* 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.
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：
[1] Patent: WO2014/60464, 2014, A1, . Location in patent: Page/Page column 15
[2] Patent: CN105254559, 2016, A, . Location in patent: Paragraph 0041; 0042
[3] Patent: US2008/15226, 2008, A1, . Location in patent: Page/Page column 10
[4] Patent: US2006/116373, 2006, A1, . Location in patent: Page/Page column 6
[5] Organic and Biomolecular Chemistry, 2018, vol. 16, # 38, p. 6900 - 6908
[6] Patent: CN105523922, 2016, A, . Location in patent: Paragraph 0023; 0032
[7] Patent: WO2004/22536, 2004, A1, . Location in patent: Page 36
[8] Patent: US5449686, 1995, A,
[9] Patent: US2013/79313, 2013, A1, . Location in patent: Paragraph 0965
[10] Research on Chemical Intermediates, 2013, vol. 39, # 5, p. 2107 - 2113
[11] Patent: WO2013/45280, 2013, A1, . Location in patent: Page/Page column 244
[12] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[13] Patent: US2014/275551, 2014, A1, . Location in patent: Paragraph 0053
[14] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[15] Patent: CN106146296, 2016, A, . Location in patent: Paragraph 0018
[16] Patent: CN106883118, 2017, A, . Location in patent: Paragraph 0038; 0046-0048
[17] Patent: CN102964297, 2018, B, . Location in patent: Paragraph 0020-0021; 0277; 0279
2
[ 2516-33-8 ]
[ 151103-09-2 ]
Yield
Reaction Conditions
Operation in experiment
96.6%
With potassium <i>tert</i>-butylate In 1,4-dioxane at 70 - 75℃; for 4 h;
45.5 g (0.631 mol, 1.2 eq) of cyclopropylmethanol and 70.8 g (0.631 mol, 1.2 eq) of potassium t-butoxide were placed in 200 mL of 1,4-dioxane. To the system were added dropwise 3-fluoro Difluoromethoxybenzaldehyde (100 g, 0.526 mol) in 150 mL of 1,4-dioxane.After completion of the dropwise addition, the system was heated to 70-75 ° C for 4h. After consumption of the raw material was monitored by TLC, the temperature was lowered to room temperature and 500 mL of water was added dropwise to the system to quench the reaction. The resulting mixture was extracted with 500 mL of ethyl acetate and the aqueous phase was reused Extract once with 200 mL of ethyl acetate.The organic phases were combined and concentrated under reduced pressure to give 123.1 g of an oil, yield 96.6percent, HPLC purity 99.5percent
With sodium hydroxide In N,N-dimethyl-formamide at 120℃; for 2 h;
To a two-necked 100ml flask was added 3-hydroxy-cyclopentyloxy (1.65g, 8.6mmol), chlorodifluoromethane sodium fluoroacetate (2.44g, 16mmol), NaOH solution (20mmol / L, 0.8ml) and N, N- dimethylformamide (DMF, 12ml), the reaction was heated to 120 2h, thin layer chromatography (TLC ) detecting the progress of the reaction, the reaction was complete after the DMF removed at reduced pressure and the residue was purified by silica gel column chromatography as a colorless oil cyclopentyloxy-4-difluoro-3- methoxybenzaldehyde (z-61.75g, yield 84percent)
Reference：
[1] Patent: CN105523954, 2016, A, . Location in patent: Paragraph 0025; 0026
4
[ 139-85-5 ]
[ 151103-09-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[2] Patent: US2014/275551, 2014, A1,
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[4] Patent: CN105254559, 2016, A,
[5] Patent: CN105523922, 2016, A,
[6] Patent: CN102964297, 2018, B,
[7] Organic and Biomolecular Chemistry, 2018, vol. 16, # 38, p. 6900 - 6908
[8] Organic and Biomolecular Chemistry, 2018, vol. 16, # 38, p. 6900 - 6908
5
[ 4049-39-2 ]
[ 151103-09-2 ]
Reference：
[1] Patent: CN105523954, 2016, A,
6
[ 1381886-14-1 ]
[ 151103-09-2 ]
Reference：
[1] Patent: CN105523954, 2016, A,
7
[ 121-33-5 ]
[ 151103-09-2 ]
Reference：
[1] Patent: CN106883118, 2017, A,
8
[ 162401-70-9 ]
[ 151103-09-2 ]
Reference：
[1] Patent: CN106883118, 2017, A,
9
[ 405-05-0 ]
[ 151103-09-2 ]
Reference：
[1] Patent: CN103304408, 2016, B,
10
[ 151103-09-2 ]
[ 162401-62-9 ]
Yield
Reaction Conditions
Operation in experiment
97%
With sodium chlorite; aminosulfonic acid In water; acetic acid at 20℃; for 1 h;
3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol) and sulfamic acid (7.3 g, 75 mmol) were dissolved in glacial acetic acid (50 ml) and the solution added with a solution of sodium chlorite (8.2 g, 75 mmol) in water (15 ml). The reaction mixture was stirred at room temperature for 1 hr then water (300 ml) was added so obtaining the precipitation of a solid that was filtered and dried at 40° C. under vacuum (12 g, 48 mmol, 97percent yield).
97%
With dihydrogen peroxide; potassium hydroxide In methanol at 65℃; for 1 h;
At 65 30percent hydrogen peroxide (1ml) was added 3- cyclopropylmethoxy-4-difluoromethoxy benzaldehyde (1.70g, 7mmol), 50percent potassium hydroxide (3.14g, 28mmol) and methanol ( 10ml) was prepared, stirred IH .. After completion of the reaction, water was added to dilute concentrated hydrochloric acid was adjusted to PH 2, there are a lot of white solid precipitated, filtered to give pure 3- cyclopropylmethoxy-4-difluoromethoxy-benzoic acid (z-7,1.75g yield97percent)
97.3%
With sodium chlorite; aminosulfonic acid In water; acetic acid at 20℃; for 1 h;
24.2 g (100 mmol) of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde and 14.6 g (150 mmol) of aminoSulfonic acid was dissolved in 200 mL of glacial acetic acid and to the solution was slowly added 13.6 g (150 mmol) of sodium chlorite in 30 mL of water solubleThe reaction mixture was stirred at room temperature for 1 hour and then water was added to give a solid precipitate which was filtered, washed with pure waterDried to give 25.1 g of an off-white solid, yield 97.3percent
97%
With sodium chlorite; aminosulfonic acid; acetic acid In water at 0 - 10℃; for 0.5 h;
To the reaction flask, 240 mL of glacial acetic acid, 80 g (0.33 mol) of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde and 48 g (0.49 mol, 1.48 eq) of sulfamic acid were added to the reaction flask and cooled to 0-10 with stirring ° C, and then 53.4g (0.59mol, 1.78eq) of aqueous solution of 120mL sodium chlorite was added dropwise to the system. The temperature was controlled at 0-10 .After the addition was completed, the mixture was incubated for 0.5 h. Then 500 mL of water was added to the system and stirred at room temperature for 1 h. The solid was rinsed with water and dried to obtain 82.7 g of a white solid with a yield of 97percent and a purity of 99.8percent.
90.1%
With manganese(IV) oxide; hypochloric acid In tetrahydrofuran; water at 48℃;
3) step 2) to give 3-cyclopropyl-methoxy-4-difluoromethoxy benzaldehyde (24.2g, 100mmol) and an oxidant (12.1 g of) the oxidation reaction, the oxidizing agent by a mass ratio of 4 : 1 MnO2 and HClO composition, the oxidationSolvent for the reaction by the volume ratio of 1: 5 composed of water and THF. The reaction temperature of the oxidation was 48 deg.] C, after the reaction, the reactionSolution was poured into ice-water, adjusted to pH 2, the filter cake was recrystallized from methanol to give 3-cyclopropyl-methoxy-4-difluoromethoxy-benzoicAcid, 23.3g, 90.1percent yield, purity of 99.68percent.
85%
at 5 - 20℃;
40 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde 160 mL of glacial acetic acid and 32.0 g of sulphamic acid (2.0 eq) were loaded in a reactor. The mixture was cooled at 5-10°C and the temperature was not allowed to exceed 20°C, adding slowly a previously prepared solution of 44.77 g of sodium chloride and 61 mL of deionised water. After the addition, the reaction was kept for 1 hour at 15-20°C. 450 mL of deionised water was loaded and then it was cooled at 0-5°C and kept for 1 h at this temperature. The solid was filtered and washed four times with 200 mL of deionised water. The product was dried for 15 h at 40°C, obtaining 36 g (yield 85percent) of 3- (cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) as solid.
85%
Stage #1: at 20℃; for 0.5 h; Stage #2: With sodium chlorite; aminosulfonic acid; sodium chloride In water at 5 - 20℃;
Acetic acid (20 mL) and 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (5.0 g, 0.02πο1) were added to the reaction flask and stirred at room temperature for 0.5 hour. Then, sulfamic acid (2.4 g, 0.025 mol, the reaction solution was cooled to 5 ° C and then 20 wtpercent aqueous sodium chlorite solution (11.2 g, containing sodium chloride 2.24 g, 0.025 mol) was added and then allowed to react at room temperature. TLC Methoxy-4-difluoromethoxybenzaldehyde was dissolved and quenched by the addition of water (100 mL). After stirring for 1 hour, the filter was washed with water and dried to give a white solid 3-cyclopropylmethoxy-4 - difluoromethoxybenzoic acid (4.5 g, yield 85percent, purity 98.6percent, HPLC chromatogram shown in Figure 4). The product was confirmed to be the target product 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid as shown in Figure 5
7.6 g
With potassium permanganate; potassium carbonate In water; acetone at 60℃; for 1 h;
To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMnO4 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60° C. for 1 h. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added, and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HCl 37percent (pH=1) and extracted twice with EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83percent yield). This product was used without any further purification.
7.6 g
With potassium permanganate In water; acetone at 60℃; for 1 h;
To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMn04 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60°C for lh. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HC1 37percent (pH = 1) and extracted twice with EtOAc. The organic phase was dried over Na2S04 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4- (difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83percent> yield). This product was used without any further purification.
0.51 kg
at 70 - 80℃; for 3 h; Large scale
644 g of the compound of formula I and 3.15 kg of glacial acetic acid were added to the reaction flask,Dropping 0.92 kg of 30percent hydrogen peroxide; heating to 70 ° C for 1 hour,And then heated to 80 ° C for 2 hours or more; then cooled to 30 ° C,Slowly pour into 9.00kg of drinking water, precipitation of solid; cooling to 5-10 , adding 0.36kg sodium thiosulfate aqueous solution, stirring crystallization 0.5 hours, pumping, drying, drying,To give 0.51 kg of the compound of formula II.(HPLC purity 99.3percent, 0.1percent single impurities, 3,4 isomers less than 0.03percent).
Reference：
[1] Patent: US2008/15226, 2008, A1, . Location in patent: Page/Page column 10
[2] Patent: CN105523954, 2016, A, . Location in patent: Paragraph 0025; 0027
[3] Patent: CN105254559, 2016, A, . Location in patent: Paragraph 0043; 0044
[4] Patent: CN103304408, 2016, B, . Location in patent: Paragraph 0038; 0039
[5] Patent: CN105523922, 2016, A, . Location in patent: Paragraph 0023; 0029; 0033
[6] Patent: WO2014/60464, 2014, A1, . Location in patent: Page/Page column 15
[7] Patent: CN106883118, 2017, A, . Location in patent: Paragraph 0038; 0049-0051
[8] Patent: WO2004/22536, 2004, A1, . Location in patent: Page 36-37
[9] Patent: US2013/79313, 2013, A1, . Location in patent: Paragraph 0966
[10] Research on Chemical Intermediates, 2013, vol. 39, # 5, p. 2107 - 2113
[11] Patent: WO2013/45280, 2013, A1, . Location in patent: Page/Page column 244
[12] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[13] Patent: US2014/275551, 2014, A1, . Location in patent: Paragraph 0054
[14] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[15] Patent: CN106916061, 2017, A, . Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041; 0042
[16] Patent: CN102964297, 2018, B, . Location in patent: Paragraph 0020-0021; 0277; 0280
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 70C 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 70C, 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 0-5C, 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 99%) 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 98.5%.
97%
With potassium carbonate; In tetrahydrofuran; at 0℃; for 14h;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, 97% yield), that was used without further purification.
96%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h;
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 (96% 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 87.7%, purity 99.41%.
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 %) of the product as viscous liquid which was used as such for step 2.
With potassium carbonate; In N-methyl-acetamide;
6a. 3-Cyclopropylmethoxy-4-difluoromethoxybenzaldehyde To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (19.55 g, 104 mmol) and potassium carbonate (21.56 g, 156 mmol) in dimethylformamide (150 mL) under an argon atmosphere at 60 C. was added bromomethylcyclopropane (15.13 mL, 156 mmol) and the mixture was stirred and heated at 65 C. After 1.5 h, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethylacetate and water and was extracted four times with ethyl acetate. The organic extract was washed twice with water and was dried (sodium sulfate). The solvent was removed in vacuo to provide an oil (26.4 g).
22.5 g
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 24h;
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, 94.8% 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 24h;
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, 94.8% yield, MS/ESI+ 243.1 [MH] +). This product was used without purification.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 75 - 80℃; for 6h;
A mixture of N,N-Dimethylformamide (5 vol. with respect to 3,4 Dihydroxybenzaldehyde) and potassium carbonate (1.2 eq respect to 3,4 Dihydroxybenzaldehyde) was taken in a vessel at 20-25 C. To this 3,4 Dihydroxybenzaldehyde was added and stirred for 10 min. The reaction mixture was heated to 80-85 C. Difluorochloromethane gas was purged for 8-10 hours. After completion of the reaction, the reaction mixture was cooled to 25-30 C. Potassium carbonate was filtered off and washed with N,N Dimethylformamide. Water was added to the filtrate slowly and extracted with EtOAc. EtOAc extracts were washed with aq. HCl and water. EtOAc was distilled under vacuum, 100-10 mbar at 45-50 C. to get a thick oil. The oil was taken in toluene and water and stirred for 10-15 min. To this potassium carbonate in water was added and stirred for 1 hour. Layers were separated and the combined aq. layer was washed with toluene. Aq. layer was cooled to 5-10 C., acidified with acetic acid, and stirred for 1 hour at 20-25 C. The solid was taken in 10% EtOAc/Heptane mixture and heated to 79-82 C. for 15 min. Slurry was filtered and silica gel was added to filtrate and heated to 79-82 C. for 15 min. The slurry was filtered and concentrated under vacuum at 55-60 C. to get a solid. The solid was taken in n-Heptane and stirred for 30 minutes at 5-10 C. The solid was concentrated under vacuum to get 4-Difluoromethoxy 3-hydroxy benzaldehyde.
With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 1h;
General procedure: General procedures: A mixture of 4-difluoromethoxy-3-hydroxybenzaldehyde14 (1.88 g, 10 mmol), alkylbromide (20 mmol), and cesium carbonate (6.51 g, 20 mmol) in DMF (15 mL) was stirred at 65 C for 1 h and monitored by TLC. Then, the reaction solution was poured into water and the solid was collected. The obtained precipitate 15 was used in all the following reactions without further purification.
31 g
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 2h;
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.
THF (200 mL) was added to the reaction flask, Potassium carbonate (11.0 g, 0.08 mol) and 3-hydroxy-4-difluoromethoxybenzaldehyde (10.0 g, 0.053 mol) were added and the mixture was stirred at room temperature for 1 hour. Then, methyl bromocyclopropane (10.8 g, 0.80 mol) was added and TLC Hydroxy-4-difluoromethoxybenzaldehyde was dissolved and the reaction was quenched by addition of water (100 mL) and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give a brown oil 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (10.5 g, yield 82%, purity 93.9%, HPLC chromatogram shown in Figure 3), without purification can be directly used in the next step reaction
With potassium carbonate; In tetrahydrofuran; for 14h;Reflux;
Dissolve M1 in THF Join K2CO3, bromomethyl cyclopropane stirring, the reaction solution was heated to reflux for 14 h. The reaction solution was cooled to room temperature, filtered, the solvent was distilled off under reduced pressure, and the residue was dissolved with dilute NaOH. The mixture was extracted with CH2Cl2, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 3-cyclopropylmethoxy-4-difluoromethoxy benzaldehyde M2.
With sodium chlorite; aminosulfonic acid; In water; acetic acid; at 20℃; for 1h;
3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol) and sulfamic acid (7.3 g, 75 mmol) were dissolved in glacial acetic acid (50 ml) and the solution added with a solution of sodium chlorite (8.2 g, 75 mmol) in water (15 ml). The reaction mixture was stirred at room temperature for 1 hr then water (300 ml) was added so obtaining the precipitation of a solid that was filtered and dried at 40 C. under vacuum (12 g, 48 mmol, 97% yield).
97%
With dihydrogen peroxide; potassium hydroxide; In methanol; at 65℃; for 1h;
At 65 30% hydrogen peroxide (1ml) was added 3- cyclopropylmethoxy-4-difluoromethoxy benzaldehyde (1.70g, 7mmol), 50% potassium hydroxide (3.14g, 28mmol) and methanol ( 10ml) was prepared, stirred IH .. After completion of the reaction, water was added to dilute concentrated hydrochloric acid was adjusted to PH 2, there are a lot of white solid precipitated, filtered to give pure 3- cyclopropylmethoxy-4-difluoromethoxy-benzoic acid (z-7,1.75g yield97%)
97.3%
With sodium chlorite; aminosulfonic acid; In water; acetic acid; at 20℃; for 1h;
24.2 g (100 mmol) of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde and 14.6 g (150 mmol) of aminoSulfonic acid was dissolved in 200 mL of glacial acetic acid and to the solution was slowly added 13.6 g (150 mmol) of sodium chlorite in 30 mL of water solubleThe reaction mixture was stirred at room temperature for 1 hour and then water was added to give a solid precipitate which was filtered, washed with pure waterDried to give 25.1 g of an off-white solid, yield 97.3%
97%
With sodium chlorite; aminosulfonic acid; acetic acid; In water; at 0 - 10℃; for 0.5h;
To the reaction flask, 240 mL of glacial acetic acid, 80 g (0.33 mol) of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde and 48 g (0.49 mol, 1.48 eq) of sulfamic acid were added to the reaction flask and cooled to 0-10 with stirring C, and then 53.4g (0.59mol, 1.78eq) of aqueous solution of 120mL sodium chlorite was added dropwise to the system. The temperature was controlled at 0-10 .After the addition was completed, the mixture was incubated for 0.5 h. Then 500 mL of water was added to the system and stirred at room temperature for 1 h. The solid was rinsed with water and dried to obtain 82.7 g of a white solid with a yield of 97% and a purity of 99.8%.
90.1%
With manganese(IV) oxide; hypochloric acid; In tetrahydrofuran; water; at 48℃;
3) step 2) to give 3-cyclopropyl-methoxy-4-difluoromethoxy benzaldehyde (24.2g, 100mmol) and an oxidant (12.1 g of) the oxidation reaction, the oxidizing agent by a mass ratio of 4 : 1 MnO2 and HClO composition, the oxidationSolvent for the reaction by the volume ratio of 1: 5 composed of water and THF. The reaction temperature of the oxidation was 48 deg.] C, after the reaction, the reactionSolution was poured into ice-water, adjusted to pH 2, the filter cake was recrystallized from methanol to give 3-cyclopropyl-methoxy-4-difluoromethoxy-benzoicAcid, 23.3g, 90.1% yield, purity of 99.68%.
85%
With aminosulfonic acid; acetic acid; at 5 - 20℃;
40 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde 160 mL of glacial acetic acid and 32.0 g of sulphamic acid (2.0 eq) were loaded in a reactor. The mixture was cooled at 5-10C and the temperature was not allowed to exceed 20C, adding slowly a previously prepared solution of 44.77 g of sodium chloride and 61 mL of deionised water. After the addition, the reaction was kept for 1 hour at 15-20C. 450 mL of deionised water was loaded and then it was cooled at 0-5C and kept for 1 h at this temperature. The solid was filtered and washed four times with 200 mL of deionised water. The product was dried for 15 h at 40C, obtaining 36 g (yield 85%) of 3- (cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) as solid.
85%
Acetic acid (20 mL) and 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (5.0 g, 0.02piomicron1) were added to the reaction flask and stirred at room temperature for 0.5 hour. Then, sulfamic acid (2.4 g, 0.025 mol, the reaction solution was cooled to 5 C and then 20 wt% aqueous sodium chlorite solution (11.2 g, containing sodium chloride 2.24 g, 0.025 mol) was added and then allowed to react at room temperature. TLC Methoxy-4-difluoromethoxybenzaldehyde was dissolved and quenched by the addition of water (100 mL). After stirring for 1 hour, the filter was washed with water and dried to give a white solid 3-cyclopropylmethoxy-4 - difluoromethoxybenzoic acid (4.5 g, yield 85%, purity 98.6%, HPLC chromatogram shown in Figure 4). The product was confirmed to be the target product 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid as shown in Figure 5
78%
With sodium chlorate; aminosulfonic acid;
Step 2: Oxidation of the aldehyde from step 1 with sodium chlorite (2.24 g, 24.75 mmol) and sulphamic acid (3.01 g, 31.03 mmol) as described for intermediate 1, step 2 gave 4.16 g (78 %) of the product as white crystalline solid, mp 118-120 C; IR(KBr)2930, 1691, 1601, 1516, 1441, 1297, 1060,765 cm"1; 'HNMR(300 MHz, CDC13) 6 0.36-0.41 (m, 2 H), 0.65-0.712 (m, 2 H), 1.2-1.37 (m, 1 H), 3.94(d, J= 6.6 Hz, 2 H), 6.72 (t, J= 74.7 Hz, 1 H), 7.22 (d, J= 8.1, Hz, 1 H), 7.65 5 (s, 1 H) 7.70 (d, J= 8.4 Hz, 1 H).
7.6 g
With potassium permanganate; potassium carbonate; In water; acetone; at 60℃; for 1h;
To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMnO4 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60 C. for 1 h. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added, and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HCl 37% (pH=1) and extracted twice with EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83% yield). This product was used without any further purification.
7.6 g
With potassium permanganate; In water; acetone; at 60℃; for 1h;
To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMn04 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60C for lh. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HC1 37% (pH = 1) and extracted twice with EtOAc. The organic phase was dried over Na2S04 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4- (difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83%> yield). This product was used without any further purification.
Glacial acetic acid (5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) was taken in a vessel and to this mixture of 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde and sulfamic acid (1.35 eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) was added. The reaction mass was cooled to 5-10 C. under stirring. In another clean reaction vessel sodium chlorite (1.63 eq) was taken in water (1.5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) and added dropwise to the above prepared reaction solution at temperature below 10 C. The reaction mixture was stirred for 1 hr at 5-10 C. After completion of the reaction, water was added to get a white slurry. The solid was filtered and washed with water and dried under vacuum at 45-50 C. to get 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid.
With dihydrogen peroxide; potassium hydroxide; In methanol; at 20℃; for 1h;
General procedure: A mixture of 4-difluoromethoxy-3-alkoxybenzaldehyde 15 (6.25 mmol), 30% H2O2 (1 mL) and KOH (2.8 g, 50 mmol) in methanol(10 ml) was stirred at room temperature for 1 h and monitored by TLC. Then, the reaction mixture was diluted by water (30 mL) and adjusted to pH 2 with concentrated hydrochloric acid. The formed precipitate was collected by filtration to pure 4-difluoromethoxy-3-alkoxybenzoic acid.
0.51 kg
With dihydrogen peroxide; acetic acid; at 70 - 80℃; for 3h;Large scale;
644 g of the compound of formula I and 3.15 kg of glacial acetic acid were added to the reaction flask,Dropping 0.92 kg of 30% hydrogen peroxide; heating to 70 C for 1 hour,And then heated to 80 C for 2 hours or more; then cooled to 30 C,Slowly pour into 9.00kg of drinking water, precipitation of solid; cooling to 5-10 , adding 0.36kg sodium thiosulfate aqueous solution, stirring crystallization 0.5 hours, pumping, drying, drying,To give 0.51 kg of the compound of formula II.(HPLC purity 99.3%, 0.1% single impurities, 3,4 isomers less than 0.03%).
With sodium chlorite; aminosulfonic acid; acetic acid;Cooling with ice;
Dissolve M2 and sulfamic acid in glacial acetic acid. Slowly add sodium chlorite solution to the reaction solution while cooling in an ice water bath. At the end of the reaction, water is added to the reaction solution. There is a solid precipitated, filter, dry, Light yellow solid crude, The resulting solid was recrystallized from toluene, compound SM-1 was obtained.
With hydroxylamine hydrochloride; triethylamine; In acetonitrile; at 20℃; for 20h;Heating / reflux;
a) 3-cyclopropylmethoxy4-difluoromethoxy-benzaldehyde oxime 4.50 g (18.58 mmol)) 3-cyclopropylmethoxy4-difluormethoxy-benzaldehyde are placed in 50 ml acetonitrile, 3.00 ml (22.00 mmol) triethylamine and 1.50 g (22.00 mmol) hydroxylamine-hydrochloride are added. The reaction mixture is refluxed for 4 hours and stirred for 16 hours at ambient temperature. Then the mixture is evaporated down to the residue. This is extracted with ethyl acetate and water, the organic phase is dried and evaporated to dryness. Yield: 4.56 g (95% of theoretical)
A solution of <strong>[151103-09-2]3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde</strong> (5.00 g) and 3,5-dichloro-4-methylpyridine (2.57 g) in 50 ml dry THF was cooled to -30 C. Solid potassium t-butoxide (tBuOK, 1.96 g) was added portionwise maintaining the temperature between -30 C. and -20 C., thus obtaining a dark red solution. After completion of the addition, the mixture was stirred at -30 C. for 1 hour. A saturated aqueous solution of NH4Cl (50 ml) was then added to the reaction mixture, maintaining the temperature between -5 C. and -10 C. The color of the reaction mixture turned to yellow.The mixture was then extracted with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed by evaporation. The residue was treated with 30 ml of a mixture of petroleum ether/EtOAc=8/2; the precipitate was filtered and dried, obtaining 4.83 g of the title compound that was employed in the next step without further purification.MS/ESI+ 404-406 [MH]+.
To a solution of IIb (30 g, 123.9 mmol, 1.0 eq) in toluene (150 mL) at 20-30 C. under N2 atmosphere were added trimethyl orthoformate (TMOF, 46.0 g, 433.7 mmol, 3.5 eq) and Amberlyst 15 wet (9.0 g, 30% w/w). The mixture was heated to reflux then kept refluxing until reaction completed. The solvent and excess TMOF were removed under reduced pressure at 50-60 C. to obtain IIIb. Toluene (150 mL) was added to the mixture and followed by the addition of IVa (21.2 g, 130.1 mmol, 1.05 eq) and TFA (2.8 g, 24.8 mmol, 0.2 eq) at a temperature of 40-50 C. The flask was connected with condenser and receiver, and the mixture was again heated to 110 C. and distillation was continued until the reaction was completed. The mixture was cooled to 50-60 C., then filtered and the solid was washed with toluene (30 mL). The filtrate was washed by saturated NaHCO3 (60 mL) and water (60 mL), respectively. The organic phase was removed under reduced pressure (30-50 mmHg). The flask was charged with 95% EtOH (150 mL) and then 75 mL of solvent was distilled under reduced pressure at 50 C. Repeatedly, 75 mL of 95% EtOH was charged to the residue then 75 mL of solvent was distilled to afford Vb in EtOH solution. The mixture was cooled to 25 C. then additional 95% EtOH was charged to the residue to 210 mL followed by H2O (90 mL) at the same temperature. The suspended solution was allowed to stirred for 30 min then cooled 0-5 C. then stirred for 1 hour. The slurry was filtered and the filter cake was washed with H2O (30 mL) and dried under reduced pressure at 40 C. for 2 hours to obtain Vb (35 g, 73% yield). MS m/z (M+1): 387.1; IR (KBr): 3000, 2940, 1635, 1550, 1270, 1550-1 cm. 1H NMR (300 MHz, CDCl3) delta 8.43 (s, 2H), 8.26 (s, 1H), 7.68 (s, 1H), 7.39-7.26 (m, 2H), 7.00-6.51 (t, 1H, J=75 Hz), 4.00 (d, 2H, J=6.9 Hz), 1.33 (m, 1H), 0.71-0.65 (m, 2H), 0.42-0.38 (m, 2H). 13C NMR (125 MHz, CDCl3) delta 165.38, 153.31, 150.98, 147.85, 144.15, 132.78, 124.23, 122.99, 122.29, 117.81 (CF2, JCF=260 Hz), 115.74 (CF2), 113.66 (CF2), 112.51, 74.01, 9.99, 3.22. 19F NMR (282 MHz, CDCl3) delta -82.24, -82.51.
23%
To a solution of lib (5.0 g, 20.6 mmol, 1.0 eq) in toluene (25 mL) were added PTSA (71 mg, 0.41 mmol, 0.02 eq) and TMOF (2.4 g, 22.6 mmol, 1.1 eq). The reaction mixture was heated to reflux for 2 hours. Then additional TMOF (2.4 g, 22.6 mmol, 1.1 eq) and PTSA (142 mg, 0.82 mmol, 0.04 eq) were added and heating was continued for 1 hour, after which the reaction was finished as assessed by TLC. The reaction temperature was lowered to 70-80C, and IVa (2.5 g, 15.3 mmol, 0.75 eq) and PTSA (142 mg, 0.82 mmol, 0.04 eq) were added. The mixture again was heated to reflux. After 15 hours, additional PTSA (355 mg, 2.05 mmol, 0.1 eq) and IVa (1.8 g, 11 mmol, 0.54 eq) were added and heating was continued for another 15 hours. Then, the mixture was cooled to room temperature and solvents were removed by evaporation. The residue was dissolved in dichloromethane and then washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgS04 and concentrated. The crude mixture was purified by column chromatography to afford 1.8 g (23% yield) of Vb as a colorless oil. 1H NMR (300 MHz, CDC13) delta 8.43 (s, 2H), 8.26 (s, 1H), 7.68 (s, 1H), 7.39-7.26 (m, 2H), 7.00-6.51 (t, 1H, J= 75 Hz), 4.00 (d, 2H, J= 6.9 Hz), 1.33 (m, 1H), 0.71-0.65 (m, 2H), 0.42-0.38 (m, 2H). 13C NMR (125 MHz, CDCl3) 6 165.38, 153.31, 150.98, 147.85, 144.15, 132.78, 124.23, 122.99, 122.29, 117.81 (CF2, JCF = 260 Hz), 115.74 (CF2), 113.66 (CF2), 112.51, 74.01, 9.99, 3.22. 19F NMR (282 MHz, CDCl3) delta - 82.24, - 82.51.
70%Chromat.
With N,O-Bis(trimethylsilyl)trifluoroacetamide; toluene-4-sulfonic acid; In acetonitrile; for 48h;Reflux;
As is evident from the embodiment, the synthesis of the compound of formula lib to the compound of formula Vb directly can be carried out with various Lewis acids in the presence of N,0-bis(trimethylsilyl)trifluoroacetamide (BSTFA). Table 2 shows the result using TMSOTf, TMSC1, PTSA, TfOH, MSA and TFA. The percentage of the convergence is observed via HPLC. The reaction is operated under conventional conditions in the presence of 0.2 equivalent of the Lewis acid. The reaction duration is from 3 to 48 hours. Table 2 Entry; Condition & materials; Vb HPLC purity 1) given respectively. IVa, BSTFA, TMSOTf, CH3CN, reflux for 3h 60%; 2). IVa, BSTFA, TMSCl, CH3CN, reflux for 24h 23%; 3). IVa, BSTFA, PTSA, CH3CN, reflux for 48h 70%; 4). IVa, BSTFA, TfDH, CH3CN, reflux for 5h 62%; 5). IVa, BSTFA, MSA, CH3CN, reflux for 20h 70%; 6). IVa, BSTFA, TFA, CH3CN, reflux for 18h 25%
With amberlyst 15 wet (9.0 g, 30percent w/w); In toluene; at 20℃;Inert atmosphere; Reflux;
To a solution of IIb (30 g, 123.9 mmol, 1.0 eq) in toluene (150 mL) at 20-30 C under N2 atmosphere were added trimethyl orthoformate (TMOF, 46.0 g, 433.7 mmol, 3.5 eq) and Amberlyst 15 wet (9.0 g, 30% w/w). The mixture was heated to reflux then kept refluxing until reaction completed. The solvent and excess TMOF were removed under reduced pressure at 50- 60 C to obtain Illb. Toluene (150 mL) was added to the mixture and followed by the addition of IVa (21.2 g, 130.1 mmol, 1.05 eq) and TFA (2.8 g, 24.8 mmol, 0.2 eq) at a temperature of 40- 50 C. The flask was connected with condenser and receiver, and the mixture was again heated to 110 C and distillation was continued until the reaction was completed. The mixture was cooled to 50-60 C, then filtered and the solid was washed with toluene (30 mL). The filtrate was washed by saturated NaHC03 (60 mL) and water (60 mL), respectively. The organic phase was removed under reduced pressure (30-50 mmHg). The flask was charged with 95% EtOH (150 mL) and then 75 mL of solvent was distilled under reduced pressure at 50 C. Repeatedly, 75 mL of 95% EtOH was charged to the residue then 75 mL of solvent was distilled to afford Vb in EtOH solution. The mixture was cooled to 25 C then additional 95% EtOH was charged to the residue to 210 mL followed by H2O (90 mL) at the same temperature. The suspended solution was allowed to stirred for 30 min then cooled 0-5 C then stirred for 1 hour. The slurry was filtered and the filter cake was washed with H20 (30 mL) and dried under reduced pressure at 40 C for 2 hours to obtain Vb (35 g, 73% yield). MS m/z (M+l): 387.1; IR (KBr): 3000, 2940, 1635, 1550, 1270, 1550-1 cm. 1H NMR (300 MHz, CDCl3) delta 8.43 (s, 2H), 8.26 (s, 1H), 7.68 (s, 1H), 7.39-7.26 (m, 2H), 7.00- 6.51 (t, 1H, J= 75 Hz), 4.00 (d, 2H, J= 6.9 Hz), 1.33 (m, 1H), 0.71-0.65 (m, 2H), 0.42-0.38 (m, 2H). 12C NMR (125 MHz, CDCl3) delta 165.38, 153.31, 150.98, 147.85, 144.15, 132.78, 124.23, 122.99, 122.29, 117.81 (CF2, JCF = 260 Hz), 115.74 (CF2), 113.66 (CF2), 112.51, 74.01, 9.99, 3.22. 19F NMR (282 MHz, CDCl3) delta -82.24, -82.51.
3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (Z)-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)vinyl ester[ No CAS ]
(S)-3-cyclopropylmethoxy-4-methanesulfonylaminobenzoicacid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethyl ester[ No CAS ]
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(hydroxymethyl)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide[ No CAS ]
(S)-3,5-dichloro-4-(2-(4-(cyclopropylmethoxy)-3-(methylsulfonamido)benzoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide[ No CAS ]
3-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-[(3,4-dichlorophenyl)carbonyl]-6,6-dimethyl-3,5,6,7-tetrahydro-1-benzofuran-4(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
General procedure: To a 100 ml RBF containing acetonitrile (10 ml), add dimedone 1 (3.57 mmole), phenacyl bromide 2 (3.92mmole), aromatic aldehyde 3 (3.57 mmole) and pyridine (5.6ml, 7.14 mmole) were heated at reflux temperature for 3.0 hrs. Add triethyl amine and the reaction mixture was heated up to reflux temperature for appropriate time (Table 1). After completion of the reaction, the resulting mixture was cooled to room temperature, poured in to ice cold water; stir the reaction mixture at RT for 10 hrs. The solid separated was filtered and washed with water to give final products. Recrystallization was carried out using ethanol to afford analytically pure products 4a-4x, 4a?-4h?.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
