 6.65 (t, 1H, J = 72.6 Hz, OCHF2), 7.26 (d, 1H,J = 8.2 Hz, H-5 Ar), 7.45 (dd, 1H, J = 8.2 Hz, 2.0 Hz, H-6 Ar), 7.12(d, 1H, J = 2.0 Hz, H-2 Ar), 9.90 (s, 1H, CHN). IR (KBr) cm1:1687 (CO), 3305 (OH). Anal. C8H6F2O3 (C, H, N).
57%
With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 0.5 h; Microwave irradiation
The 4-(difiuoromethoxy)-3-hydroxybenzaidehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3,4-dihydroxybenzaIdehyde (0.415 g, 3 mmol) in an. DMF (5 mL), CS2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate (0.520 g, 3.6 mmol) were added; then the mixture was irradiated with microwaves, under pressure, increasing the potency until 300 W in 2 minutes and cooling by compressed air to avoid the temperature increasing over 90 °C; the irradiation was carried on for further 3 minutes and then the mixture was cooled to room temperature, with compressed air, in 1 minute. The cycle was repeated five time for a total reaction time of 30 minutes, The mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL); the organic phase was washed with water (20 mL), brine (20 mL), dried (MgS04) and concentrated under reduced pressure, yielding a brown oil which was purified by silicagel (100-200 mesh) column chromatography eluting with an ethylacetate /exane mixture (15:85). The pure product was obtained as a light grey solid. (0324) Yield; 57percent (lit.: 15-30percent). Mp: 86-88 °C. -NMR (CDC13): δ 6.05 (br s, IH, OH, 1H disappears with D20), 6.65 (t, J = 72.6 Hz, OCHF2)f 7.26 (d, J = 8.2 Hz, IH, H-5 Ar), 7.45 (dd, J = 8.2, 2.0 Hz, 1H( H-6 Ar), 7.12 (d, J = 2.0 Hz, H-2 Ar), 9.90 (s, IH, CH=N). IR (KBr) (cm's): 1687 (OO), 3305 (OH). Anal. (C8H6F203) C, H. (percent calculated/found) C: 51.07/ 50.96; H: 3.21/ 331.
38%
With potassium carbonate In N,N-dimethyl-formamide
EXAMPLE 10 Preparation of 4-difluoromethoxy-3-hydroxybenzaldehyde 3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol, Aldrich), methyl chlorodifluoroacetate (0.52 g, 3.62 mmol, Aldrich) and potassium carbonate (0.50 g, 3.62 mmol) were combined in DMF (5.0 mL) under an argon atmosphere. After stirring at 60°-65° C. for 3 h, DMF was removed in vacuo and the residue was partioned between aqueous 3N HCl and ether. The aqueous layer was extracted three times with ether. The combined organic extracts were washed with water, with brine, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25percent ethyl acetate/hexanes) to provide the title compound as a white solid (0.20 g, 38percent). mp 83°-85° C.
33%
With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 3 h;
To a solution of 3,4-hydroxybenzaldehyde [1 (Figure2), 1.38 g, 10 mmol] in dimethylformamide (DMF) (20 mL)were added methyl chlorodifluoroacetate (1.39 mL, 13 mmol)and cesium carbonate (4.23 g, 13 mmol). After the mixturerhad been stirred at 70 °C for 3 h under an air atmosphere,DMF was removed in vacuo. The residue was portionedbetween aqueous 3 N HCl and ethyl acetate. Layers wereseparated, and the aqueous layer was extracted with ethylacetate (3 × 30 mL). Combined organic layers were washedwith brine, dried over Na2SO4, and concentrated in vacuo. Thecrude product was purified by flash chromatography (5:1hexane/EtOAc) to afford compound 2 (0.61 g, 33percent) as awhite solid: 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.45 (dd, J = 4.0, 8.4 Hz, 1H), 7.28 (d, J =8.4 Hz, 1H), 6.67 (t, J = 72.8 Hz, 1H), 6.17 (br s, 1H).
Reference：
[1] Patent: CN105254559, 2016, A, . Location in patent: Paragraph 0035; 0036
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3426 - 3435
[3] Patent: WO2015/121212, 2015, A1, . Location in patent: Paragraph 46-47
[4] Patent: US5731477, 1998, A,
[5] Biochemistry, 2018, vol. 57, # 30, p. 4518 - 4525
[6] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 11, p. 1457 - 1461
[7] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 16, p. 2149 - 2152
25
[ 1514-87-0 ]
[ 139-85-5 ]
[ 127842-54-0 ]
[ 151103-08-1 ]
Yield
Reaction Conditions
Operation in experiment
13%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h;
Methyl chlorodifluoroacetate (15.3 mL, 145 mmol) was added to a suspension of 3,4- dihydroxybenzaldehyde (5.0 g, 36 mmol) and potassium carbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 0C for 16 h and then diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCOs, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH (400 MHz, CDCI3) 6.60 (t, J = 72 Hz, 1 H, OCHF2), 6.64 (t, J = 72 Hz, 1 H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.76-7.78 (m, 2H, HZ, H6), 9.96 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.2 (t, J = 259 Hz), 1 15.4 (t, J = 259 Hz), 121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; vmax 794, 1038, 1381 , 1509, 1698, cm"1. Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21 percent) as a colourless crystalline solid; mp 94-95 0C (recrystallized from EtOAc); δH (500 MHz, CDCI3) 5.82 (s, 1 H, OH), 6.65 (t, J = 72.0 Hz, 1 H, CHF2), 7.27 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1 H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1 H, HZ), 9.92 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.6 (t, J = 259 Hz), 117.1 , 119.2, 123.1 , 134.6, 142.9, 147.8, 190.9; vmax 1087, 1237, 1508, 1592, 1686, 2859, 3313 cm"1.
13%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h;
Methyl chlorodifluoroacetate (15.3 mL, 145mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (5.0 g, 36 mmol) and potassiumcarbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 °C for 16 h and then diluted with water. The aqueous phase wasextracted with EtOAc and the combined organic fractions were washed withsaturated aqueous NaHCO3, water, brine, dried and concentrated. Theresidue was purified by column chromatography, eluting with 10percent EtOAc/petrol togive 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH(400 MHz, CDCl3) 6.60 (t, J= 72 Hz, 1H, OCHF2), 6.64(t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1H, H5), 7.76–7.78 (m, 2H, H2, H6),9.96 (s, 1H, CHO); δC (125MHz, CDCl3) 115.2 (t, J =259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm–1.Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21percent)as a colourless crystalline solid; mp 94–95 °C (recrystallized from EtOAc); δH (500 MHz, CDCl3)5.82 (s, 1H, OH), 6.65 (t, J = 72.0 Hz, 1H, CHF2), 7.27 (d, J5,6= 8.0 Hz, 1H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1H, H2),9.92 (s, 1H, CHO); δC (125MHz, CDCl3) 115.6 (t, J =259 Hz), 117.1, 119.2, 123.1, 134.6, 142.9, 147.8, 190.9; nmax 1087, 1237, 1508, 1592, 1686,2859, 3313 cm–1.
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 7673 - 7688
[2] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 35
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
26
[ 1514-87-0 ]
[ 121-33-5 ]
[ 162401-70-9 ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium carbonate In N,N-dimethyl-formamide at 65 - 70℃; for 16 h;
Methyl chlorodifluoroacetate (1.4 ml_, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 ml_). The suspension was heated to 65-70 0C for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41 percent) as a colourless oil; δH (400 MHz, CDCI3) 3.95 (s, 3H, OCH3), 6.60 (t, J = 74 Hz, 1 H, OCHF2), <n="39"/>7.30 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.45 (dd, J5,6 = 8.0, J2β = 2.0 Hz, 1 H, H6), 7.50 (d, J2β = 2.0 Hz, 1 H, HZ), 9.93 (s, 1 H, CHO); δc (100 MHz, CDCI3) 56.2, 110.9, 115.5 (t, J = 256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8.
41%
With potassium carbonate In N,N-dimethyl-formamide at 65 - 70℃; for 16 h;
Methyl chlorodifluoroacetate (1.4 mL, 13mmol) was added to a suspension of vanillin (15) (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) inDMF (10 mL). The suspension was heated to 65–70 °C for 16 h and the suspension was diluted with water. The aqueousphase was extracted with EtOAc and the combined organic fractions were washedwith saturated aqueous NaHCO3, water, brine, dried and concentrated.The residue was purified by column chromatography, eluting with 10percentEtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41percent) asa colourless oil; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J = 74 Hz, 1H, OCHF2), 7.30 (d, J5,6= 8.0 Hz, 1H, H5), 7.45 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.50 (d, J2,6 = 2.0 Hz, 1H, H2),9.93 (s, 1H, CHO); δC (100MHz, CDCl3) 56.2, 110.9, 115.5 (t, J = 256 Hz), 121.5, 125.0,134.5, 144.9, 151.5, 190.8.
Reference：
[1] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 37-38
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
[3] Patent: WO2009/98283, 2009, A1, . Location in patent: Page/Page column 131
27
[ 1514-87-0 ]
[ 5326-34-1 ]
[ 154057-13-3 ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium fluoride; copper(I) iodide In N,N-dimethyl-formamide
Step A 2-Nitro-4-methylbenzotrifluoride A mixture of 6.00 g (27.8 mmol) of 4-bromo-3-nitrotoluene, 5.86 mL (8.03 g, 55.6 mmol) of methyl chlorodifluoroacetate, 1.93 g (33.4 mmol) of potassium fluoride, 5.31 g (27.8 mmol) of cuprous iodide, and 25 mL of dry DMF was stirred at 110° C. for 2 days. The cooled material was diluted with aqueous citric acid and extracted 3* with ethyl acetate. The combined organic extracts were washed with H2 O, then with brine, and dried over anhydrous Na2 SO4. The residue obtained upon concentration of the filtered solution was flash chromatographed 3* on silica gel (elution with 100:1 and 25:1 hexane-EtOAc) to give 3.25 g (57percent) of the title compound as a yellow liquid; homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 205 (M+). 400 MHz 1 H NMR (CDCl3) δ2.48 (s, 3H), 7.49 (d, J=8 Hz, 1H), 7.67 (s, 1H) overlapping 7.68 (d, J=8 Hz, 1H).
Reference：
[1] Patent: US5262412, 1993, A,
28
[ 1514-87-0 ]
[ 4983-28-2 ]
[ 1192813-64-1 ]
Yield
Reaction Conditions
Operation in experiment
43%
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1 h;
To a solution of 93 mg (0.71 mmol) of 4-hydroxy-1-methyl piperidine in 1.0 ml of N,N-dimethylformamide, 0.28 g (0.86 mmol) of cesium carbonate and 0.32 mg (2.2 mmol) of methyl chlorodifluoroacetate were added, and the reaction solution was stirred at 100° C. for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=75/25 (V/V)] to provide 55 mg of the title compound as a colorless oil (yield: 43percent). 1H-NMR spectrum (500 MHz, CDCl3) δ ppm: 8.53 (2H, s), 6.62 (1H, t, J=71 Hz).
methyl 4-bromo-2-(difluoromethoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 66h;
Production Example 54 Mothyl 4-bromo-2-(difluoromethoxy)benzoate To a 70 ml dimethylformamide solution of 5.0 g (21.7 mmol) of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong>, 3.4 ml (32.6 mmol) of methyl chlorodifluoroacetate and 3.0 g (21.7 mmol) of potassium carbonate were added.. The mixture was stirred at 60C for 6 hours and at room temperature for 60 hours.. Then, water was added to the reaction mixture, and the mixture was extracted with ether.. The organic layer was washed with water and a saturated aqueous solution of sodium chloride.. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 8/1) to obtain 1.4 g (23%) of the captioned compound.
With tetrabutylammonium hydrogen sulfide; sodium hydroxide; at 60 - 65℃; for 3h;
The 138.1g (1mol) 3,4- dihydroxybenzaldehyde was added to a concentration of 1L 7mol / L sodium hydroxide solution was added phase transfer catalyst tetrabutylammonium 16.6 g Ammonium, chloro-difluoro-acetic acid methyl ester 180.5g (1.3mol), stirred, solution was reacted at 60 -65 3 hours the reaction is complete, diluted with 1L of water and twice with 500mL ethyl acetate, the aqueous layer was collected, concentrated hydrochloric add was adjusted to pH 2 with 1.5L extracted three times with ethyl acetate, ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to dryness and the residue with petroleum ether - ethyl acetate (3: l) recrystallization, white crystals 149.4g, yield 79.4%, 99.45% purity.,
57%
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃; for 0.5h;Microwave irradiation; Green chemistry;
Method (a): A suspension of 3,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) in an. DMF (15 mL) was stirred under nitrogen atmosphere for 10 min. Then, Cs2CO3 (3.26 g, 10 mmol) and methyl chlorodifluoroacetate (1.73 g, 12 mmol) were added. The mixture was stirred at 60-70 C for 6 h. After cooling to room temperature, the solution was poured into water (30 mL) and extracted with ethylacetate (3 * 20 mL), washed with brine (3 * 10 mL), dried (MgSO4) and concentrated under reduced pressure. The obtained oil was purified by Silicagel (100-200 mesh) column chromatography using a mixture of ethylacetate/exane (15:85) as the eluent. The pure product was obtained as a white solid. Yield: 39% (lit.:15-30%). 27 Mp: 86-88 C. Method (b): The 4-(difluoromethoxy)-3-hydroxybenzaldehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3,4-dihydroxybenzaldehyde (0.415 g, 3 mmol)in an. DMF (5 mL), Cs2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate(0.520 g, 3.6 mmol) were added; then the mixturewas irradiated with microwaves, under pressure, increasing theemitted power until 300W in 2 min and at the same time coolingby compressed air to avoid the temperature increasing over 90 C; the irradiation was carried on for further 3 min and then the mixturewas cooled to room temperature, with compressed air, in1 min. The cycle was repeated five times for a total reaction timeof 30 min. The mixture was poured into water (100 mL) andextracted with ethyl acetate (3 20 mL); the organic phase waswashed with water (20 mL), brine (20 mL), dried (MgSO4) and concentratedunder reduced pressure, yielding a brown oil which waspurified by Silicagel (100-200 mesh) column chromatographyeluting with an ethylacetate/exane mixture (15:85). The pureproduct was obtained as a light gray solid. Yield: 57% (lit. 15-30%).27 Mp: 86-88 C. 1H NMR (CDCl3): d 6.05 (br s, 1H, OH, 1H disappearswith D2O), 6.65 (t, 1H, J = 72.6 Hz, OCHF2), 7.26 (d, 1H,J = 8.2 Hz, H-5 Ar), 7.45 (dd, 1H, J = 8.2 Hz, 2.0 Hz, H-6 Ar), 7.12(d, 1H, J = 2.0 Hz, H-2 Ar), 9.90 (s, 1H, CHN). IR (KBr) cm1:1687 (CO), 3305 (OH). Anal. C8H6F2O3 (C, H, N).
57%
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 0.5h;Microwave irradiation;
The 4-(difiuoromethoxy)-3-hydroxybenzaidehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3,4-dihydroxybenzaIdehyde (0.415 g, 3 mmol) in an. DMF (5 mL), CS2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate (0.520 g, 3.6 mmol) were added; then the mixture was irradiated with microwaves, under pressure, increasing the potency until 300 W in 2 minutes and cooling by compressed air to avoid the temperature increasing over 90 C; the irradiation was carried on for further 3 minutes and then the mixture was cooled to room temperature, with compressed air, in 1 minute. The cycle was repeated five time for a total reaction time of 30 minutes, The mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL); the organic phase was washed with water (20 mL), brine (20 mL), dried (MgS04) and concentrated under reduced pressure, yielding a brown oil which was purified by silicagel (100-200 mesh) column chromatography eluting with an ethylacetate /exane mixture (15:85). The pure product was obtained as a light grey solid. (0324) Yield; 57% (lit.: 15-30%). Mp: 86-88 C. -NMR (CDC13): delta 6.05 (br s, IH, OH, 1H disappears with D20), 6.65 (t, J = 72.6 Hz, OCHF2)f 7.26 (d, J = 8.2 Hz, IH, H-5 Ar), 7.45 (dd, J = 8.2, 2.0 Hz, 1H( H-6 Ar), 7.12 (d, J = 2.0 Hz, H-2 Ar), 9.90 (s, IH, CH=N). IR (KBr) (cm's): 1687 (OO), 3305 (OH). Anal. (C8H6F203) C, H. (% calculated/found) C: 51.07/ 50.96; H: 3.21/ 331.
38%
With potassium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 10 Preparation of 4-difluoromethoxy-3-hydroxybenzaldehyde 3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol, Aldrich), methyl chlorodifluoroacetate (0.52 g, 3.62 mmol, Aldrich) and potassium carbonate (0.50 g, 3.62 mmol) were combined in DMF (5.0 mL) under an argon atmosphere. After stirring at 60-65 C. for 3 h, DMF was removed in vacuo and the residue was partioned between aqueous 3N HCl and ether. The aqueous layer was extracted three times with ether. The combined organic extracts were washed with water, with brine, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes) to provide the title compound as a white solid (0.20 g, 38%). mp 83-85 C.
33%
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h;
To a solution of 3,4-hydroxybenzaldehyde [1 (Figure2), 1.38 g, 10 mmol] in dimethylformamide (DMF) (20 mL)were added methyl chlorodifluoroacetate (1.39 mL, 13 mmol)and cesium carbonate (4.23 g, 13 mmol). After the mixturerhad been stirred at 70 C for 3 h under an air atmosphere,DMF was removed in vacuo. The residue was portionedbetween aqueous 3 N HCl and ethyl acetate. Layers wereseparated, and the aqueous layer was extracted with ethylacetate (3 × 30 mL). Combined organic layers were washedwith brine, dried over Na2SO4, and concentrated in vacuo. Thecrude product was purified by flash chromatography (5:1hexane/EtOAc) to afford compound 2 (0.61 g, 33%) as awhite solid: 1H NMR (400 MHz, CDCl3) delta 9.92 (s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.45 (dd, J = 4.0, 8.4 Hz, 1H), 7.28 (d, J =8.4 Hz, 1H), 6.67 (t, J = 72.8 Hz, 1H), 6.17 (br s, 1H).
Step 1: The reaction was performed in three identical experiments of equal size: <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (altogether 15.0 g, 79.6 mmol), copper(I)-iodide (6.06 g, 31.8 mmol, 1.2 eq.) and potassium fluoride (3.08 g, 53.0 mmol, 2.0 eq.) were suspended in DMF (30 ml), and methyl chlorodifluoroacetate (7.1 ml, 66.3 mmol, 2.5 eq.) was added. The mixture was stirred at 125C for 13 h and was allowed to cool to room temperature. The reaction mixture was poured into a mixture of conc. aq. NH3-solution (140 ml) and saturated aq. NH4Cl-solution (210 ml), and the deep-blue solution was stirred for 1.5 h at room temperature. Extraction with EA (3x150ml) was followed by washing of the combined organic layer with 1/4-saturated NaCl-solution (100 ml) and brine (2*50 ml), drying over Na2SO4 and evaporation of the solvent. The crude product (20 g) was purified by flash chromatography (eluent hexane/DCM 6:1 to 4:1) to give 14.0 g (62.9 mmol, 79%) of 6-methoxy-3-nitro-2-(trifluoromethyl)pyridine as a yellow oil. TLC (hexane/DCM 4:1) Rf: 0.29. 1H-NMR (method B, DMSO-d6): 8.53 (dd, J = 0.5, 9.0, 1H), 7.39 (dd, J = 0.4, 9.0, 1H), 4.02 (s, 3H).
71%
General procedure: To a solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (0.6 g, 3.2 mmol) in DMF (1.2 mL) were added Cul (0.73 g, 3.8 mmol) and KF (0.37 g, 6.4 mmol), followed by methyl chlorodifluoro acetate (1.15 g, 7.97 mmol). The reaction mixture was heated for 13 h at 120C. The reaction mixture was then cooled to room temperature and poured onto a mixture of NH4OH and saturated aqueous NH4CI solution (1 : 1). The resulting solution was stirred for 1.5 h at room temperature. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, DCM:hexane 3- 4%) to afford the title compound (0.5 g, 71%) as a colourless oil. 5H (CDCI3) 8.17 (d, J 8.9 Hz, 1H), 7.03 (d, J 8.9 Hz, 1H), 4.09 (s, 3H).
71%
With potassium fluoride; copper(l) iodide; In N,N-dimethyl-formamide; at 120℃; for 13h;
Intermediate 69 6-Methoxy-3-nitro-2-(trifluoromethyl)pyridine [0290] To a solution of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (0.6 g, 3.2 mmol) in DMF (1.2 mL) were added CuI (0.73 g, 3.8 mmol) and KF (0.37 g, 6.4 mmol), followed by methyl chlorodifluoroacetate (1.15 g, 7.97 mmol). The reaction mixture was heated for 13 h at 120 C. The reaction mixture was then cooled to room temperature and poured onto a mixture of NH4OH and saturated aqueous NH4Cl solution (1:1). The resulting solution was stirred for 1.5 h at room temperature. The organic layer was washed with water and brine, dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, DCM: hexane 3-4%) to afford the title compound (0.5 g, 71%) as a colourless oil. deltaH (CDCl3) 8.17 (d, J=8.9 Hz, 1H), 7.03 (d, J=8.9 Hz, 1H), 4.09 (s, 3H).
65%
With potassium fluoride;copper(l) iodide; In DMF (N,N-dimethyl-formamide); at 130℃; for 8h;
2-Chloro-6-methoxy-3-nitropyridine (5g) was heated with Cul (6.05g), KF (anhydrous, 3. 0G), methyl 2-chloro-2, 2-difluoroacetate (6. 8ml) in DMF (28MOI) at 130OC for 8hrs. After cooling, it was poured into 1: 9 mixture of NH4OH/NH4Cl(100ml), stirred until homogeneous and extracted with Ethyl acetate. The organic layer were combined, washed with brine and dried (MGS04), The flash column chromatography (SIO2, 1-3% EtOAc in heptane) yielded 3.90g (65%). 1H NMR (CDCL3) No. 4. 02,6. 96,8. 10 ; IR (LIQ.) 2389 (w), 2254 (w), 2196 (w), 2163 (w), 2017 (w), 1605 (s), 1586 (s), 1538 (s), 1482 (s), 1340 (s), 1290 (s), 1261 (s), 1205 (s), 1180 (s), 1155 (s) CM-1 ANAL. CALCD for G7 H5 F3 N2 Os : C, 37.85 ; H, 2.27 ; N, 12.61 ; F, 25. 66. Found: C, 37.68 ; H, 2.29 ; N, 12.30.
42.5%
2-Chloro-6-methoxy-3-nitro-pyridine (3g, 15.9mmol), Cul (3.63g, 36.7mmol), anhydrous KF (1.8g, 31mmol) and dry DMF (20ml) were placed in a reaction vessel followed by the addition of chloro-difluoro-acetic acid methyl ester (5.61g, 38.8mmol). The mixture was stirred at 127-130 C for 8 h under an atmosphere of nitrogen. The mixture was allowed cool to room temperature, poured into a mixture of aqueous NH4OH (25ml) and NH4Cl (40g), stirred for 0.5h and extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica (eluent hexanes: chloroform 10:9) to give 1.5g (42.5%) of 6-methoxy-2-trifluoromethyl-3-nitro-pyridine as colourless oil.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 90℃; for 16h;
To a solution of <strong>[154607-00-8]methyl 2-bromo-5-hydroxybenzoate</strong> (5.63 mmol, 1.30 g) in DMF (8 mL) was added cesium carbonate (11.3 MMOL, 3.67 g) and methyl CHLORODIFLUOROACETATE (6.75 MMOL, 0.71 mL), and the reaction mixture stirred at 90C for 16 h. After cooling to rt and dilution with ethyl acetate, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane/EtOAc (9: 1, V/V) as the eluent. The product was obtained as a light yellow oil (560 mg, 35%).
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 90℃; for 24h;Heating / reflux;
A solution of 4-nitrobenzene-1,2-diol (4.18 g, 27.1 mmol), methyl chlorodifluoroacetate (3.0 mL, 28.5 mmol) and cesium carbonate (11.05 g, 33.9 mmol) in DMF (75 mL) was heated at 90C for 24h. The reaction was cooled, evaporated and diluted with ethyl acetate. Product was extracted twice into 1N NaOH, the combined aqueous phase was acidified, extracted with ethyl acetate (twice) and the organic layers were washed with water (twice) and brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 2:8 ethyl acetate : hexanes provided 2-difluoromethoxy-5-nitro-phenol (1.50 g, 27% yield) as a bright yellow solid.. 1H-NMR (DMSO-d6, 500 MHz) 10.9 (s, 1H), 7.76 (d, 1H), 7.73 (dd, 1H), 7.36 (d, 1H), 7.28 (t, 1H) ppm; MS (FIA) 204.1 (M-H); HPLC (Method A) 3.307 min.
With potassium fluoride; copper(I) iodide; In N,N-dimethyl-formamide;
Step A 2-Nitro-4-methylbenzotrifluoride A mixture of 6.00 g (27.8 mmol) of 4-bromo-3-nitrotoluene, 5.86 mL (8.03 g, 55.6 mmol) of methyl chlorodifluoroacetate, 1.93 g (33.4 mmol) of potassium fluoride, 5.31 g (27.8 mmol) of cuprous iodide, and 25 mL of dry DMF was stirred at 110 C. for 2 days. The cooled material was diluted with aqueous citric acid and extracted 3* with ethyl acetate. The combined organic extracts were washed with H2 O, then with brine, and dried over anhydrous Na2 SO4. The residue obtained upon concentration of the filtered solution was flash chromatographed 3* on silica gel (elution with 100:1 and 25:1 hexane-EtOAc) to give 3.25 g (57%) of the title compound as a yellow liquid; homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 205 (M+). 400 MHz 1 H NMR (CDCl3) delta2.48 (s, 3H), 7.49 (d, J=8 Hz, 1H), 7.67 (s, 1H) overlapping 7.68 (d, J=8 Hz, 1H).
With potassium carbonate; In ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 6 Preparation of 4-difluoromethoxybenzonitrile 4-Cyanophenol (0.12 G, 1.0 mmol, Aldrich), methyl chlorodifluoroacetate (0.29 g, 2.0 mmol, Aldrich) and potassium carbonate (0.29 g, 2.1 mmol) were combined in dry DMF (0.5 mL) under an argon atmosphere. After stirring at 75-80 C. for 0.3 h, the mixture was cooled to RT, ethyl acetate (20 mL) was added and the organic layer was washed twice with 10% NaOH. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ether/hexanes) to provide the title compound as a colorless solid (0.09 g, 53%). mp 34-35 C.
With potassium carbonate In ethyl acetate; N,N-dimethyl-formamide
8 Preparation of 4-difluoromethoxynitrobenzene
EXAMPLE 8 Preparation of 4-difluoromethoxynitrobenzene 4-Nitrophenol (0.14 g, 1.0 mmol, Aldrich), methyl chlorodifluoroacetate (0.29 g, 2.0 mmol, Aldrich) and potassium carbonate (0.29 g, 2.1 mmol) were combined in dry DMF (0.5 mL) under an argon atmosphere. After stirring at 95°-100° C. for 0.5 h, the mixture was cooled to RT, ethyl acetate (20 mL) was added and the organic layer was washed three times with 10% NaOH. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ether/hexanes) to provide the title compound as a white solid (0.12 g, 65%). mp 33°-35° C.
4-ethoxy-α,α,-difluoro-α-chloroacetophenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With iodine; In diethyl ether;
EXAMPLE 5 This Example illustrates the preparation of 4-ethoxy-alpha,alpha-difluoro-alpha-chloroacetophenone. Magnesium turnings (2.64 g), diethyl ether (dried over molecular sieves, 50 cm3) and a few crystals of iodine were placed in a 3 neck round-bottom flask and were stirred under an atmosphere of nitrogen. About 10% of a solution of 4-bromo phenetole (20 g) in dry diethyl ether (100 cm3) was added, and the mixture was warmed gently to initiate the Grignard reaction. When the reaction had begun, the rest of the bromophenetole solution was added at a rate sufficient to maintain a gentle reflux. At the end of the addition the solution was stirred for one hour. Methyldifluorochloroacetate (28.75 g) in diethylether (100 cm3) was placed in a flask under nitrogen and cooled to about -7 C. (internal temperature). The solution of the 4-ethoxyphenyl magnesium bromide was added dropwise with stirring, then the mixture was allowed to warm to the ambient temperature for about half an hour. The mixture was quenched with water and acidified with hydrochloric acid to assist solubilisation of the magnesium salts. The layers were separated and the aqueous phase was extracted twice with diethylether. The combined ether layers were washed twice with water, then dried over anhydrous magnesium sulphate before being concentrated by evaporation under reduced pressure to give a golden brown oil (22.7 g). The oil was heated at about 110 C. under reduced pressure (ca. 15 mmHg) to remove residual phenetole. The residual oil was then distilled under high vacuum (ca. 0.1 mmHg). A forefraction boiling between 60 C. and 80 C. was discarded, and the product was distilled at about 80 C., and was shown to be 97% pure by gas liquid chromatography (3.24 g). 1 H NMR (CDCl3) delta(ppm): 1.46 (3H, t); 4.16 (2H, q); ca. 7.0 and 8.1 (each 2H, d) 19 F NMR (CDCl3) delta(ppm--relative to CFCl3): -60.7 (CF2, Cl, s); infra (liquid film): 1710 cm-1
With iodine; In diethyl ether;
EXAMPLE 5 This Example illustrates the preparation of 4-ethoxy-alpha,alpha,-difluoro-alpha-chloroacetophenone. Magnesium turnings (2.64g), diethyl ether (dried over molecular sieves, 50 cm3) and a few crystals of iodine were placed in a 3 neck round-bottom flask and were stirred under an atmosphere of nitrogen. About l0% of a solution of 4-bromo phenetole (20g) in dry diethyl ether (l00 cm3) was added, and the mixture was warmed gently to initiate the Grignard reaction. When the reaction had begun, the rest of the bromophenetole solution was added at a rate sufficient to maintain a gentle reflux. At the end of the addition the solution was stirred for one hour. Methyldifluorochloroacetate (28.75g) in diethylether (l00 cm3) was placed in a flask under nitrogen and cooled to about -7C (internal temperature). The solution of the 4-ethoxyphenyl magnesium bromide was added dropwise with stirring, then the mixture was allowed to warm to the ambient temperature for about half an hour. The mixture was quenched with water and acidified with hydrochloric acid to assist solubilisation of the magnesium salts. The layers were separated and the aqueous phase was extracted twice with diethylether. The combined ether layers were washed twice with water, then dried over anhydrous magnesium sulphate before being concentrated by evaporation under reduced pressure to give a golden brown oil (22.7g). The oil was heated at about ll0C under reduced pressure (ca. l5 mmHg) to remove residual phenetole. The residual oil was then distilled under high vacuum (ca. 0.l mmHg). A forefraction boiling between 60C and 80C was discarded, and the product was distilled at about 80C, and was shown to be 97% pure by gas liquid chromatography (3.24g). 1H NMR (CDCl3) delta (ppm): l.46 (3H,t); 4.l6 (2H,q); ca. 7.0 and 8.l (each 2H,d) 19F NMR (CDCl3) delta (ppm - relative to CFCl3): -60.7 (CF2,Cl,s); infra (liquid film): l7l0 cm1
With potassium carbonate; In hexane; ethyl acetate; N,N-dimethyl-formamide;
Step 1 6-Bromo-2-difluoromethoxynaphthalene Methyl chlorodifluoroacetate (5.3 mL) was added dropwise to <strong>[91270-68-7]6-bromonaphthol</strong> (10.25 g; 45.9 mmol) and potassium carbonate (7.61g; 55.1 mmol) at 90 C in 160 mL of DMF for 6 h. Purification by gel silica chromatography (3% EtOAc in hexane) gave 4.80 g (38%) of the title compound. 1H NMR (CDCl3) delta6.61 (1H, t), 7.31 (1H,dd), 7.48 (1H, d), 7.56 (1H, dd), 7.67 (1H, d), 7.72 (1H, d) and 8.01 (1H, d).
With potassium carbonate; In ISOPROPYLAMIDE; at 110℃; for 3h;
To a solution of 4.6 g of <strong>[186590-01-2]4-fluoro-2-hydroxy-benzonitrile</strong> in 15 ml_ of anhydrous dimethylacetamide were added 6.8 g of methyl chlorodifluororacetate and 6.5 g of potassium carbonate. The resulting mixture was degassed by bubbling argon through it and heated to 1100C for 2h then an additional 6.5 g of methyl chlorodifluororacetate and 6.5 g of potassium carbonate were added. The resulting mixture was heated to 11O0C for another hour then concentrated under reduced pressure. The residue was taken into ethyl acetate, washed twice with a molar aqueous solution of sodium hydroxide, with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 80/ ehtyl acetate 20) to give 4.78 g of 2-difluoromethoxy-4-fluoro-benzonitrile as a yellowish liquid. C8H4F3NO (187.12), MS(ESI): 188.0 (M+H+).
With potassium carbonate; In ISOPROPYLAMIDE; at 110℃; for 3h;
To a solution of 4.6 g of <strong>[186590-01-2]4-fluoro-2-hydroxy-benzonitrile</strong> in 15 mL of anhydrous dimethylacetamide were added 6.8 g of methyl chlorodifluororacetate and 6.5 g of potassium carbonate. The resulting mixture was degassed by bubbling argon through it and heated to 110 C. for 2 h then an additional 6.5 g of methyl chlorodifluororacetate and 6.5 g of potassium carbonate were added. The resulting mixture was heated to 110 C. for another hour then concentrated under reduced pressure. The residue was taken into ethyl acetate, washed twice with a molar aqueous solution of sodium hydroxide, with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 80/ethyl acetate 20) to give 4.78 g of 2-difluoromethoxy-4-fluoro-benzonitrile as a yellowish liquid.C8H4F3NO (187.12), MS (ESI): 188.0 (M+H+).
With potassium fluoride; copper(l) iodide; In N,N-dimethyl-formamide; at 115℃; for 5h;
Example 15. Production of methyl 3-trifluoromethyl-pyrazine-2-carboxylate (compound No. 3-4) <strong>[27825-21-4]Methyl 3-chloropyrazine-2-carboxylate</strong> (2 g, 11.6 mmol), cuprous iodide (3.3 g, 17.3 mmol), potassium fluoride (1.34 g, 23 mmol) and methyl chlorodifluoroacetate (3.36 g, 18.2 mmol) were dissolved in DMF (20 ml) and stirred at 115C for 5 hours under argon atmosphere. The reaction solution was filtered with celite, followed by dilution of the filtrate with ethyl acetate, and washing four times with water. The filtrate was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 700 mg of the desired compound as paste state. Yield: 29% Property: 1H-NMR [CDCl3/TMS, delta (ppm)] 8.85 (d, 1H), 8.83(d, 1H), 4.05(s,3H)
With potassium carbonate; In N,N-dimethyl-formamide; at 65 - 70℃; for 16h;
Methyl chlorodifluoroacetate (1.4 ml_, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 ml_). The suspension was heated to 65-70 0C for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10% EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41 %) as a colourless oil; deltaH (400 MHz, CDCI3) 3.95 (s, 3H, OCH3), 6.60 (t, J = 74 Hz, 1 H, OCHF2), <n="39"/>7.30 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.45 (dd, J5,6 = 8.0, J2beta = 2.0 Hz, 1 H, H6), 7.50 (d, J2beta = 2.0 Hz, 1 H, HZ), 9.93 (s, 1 H, CHO); deltac (100 MHz, CDCI3) 56.2, 110.9, 115.5 (t, J = 256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8.
41%
With potassium carbonate; In N,N-dimethyl-formamide; at 65 - 70℃; for 16h;
Methyl chlorodifluoroacetate (1.4 mL, 13mmol) was added to a suspension of vanillin (15) (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) inDMF (10 mL). The suspension was heated to 65-70 C for 16 h and the suspension was diluted with water. The aqueousphase was extracted with EtOAc and the combined organic fractions were washedwith saturated aqueous NaHCO3, water, brine, dried and concentrated.The residue was purified by column chromatography, eluting with 10%EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41%) asa colourless oil; deltaH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J = 74 Hz, 1H, OCHF2), 7.30 (d, J5,6= 8.0 Hz, 1H, H5), 7.45 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.50 (d, J2,6 = 2.0 Hz, 1H, H2),9.93 (s, 1H, CHO); deltaC (100MHz, CDCl3) 56.2, 110.9, 115.5 (t, J = 256 Hz), 121.5, 125.0,134.5, 144.9, 151.5, 190.8.
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h;
A mixture of 4-hydroxy-3-methoxybenzaldehyde (6 g), CS2CO3 (25.7 g) and methyl 2- chloro-2,2-difluoroacetate (5 ml) in DMF (50 ml) was stirred at 9O0C for 1 h. At room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed twice with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1 :1 (v/v)] as eluent. Yield: 2.1 g. LC/MS-ESI: [M+H]+ = 203.1
In a solution of 5.0 g of <strong>[3032-81-3]3,5-dichloro-1-iodobenzene</strong> in 50 ml of t-butylmethylether, 12.2 ml of n-butyl lithium (1.58M hexane solution) was added dropwise at -78°C with stirring, after the completion of the addtion dropwise, stirred at the same temperature for 30 minutes. 6.6 g of chlorodifluoroacetic acid methyl ester was added dropwise at -78°C with stirring in the reaction mixture, after the completion of the addition drropwise, continued to stir at 0°C for further 30 minutes. After the completion of the reaction, the reaction mixture was poured in 100 ml of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (100 ml x 1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 4.6 g of crude aimed product as pale yellow oily substance. The resulting product was used as such without purification for the next step. 1H NMR (CDCl3, Me4Si, 300MHz) delta7.97 (s, 2H), 7.68 (s, 1 H).
With potassium carbonate In N,N-dimethyl-formamide at 20 - 100℃;
8
(Comparative Example 8); 2- (Difluoromethoxy) -4 -fluoro-1-nitrobenzeneTo a solution of 5-fluoro-2-nitrophenol (3.1 g, 20 mmol) in DMF (40 mL) , potassium carbonate (4.2 g, 30 mmol) and chlorodifluoroacetic acid methyl ester (3.2 mL, 30 mmol) were successively added at room temperature. Subsequently, the temperature of the mixture was raised to 1000C, and the mixture was stirred for 2 hours. The mixture was cooled to room temperature, and water (100 mL) was added to the reaction mixture, followed by extraction with diethyl ether (200 mL) once. The organic layer was successively washed with water (100 mL) and a saturated aqueous sodium chloride solution (100 mL) , and after it was dried with sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (3.1 g, yield: 75%) . 1H-NMR (400 MHz, CDCl3) δ: 8.03 (IH, dd, J = 9.0, 5.9 Hz) , 7.17-7.06 (2H, m) , 6.65 (IH, t, J = 72.3 Hz) .
745 mg
Stage #1: 5-fluoro-2-nitrophenol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.333333h;
Stage #2: metyhyl chlorodifluoroacetate In N,N-dimethyl-formamide at 20 - 90℃; for 3.5h;
19-1.1 2-(Difluoromethoxy)-4-fluoroaniline
(1) Potassium carbonate (2.42 g, 17.5 mmol) was added to a solution of 5-fluoro-2-nitrophenol (785 mg, 5.00 mmol) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 20 min. Chlorodifluoroacetic acid methyl ester (1.33 mL, 12.5 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 min and then stirred at an external temperature of 90°C for 3 hr. After cooling, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 → 4:1) to afford 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene as a pale yellow oil (745 mg).
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;
8.1 Step 1: Preparation of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene
5-fluoro-2-nitrophenol (3.1 g) was dissolved in dimethylformamide (40 mL), and potassium carbonate (4.2 g) and chlorodifluoroacetic acid methyl ester (3.2 mL) were slowly dropwisely added at room temperature. The mixed solution was isothermally maintained to 100° C., stirred for 2 hours, and then cooled to room temperature. Then, the resultant was added with water (100 ml) and extracted with diethyl ether (200 mL). The resulting organic layer was washed with saturated brine and dried with sodium sulfate and filtered. The resulting mixture was purified by column chromatography (silica gel, hexane/ethyl acetate) to obtain a target compound as a bright yellow solid. [0221] 1H NMR (300 MHz, CD3OD) δ 8.03 (dd, J=9.0, 5.9 Hz, 1H), 7.17-7.06 (m, 2H), 6.65 (t, J=72.3 Hz, 1H).
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;
8.1 Step 1: Preparation of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene
Step 1: Preparation of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene 5-fluoro-2-nitrophenol(3.1 g)was dissolved in dimethylformamide (40 mL), and potassium carbonate (4.2 g) and chlorodifluoroacetic acid methyl ester(3.2 mL) were slowly dropwisely added at room temperature. The mixed solution was isothermally maintained to 100°C, stirred for 2 hours, and then cooled to room temperature. Then, the resultant was added with water(100 mL) and extracted with diethyl ether(200 mL). The resulting organic layer was washed with saturated brine and dried with sodium sulfate and filtered. The resulting mixture was purified by column chromatography (silica gel, hexane/ethyl acetate) to obtain a target compound as a bright yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.03(dd, J = 9.0, 5.9 Hz, 1 H), 7.17-7.06(m, 2 H), 6.65(t, J = 72.3 Hz, 1 H).
With potassium fluoride; copper(l) iodide; In N,N-dimethyl-formamide; at 120℃;
Step 1 2-Methoxy-4-nitro-1-trifluoromethyl-benzene Following the procedure reported in JACS 2003, 125, 12502, <strong>[5458-84-4]2-iodo-5-nitroanisole</strong> (2.79 g, 10.0 mmol), copper(I) iodide (2.2 eq, 4.19 g), and potassium fluoride (2.2 eq, 1.28 g) were dissolved in DMF. ClF2CCO2CH3 (4.4 eq, 4.7 ml) was added and the mixture was heated to 120 C. overnight. Upon cooling, the mixture was diluted with water and diethyl ether and filtered through celite. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 1:1 Hexanes/Ethyl Acetate) to give 2-methoxy-4-nitro-1-trifluoromethyl-benzene (1.13 g, 51.1%) as a yellow oil.
With potassium carbonate In N,N-dimethyl-formamide at 20 - 65℃; for 22h;
B.8.a.1
To a solution of 500 mg (2.271 mmol) 2-hydroxy-4-trifluoromethyl-benzoic acid methyl ester (CAS: 345-28-8) in 5 ml N,N-dimethylformamide at room temperature, was added 470.8 mg (3.407 mmol) potassium carbonate, followed by dropwise addition of 293.4 ul (2.725 mmol) methyl chlorodifluoroacetate. The reaction mixture was heated at 65° C. oil bath for 22 hours. Water and ethyl acetate were added. The organic phase was washed 3 times with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to provide 449 mg of the title compound as a pink oil which was used in the next step without any further purification.
With potassium fluoride; copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 120℃;Inert atmosphere;
NMP (145 mL) is degassed 30 min with Ar and is then heated to 80 C. KF (7.62 g, 131 mmol), Cul (I) (24.99 g, 131 mmol) and <strong>[40263-57-8]2-iodopyridin-3-ol</strong> (29 g, 131 mmol) are added in one portion, followed by methyl 2-chloro-2,2-difluoroacetate (55.4 mL, 525 mmol).The resulting mixture is heated at 120 C under N2 for 3 nights. The mixture is allowed to cool to RT and is then poured gently into a slowly stirring mixture of 50% concentrated NaCI (1 L) solution and Et20 (4L). The organic layer is decanted carefully and the aqueous layer is extracted with Et20 (3x). The combined organic layers are concentrated, washed with brine (4x), dried with MgS04, filtered and concentrated. Flash chromatography on silica (DCM:MeOH 1.2%-10) then with (i- Pr20:EtOAc 9:1 ) follwed by trituration in heptane provides 12a1.
With potassium fluoride;copper(l) chloride; In N,N-dimethyl-formamide; at 120℃; for 12.0h;
Example 5 Preparation of Methyl 3-trifluoromethyl-pyrazine-2-carboxylate (8) To <strong>[173290-17-0]methyl 3-iodopyrazine-2-carboxylate</strong> (7) (10 g, 37.88 mmol) in DMF (Volume: 300 mL) was added methyl chlorodifluoroacetate (27 g, 0.189 mol), potassium fluoride (13.2 g, 0.227 mol), and copper chloride (22.47 g., 0.227 mol). The reaction was heated at 120 C. for 12 h. The reaction mixture was poured into ethyl ether (1000 ml) and washed with brine (3*300 ml), dried over MgSO4 before the solvent was removed. The residue was loaded onto a silica column and was eluted using ethyl acetate/hexanes gradient to afford the title compound (3.19 g, 41%) as an amber oil: 1H NMR (400 MHz, CDCl3) delta 8.85 (d, J=5.4 Hz, 1H), 8.82 (d, J=5.4 Hz, 1H), 4.05 (s, 3H); EIMS m/z 206.
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;
To a solution of 93 mg (0.71 mmol) of 4-hydroxy-1-methyl piperidine in 1.0 ml of N,N-dimethylformamide, 0.28 g (0.86 mmol) of cesium carbonate and 0.32 mg (2.2 mmol) of methyl chlorodifluoroacetate were added, and the reaction solution was stirred at 100° C. for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=75/25 (V/V)] to provide 55 mg of the title compound as a colorless oil (yield: 43percent). 1H-NMR spectrum (500 MHz, CDCl3) delta ppm: 8.53 (2H, s), 6.62 (1H, t, J=71 Hz).
With potassium fluoride; copper(l) iodide; In N,N-dimethyl-formamide; at 120.0℃; for 18.0h;Inert atmosphere; Sealed tube;
Example A51 a) Preparation of intermediate Chloro-difluoro-acetic acid methyl ester (1.38 mL, 13.082 mmol) was added to a stirred mixture of l-bromo-3-iodo-5-trifluoromethoxybenzene (2 g, 5.451 mmol), potassium fluoride (380 mg, 6.541 mmol) and copper iodide (1.38 g, 6.541 mmol) in DMF (20 mL) in a sealed tube and under N2 atmosphere. The mixture was stirred at 120 C for 18 h, then it was diluted with water and extracted with Et20. The organic layer was separated, dried over MgSC^, filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; pentane). The desired fractions were collected and concentrated in vacuo (200 mbar) to yield a colourless oil (1.41 g, 83%, volatile compound).
With copper(l) iodide; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan/[18F]fluoride; N,N,N,N,-tetramethylethylenediamine In N,N-dimethyl-formamide; acetonitrile at 100 - 150℃; for 0.333333h; Inert atmosphere; Sealed tube; regioselective reaction;
General radiochemical procedure for [18F]trifluoromethylation
General procedure: [18F]KF/K222 inMeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The solvent was evaporated under N2 at 100 °C (2 min). The vial was removed from heat,and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed vial was heated at 150° C for 20 min. The reaction was quenched by the addition ofwater (100 ml). An aliquot was removed for analysis by radioTLC and HPLC toobtain the RCY and product identity, respectively.
With copper(l) iodide; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan/[18F]fluoride; N,N,N,N,-tetramethylethylenediamine In N,N-dimethyl-formamide; acetonitrile at 100 - 150℃; for 0.333333h; Inert atmosphere; Sealed tube; regioselective reaction;
General radiochemical procedure for [18F]trifluoromethylation
General procedure: [18F]KF/K222 inMeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The solvent was evaporated under N2 at 100 °C (2 min). The vial was removed from heat,and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed vial was heated at 150° C for 20 min. The reaction was quenched by the addition ofwater (100 ml). An aliquot was removed for analysis by radioTLC and HPLC toobtain the RCY and product identity, respectively.
With copper(l) iodide; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan/[18F]fluoride; N,N,N,N,-tetramethylethylenediamine; In N,N-dimethyl-formamide; acetonitrile; at 100 - 150℃; for 0.333333h;Inert atmosphere; Sealed tube;
General procedure: [18F]KF/K222 inMeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The solvent was evaporated under N2 at 100 C (2 min). The vial was removed from heat,and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed vial was heated at 150 C for 20 min. The reaction was quenched by the addition ofwater (100 ml). An aliquot was removed for analysis by radioTLC and HPLC toobtain the RCY and product identity, respectively.
With copper(l) iodide; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan/[18F]fluoride; N,N,N,N,-tetramethylethylenediamine In N,N-dimethyl-formamide; acetonitrile at 100 - 150℃; for 0.333333h; Inert atmosphere; Sealed tube; regioselective reaction;
General radiochemical procedure for [18F]trifluoromethylation
General procedure: [18F]KF/K222 inMeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The solvent was evaporated under N2 at 100 °C (2 min). The vial was removed from heat,and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed vial was heated at 150° C for 20 min. The reaction was quenched by the addition ofwater (100 ml). An aliquot was removed for analysis by radioTLC and HPLC toobtain the RCY and product identity, respectively.
With copper(l) iodide; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan/[18F]fluoride; N,N,N,N,-tetramethylethylenediamine In N,N-dimethyl-formamide; acetonitrile at 100 - 150℃; for 0.333333h; Inert atmosphere; Sealed tube; regioselective reaction;
General radiochemical procedure for [18F]trifluoromethylation
General procedure: [18F]KF/K222 inMeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The solvent was evaporated under N2 at 100 °C (2 min). The vial was removed from heat,and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed vial was heated at 150° C for 20 min. The reaction was quenched by the addition ofwater (100 ml). An aliquot was removed for analysis by radioTLC and HPLC toobtain the RCY and product identity, respectively.
With copper(l) iodide; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan/[18F]fluoride; N,N,N,N,-tetramethylethylenediamine; In N,N-dimethyl-formamide; acetonitrile; at 100 - 150℃; for 0.333333h;Inert atmosphere; Sealed tube;
General procedure: [18F]KF/K222 inMeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The solvent was evaporated under N2 at 100 C (2 min). The vial was removed from heat,and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed vial was heated at 150 C for 20 min. The reaction was quenched by the addition ofwater (100 ml). An aliquot was removed for analysis by radioTLC and HPLC toobtain the RCY and product identity, respectively.
With copper(l) iodide; 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosan/[18F]fluoride; N,N,N,N,-tetramethylethylenediamine; In N,N-dimethyl-formamide; acetonitrile; at 100 - 150℃; for 0.333333h;Inert atmosphere; Sealed tube;
General procedure: [18F]KF/K222 inMeCN was added to a V-vial containing CuI (11 mg) and a magnetic stirrer bar. The solvent was evaporated under N2 at 100 C (2 min). The vial was removed from heat,and a solution of methyl chlorodifluoroacetate (6 ml), TMEDA (9 ml) and aryl (or heteroaryl) iodide (0.037 mmol) in DMF (300 ml) was added via syringe. The sealed vial was heated at 150 C for 20 min. The reaction was quenched by the addition ofwater (100 ml). An aliquot was removed for analysis by radioTLC and HPLC toobtain the RCY and product identity, respectively.
4-(difluoromethoxy)-2-hydroxy-3-methylbenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.7%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
Potassium carbonate (454 mg, 3.29 mmol)And methyl chlorodifluoroacetate (350 [mu] L, 3.29 mmol).Was added to GDD-4-86 (500 mg, 3.29 mmol)In DMF (20 mL)100 under the conditions of reaction 2h.After the completion of the reaction, water and ethyl acetate were added,Combine the organic phase, saturated sodium chloride to wash the organic phase,Dried over anhydrous sodium sulfate, concentrated under reduced pressure,The product was purified by silica gel column chromatography (530 mg, 79.7%);
5-bromo-6-(difluoromethoxy)-2,3-dihydro-1H-indene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 90℃; for 20.0h;Inert atmosphere;
To a solution of 6-bromo-2,3-dihydro-lH-inden-5-ol (500 mg, 2.34 mmol) in N,N- dimethylformamide (30 mL) was added sodium hydride (800 mg, 60%> in mineral oil, 20.0 mmol) under nitrogen. Methyl 2-chloro-2,2-difluoroacetate (1.70 g, 11.7 mmol) was added and the resulting mixture was stirred at 90 C for 20 h. The reaction mixture was allowed to cool to RT and diluted with ethyl acetate (100 mL). Water (30 mL) was added and the phases were separated. The organic phase was washed with water (2x), brine, dried and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (1/10). The appropriate fractions were combined and concentrated under vacuum to afford 5-bromo-6-(difluoromethoxy)-2,3-dihydro-lH-indene (240 mg, 39%>) as an off-white solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 19.5h;
A mixture of 1-(3-hydroxy-1H-pyrazol-1-yl)ethanone (20.0 g), m<strong>[383-62-0]ethyl 2-chloro-2,2-difluoroacetate</strong> (23.6 g), <strong>[383-62-0]ethyl 2-chloro-2,2-difluoroacetate</strong> (3.99 g) and potassium carbonate (32.6 g) in DMF (160 mL) was stirred at 50 C. for 19.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (623 mg). 1H NMR (300 MHz, CDCl3) delta5.98 (1H, d, J=2.7 Hz), 6.83 (1H, t, J=73.0 Hz), 7.45 (1H, d, J=2.7 Hz), 8.06 (1H, brs); MS m/z 135.1 [M+1]+.
methyl 3-bromo-5-(difluoromethoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18h;
443.A Step A. Intermediate 443A. Preparation of methyl 3-bromo-5-(difluoromethoxy) benzoate
To a stirred solution of methyl 3-bromo-5-hydroxybenzoate (900 mg, 3.9 mmol) (Park, K. et al. WO 2014/112798) in DMF (18 mL) was added potassium carbonate (540 mg, 3.9 mmol) followed by methyl chlorodifluoroacetate (560 mg, 3.9 mmol). The mixture was stirred at 80° C. After 18 h, the reaction was cooled, concentrated, diluted with water and extracted with ethyl acetate (2*30 mL). The organic layer was combined, washed with brine, dried over MgSO4, and concentrated. The crude product was purified by flash column chromatography (40 g silica gel cartridge; A=PE, B=EtOAc; 20 min grad.; 0% B to 50% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to provide the title compound (350 mg, 1.2 mmol, 30% yield) as a viscous oil. MS (ESI) 281 (M+H).
methyl 4-chloro-5,5-diethoxy-2,2-difluoropentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With chloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]copper(I); 3,5-difluoro-2,4,6-tris(N-phenylanilino)benzonitrile; N-benzyl-N,N,N-triethylammonium chloride; triphenylphosphine In dichloromethane at -20 - 20℃; for 20h; Inert atmosphere; Sealed tube; Irradiation;
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