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Structure of 36805-97-7 * 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.
4-Hydroxy-benzoic acid (3 g, 21.7 mmol) was stirred in toluene (35 ml, dried over mol. sieves). The solution was heated to 80 °C under N2, and λ/,λ/-dimethylformamide di-tert- butyl acetal (10.42 ml_, 43.4 mmol) was added over ca. 5 min. The mixture was stirred at 80 °C for 1 h 10 min., and cooled to rt. The solution was washed with water, twice with sat. NaHCO3 and sat. NaCI (15 ml. each), dried over MgSO4, and concentrated to yield a yellow oil (2.77 g). The product was purified by flash chromatography (380 g silica, eluant: 4:6 AcOEt/heptane (2 L) and 1 :1 AcOEt/heptane 700 mL) to yield white crystals (2.07g, 49percent yield).HPLC-MS m/z: 217 (M+23).1H-NMR (CDCI3, 400 MHz) 7.90 (d, 2H), 6.85 (d, 2H), 6.10 (s, 1 H), 1.59 (s, 9H).
23%
for 1 h; Heating / reflux
Intermediate 39; 4-Hydroxy-benzoic acid tert-butyl ester; 4-Hydroxybenzoic acid (5.29 g, 38.3 mmol) (Aldrich) was suspended in dry benzene (200 mL) and the mixture was heated to reflux. N,N'-Dimethylformamide di-t-butyl acetal (36.7 mL, 0.15 mol) (Aldrich) was added dropwise and the mixture was heated at reflux for a further 1 hour. The cooled solution was washed with water, saturated aqueous sodium bicarbonate solution and brine. After drying (magnesium sulfate) and filtering, the solvent was evaporated. The residue was purified by flash chromatography eluting with 25percent hexanes in dichloromethane and 10percent ethyl acetate in dichloromethane to give 4-hydroxy-benzoic acid tert-butyl ester. (Yield 1.72 g, 23percent).
Reference：
[1] Journal of Physical Chemistry B, 1999, vol. 103, # 30, p. 6206 - 6214
[2] Patent: WO2007/128817, 2007, A2, . Location in patent: Page/Page column 87
[3] Patent: US2007/60607, 2007, A1, . Location in patent: Page/Page column 30
11
[ 2304-94-1 ]
[ 36805-97-7 ]
[ 18605-26-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 7, p. 1497 - 1503
12
[ 619-66-9 ]
[ 36805-97-7 ]
[ 65874-27-3 ]
Yield
Reaction Conditions
Operation in experiment
81%
for 1.5 h; Reflux
To a solution of 4-formylbenzoic acid (1.0 g, 6.7 mmol) in refluxing benzene (12.6 mL, 0.50 M) was added 1,1-di-tert-butoxy-N,Ndimethylmethanamine (6.4 mL, 26.6 mmol, 4.0 equiv) over a period of 1 hr. The reaction was then allowed to continue refluxing for 30 mm before being cooled to rt and diluted with water. After washing with saturated sodium bicarbonate (2x), the combined organic layers were washed with brine,dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified using flash column chromatography on Si02 (Hexanes/EtOAc: 6/1) to yield a white solid (1.1 g, 81 percent).
57%
at 20℃; Heating / reflux
Step (2): synthesis of 4-formyl-benzoic acid tert-butyl ester:; 4-Formylbenzoic acid was suspended in 60 mL of benzene, and the mixture was placed under a nitrogen atmosphere. The mixture was brought to reflux and N,N -dimethylformamide di-tert-butylacetal was added dropwise via an addition funnel over 45 minutes. The yellowish suspension gradually turned golden yellow and became a homogeneous solution. The solution was refluxed an additional 60 minutes before stirring overnight at room temperature. The resulting orange solution was diluted to about 100 mL with ethyl acetate ("EtOAc"), and the resulting solution was washed sequentially with water, saturated sodium bicarbonate (2 x 100 mL), and brine (100 mL). The solvent was removed by rotary evaporation. The resulting amber oil was injected on to a BIOTAGE.(R). Flash 65i (350 g, silica gel) cartridge and purified with a 30-minute gradient of from 5percent to 25percent v/v EtOAc in heptane. Product fractions were pooled, and the solvent was rotary evaporated. The resulting golden oil was dried under house high vacuum overnight at room temperature to give 3.92 g (57percent yield) of 4- formyl-benzoic acid tert-butyl ester as a yellow solid; IH NMR (400 MHz, DMSO-D6) δ ppm 1.54 (s, 9 H) 8.00 (dm, /=8.30, Hz, 2 H) 8.07 (dm, /=8.30, 2 H) 10.08 (s, 1 H); Mass Spectrum MH" 206.
45%
for 1.41667 h; Heating / reflux
A solution of 4-carboxybenzaldehyde (15A) (0.35 g, 2.1 mmol) in toluene (9 mL) was heated to reflux and N,N-dimethylformamide di-tert-butyl-acetal (3.8 mL, 16.0 mmol) was added over 25 minutes. After the addition was complete, the reaction was stirred at reflux for an additional hour then cooled to room temperature. The reaction mixture was washed sequentially with water, 5percent aqueous NaHCO3, and brine. The organic phase was separated, <n="147"/>dried over MgSO4, filtered and concentrated in vacuo to provide compound 16A, which was used without further purification (0.37 g, 45percent).
35.4%
for 3 h; Reflux
Compound 2 was prepared according to a similar previously described protocol. 42 To the solution of 4-carboxybenzaldehyde (521 mg, 3.45 mmol) in benzene (6.5 mL) N,N-dimethylformamide di-tert-butyl acetal (2.5 eq, 1760 mg) was added dropwise over a period of 1 h and refluxed. After 2 h the mixture was cooled down to room temperature and water was added (10 mL). The organic layer was collected and concentrated in vacuum. Product was purified chromatographically (silica gel, eluted with Hexane:EtOAc 6:1, v:v). Compound 2 was obtained in 35.4percent yield.
Reference：
[1] Patent: WO2014/25942, 2014, A1, . Location in patent: Page/Page column 29
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2334 - 2356
[3] Journal of Medicinal Chemistry, 2001, vol. 44, # 10, p. 1491 - 1508
[4] Patent: WO2006/61715, 2006, A2, . Location in patent: Page/Page column 37
[5] Patent: WO2008/130584, 2008, A1, . Location in patent: Page/Page column 145-146
[6] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 5062 - 5068
[7] Journal of Organic Chemistry, 1998, vol. 63, # 17, p. 5818 - 5823
The carboxylic acid (10 g, 60.9 mmol) and Me2NCH(OtBu)2 (25 g) were heated in toluene (300 ml_) for 5 hours (85 0C). More Me2NCH(OtBu)2 (25 g) was added, and the reaction was heated at 85 0C for 14 hours. The solution was partitioned between EtOAc and sat. NaHCO3(aq.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solution residue was filtered through a plug of SiO2 rinsing with CH2CI2. This afforded 4.7 g (35 percent) of the tert-butyl ester as a solid.
A solution of 10.0 g (63.4 mmol) 2-chloro-isonicotinic acid in 100 ml chloroform is heated to reflux temperature. In total 91.2 ml (380 mmol, 6 eq) N,N-dimethylformamide di-tert-butylacetal is added in 3 portions of each 30.4 ml at the start, after 1 h and after 2 h. After cooling to rt the mixture is diluted with EtOAc, washed with aq. bicarbonate and brine, and dried over sodium sulfate. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give 7.6 g (35.6 mmol, 56percent) of the product as white solid.MS (LC/MS): 158=[M+H-tBu]+1H-NMR (300 MHz, CDCl3): 8.55 (d, 1H), 7.85 (s, 1H), 7.76 (d, 1H), 1.64 (s, 9H).
33%
at 90℃; for 20 h;
a) To a solution of 2-chloroisonicotinic acid (5.00 g, 31.7 mmol) in toluene is added N,Ndimethylformamide di-tert. butylacetal (17.9 g, 79.3 mmol). The mixture is stirred at 90°C for 20 h. The mixture is concentrated, filtered and the filtrate is diluted with EA and washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting heptane:EA 5:1 to give tert. butyl 2-chloroisonicotinate (2.23 g, 33percent) as a colourless oil; LC-MS: tR = 0.98 mm, [M+1+CH3CN] = 255.31.
Reference：
[1] Patent: US2008/132477, 2008, A1, . Location in patent: Page/Page column 28
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 1, p. 110 - 130
[3] Patent: WO2014/141171, 2014, A1, . Location in patent: Page/Page column 17; 18
21
[ 5398-44-7 ]
[ 36805-97-7 ]
[ 75308-46-2 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 80℃; Inert atmosphere
PREPARATION 32; ferf-butyl 2-chloro-6-(pyrazin-2-ylamino)isonicotinate; a) iert-Butyl 2,6-dichloroisonicotinate; To a solution of 2,6-dichloroisonicotinic acid (2 g, 10.4 mmol) in toluene (50 mL) N,N- dimethylformamide di-fert-butil acetal (15 mL, 62.5 mmol) was added under nitrogen atmosphere and mixture heated at 80°C overnight. Ethyl acetate was added and organic layer was washed with water and brine, dried (MgS04), filtered and concentrated to yield the title compound (2.34 g, 87percent) as a solid.LRMS (m/z): 249 (M+1)+.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.60 (s, 9 H) 7.74 (s, 2 H)
87%
at 80℃; Inert atmosphere
To a solution of 2,6-dichloroisonicotinic acid (2 g, 10.4 mmol) in toluene (50 mL) N,N dimethylformamide di-tert-butil acetal (15 mL, 62.5 mmol) was added under nitrogen atmosphere and mixture heated at 80 Ethyl acetate was added and organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated to yield the title compound (2.34 g, 87percent) as a solid.LRMS (m/z): 249 (M+1)+.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.60 (s, 9 H) 7.74 (s, 2 H)
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 4, p. 595 - 604
[2] Patent: WO2012/41476, 2012, A1, . Location in patent: Page/Page column 67
[3] Patent: EP2441755, 2012, A1, . Location in patent: Paragraph 0184
[4] Patent: WO2008/29371, 2008, A1, . Location in patent: Page/Page column 38-39
[5] Patent: WO2009/24905, 2009, A1, . Location in patent: Page/Page column 53-54
[6] Patent: US2010/63108, 2010, A1, . Location in patent: Page/Page column 15
[7] Patent: US2010/87417, 2010, A1, . Location in patent: Page/Page column 13
[8] Patent: US2011/212998, 2011, A1, . Location in patent: Page/Page column 20
[9] Patent: WO2008/114157, 2008, A1, . Location in patent: Page/Page column 31
22
[ 505-54-4 ]
[ 36805-97-7 ]
[ 843666-27-3 ]
Yield
Reaction Conditions
Operation in experiment
47.6%
Reflux
Hexadecanedioic acid (4.5 g, 15.71 mmol) was suspended in Toluene (28.1 ml) and the mixture was heated to reflux. 1,1 -di-tert-butoxy-N,Ndimethylmethanamine (10.10 ml, 42.1 mmol) was added drop-wise over 30 mm. Themixture was reflux overnight. The solvent was removed in vacuo at 50°C and the crude material was suspended in CH2C12/EtOAc (75 mL. 1:1) ans stirred for 15 mm. The solids were removed by filtration and washed with CH2C12 (25 mL). The filtration was evaporated in vacuo. The resulting material was suspended in CH2C12 (6 mL), cooled with ice for 10 mins, and filtered. The solvent was removed invacuo to leave crude product which was purified by flash chromatography (silic gel,EtOAc/Hexane) to get 16-(tert-butoxy)-16-oxohexadecanoic acid (2.56 g, 7.47 mmol,47.6 percent yield). Analysis condition D: Retention time = 5.04 mm; ESI-MS(+) m/z269.3 [M — OC(CH3)3]; ‘H NMR (500MHz, METHANOL-d4) ö 2.33 - 2.18 (m, 4H),1.66 - 1.54 (m, 4H), 1.50 - 1.43 (m, 9H), 1.40 - 1.25 (m, 20H).
33%
Stage #1: at 50℃; Stage #2: With ethyl acetate In dichloromethane for 0.25 h;
Hexadecadioic acid (40.0 g, 140 mmol) was suspended in toluene (250 ml) and the mixture was heated to reflux. λ/,λ/-dimethylformamide di-tert-butyl acetal (76.3 g, 375 mmol) was added drop-wise over 4 hours. The mixture was refluxed overnight. The solvent was removed in vacuo at 50 0C, and the crude material was suspended in DCM/AcOEt (500 ml, 1 :1 ) and stirred for 15 mins. The solids were collected by filtration and triturated with DCM (200 ml). The filtrated were evaporated in vacuo to give crude mono-tert-butyl hexadecandioate, 30 grams. This material was suspended in DCM (50 ml), cooled with ice for 10 mins, and filtered. The solvent was removed in vacuo to leave 25 gram crude mono- tert-butyl hexadecandioate, which was recrystallized from heptane (200 ml) to give mono- tert-butyl hexadecandioate, 15.9 g (33 percent).1H-NMR (CDCI3) δ: 2.35 (t, 2H), 2.20 (t, 2H), 1.65-1.55 (m, 4H), 1.44 (s, 9H), 1.34- 1.20 (m, 20 H).
33%
Reflux
Hexadecandioic acid (40.0 g, 140 mmol) was suspended in toluene (250 ml) and the mixture was heated toreflux. N,N-Dimethylformamide di-tert-butyl acetal (76.3 g, 375 mmol) was added drop-wise over 4 hours. The mixturewas refluxed overnight. The solvent was removed in vacuo at 50 °C, and the crude material was suspended in dichloromethane/ethyl acetate (500 ml, 1:1) and stirred for 15 mins. The solids were collected by filtration and triturated withdichloromethane (200 ml). The filtrated were evaporated in vacuo to give crude mono-tert-butyl hexadecandioate, 30grams. This material was suspended in dichloromethane (50 ml), cooled with ice for 10 mins, and filtered. The solventwas removed in vacuo to leave 25 gram crude mono-tert-butyl hexadecandioate, which was recrystallized from heptane(200 ml) to give mono-tert-butyl hexadecandioate, 15.9 g (33 percent). Alternatively to recrystallization, the mono-ester canbe purified by silica chromatography with ethyl acetate/heptane. 1H-NMR (CDCl3) δ: 2.35 (t, 2H), 2.20 (t, 2H), 1.65-1.55(m, 4H), 1.44 (s, 9H), 1.34-1.20 (m, 20 H).
33%
for 4 h; Reflux
The hexadecanedioic acid (20.0 g, 69.8 mmol) was suspended in toluene (125 ml) according to the process for the preparation of tert-butyl hexadecanedioate disclosed in No. 4 of Novo Nordisk Company Patent No. CN1829738.The mixture was heated to reflux. N,N-dimethylformamide di-tert-butyl acetal (38.2 g, 187.5 mmol) was added dropwise over 4 hours and the mixture was refluxed overnight. Remove the solvent in vacuo at 50°C,It was suspended in DCM/AcOEt (250 ml, 1:1) and stirred for 15 minutes. The solid was collected by filtration, resuspended by the addition of DCM (50 ml), and the filtrate was collected by filtration, distilled under reduced pressure, and the resulting product was suspended in DCM (25 ml) pre-cooled to 0°C.The temperature was reduced to 4°C, and the solvent was distilled off under reduced pressure. Recrystallization from n-heptane (100 ml) gave 7.9 g (33percent) of mono-tert-butyl hexadecanedioate, which was not suitable for industrial scale-up.
A suspension of octadecanedioic acid (15 g, 47.7 mmol) in Toluene (191 ml) was brought to reflux in 3 neck 1 L round bottom flask. When all of the acid was in solution, 1,1 -di-tert-butoxy-N,N-dimethylmethanamine (22.87 ml, 95 mmol) wasadded dropwise over 30 minutes. The reaction mixture was heated under reflux overnight. The reaction was stopped after 20 total hours of heating. The reaction mixture was cooled to room temperature resulting in precipitation of solids. The mixture was filtered by vacuum filtration. The resulting white solid was suspended in 200 ml dichloromethane and stirred for 15 minutes. The remaining solids wereremoved via vacuum filtration. The collected solids were again suspended in dichloromethane and stirred for 15 minutes. After a second filtration the combined filtrates were concentrated in vacuo and the resulting white powder was dried undervacuum. 18-(tert-butoxy)-18-oxooctadecanoic acid (10.14 g, 27.4 mmol, 57.4 percent yield) was isolated as a white solid. ‘H NMR (400MHz, CHLOROFORM-d) ö 2.35(t, J=7.5 Hz, 2H), 2.21 (t, J=7.5 Hz, 2H), 1.70 - 1.52 (m, 4H), 1.45 (s, 9H), 1.36 -1.22 (m, 24H).
To a solution of 4-formylbenzoic acid (1.0 g, 6.7 mmol) in refluxing benzene (12.6 mL, 0.50 M) was added 1,1-di-tert-butoxy-N,Ndimethylmethanamine (6.4 mL, 26.6 mmol, 4.0 equiv) over a period of 1 hr. The reaction was then allowed to continue refluxing for 30 mm before being cooled to rt and diluted with water. After washing with saturated sodium bicarbonate (2x), the combined organic layers were washed with brine,dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified using flash column chromatography on Si02 (Hexanes/EtOAc: 6/1) to yield a white solid (1.1 g, 81 %).
57%
In benzene; at 20℃;Heating / reflux;
Step (2): synthesis of 4-formyl-benzoic acid tert-butyl ester:; 4-Formylbenzoic acid was suspended in 60 mL of benzene, and the mixture was placed under a nitrogen atmosphere. The mixture was brought to reflux and N,N -dimethylformamide di-tert-butylacetal was added dropwise via an addition funnel over 45 minutes. The yellowish suspension gradually turned golden yellow and became a homogeneous solution. The solution was refluxed an additional 60 minutes before stirring overnight at room temperature. The resulting orange solution was diluted to about 100 mL with ethyl acetate ("EtOAc"), and the resulting solution was washed sequentially with water, saturated sodium bicarbonate (2 x 100 mL), and brine (100 mL). The solvent was removed by rotary evaporation. The resulting amber oil was injected on to a BIOTAGE Flash 65i (350 g, silica gel) cartridge and purified with a 30-minute gradient of from 5% to 25% v/v EtOAc in heptane. Product fractions were pooled, and the solvent was rotary evaporated. The resulting golden oil was dried under house high vacuum overnight at room temperature to give 3.92 g (57% yield) of 4- formyl-benzoic acid tert-butyl ester as a yellow solid; IH NMR (400 MHz, DMSO-D6) delta ppm 1.54 (s, 9 H) 8.00 (dm, /=8.30, Hz, 2 H) 8.07 (dm, /=8.30, 2 H) 10.08 (s, 1 H); Mass Spectrum MH" 206.
45%
In toluene; for 1.41667h;Heating / reflux;
A solution of 4-carboxybenzaldehyde (15A) (0.35 g, 2.1 mmol) in toluene (9 mL) was heated to reflux and N,N-dimethylformamide di-tert-butyl-acetal (3.8 mL, 16.0 mmol) was added over 25 minutes. After the addition was complete, the reaction was stirred at reflux for an additional hour then cooled to room temperature. The reaction mixture was washed sequentially with water, 5% aqueous NaHCO3, and brine. The organic phase was separated, <n="147"/>dried over MgSO4, filtered and concentrated in vacuo to provide compound 16A, which was used without further purification (0.37 g, 45%).
35.4%
In benzene; for 3h;Reflux;
Compound 2 was prepared according to a similar previously described protocol. 42 To the solution of 4-carboxybenzaldehyde (521?mg, 3.45?mmol) in benzene (6.5?mL) N,N-dimethylformamide di-tert-butyl acetal (2.5?eq, 1760?mg) was added dropwise over a period of 1?h and refluxed. After 2?h the mixture was cooled down to room temperature and water was added (10?mL). The organic layer was collected and concentrated in vacuum. Product was purified chromatographically (silica gel, eluted with Hexane:EtOAc 6:1, v:v). Compound 2 was obtained in 35.4% yield.
Following the general procedure of Tagat (Tagat, J.R.; McCombie, S.W.; Nazareno, D.V.;Boyle, CD.; Kozlowski, J.A.; Chackalamannil, S.; Josien, H.; Wang, Y.; Zhou, G. J. Org. Chem. 2002, 67, 1171-77), a suspension of the bromo acid x (3.0 g, 12.0 mmol) in toluene (18 mL) was heated at 80 0C. To this reaction mixture was added dropwise N,N- dimethylformamide i-tert-butyl acetal (10.0 mL, 42 mmol), and the resulting mixture was heated for an additional 30 min. It was cooled to it, washed with water, saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford 2.87 g (78%) of f-butyl ester k_l as a yellow oil, which was carried on without further purification.
To a suspension of 1 g (6.35 mmol) of 6-chloropyridine-3-carboxylic acid in 10 mL of refluxing toluene are added dropwise 7.6 mL (31.75 mmol) of 1,1-di-tert-butoxy-N,N-dimethylmethanamine, and the reaction medium is then refluxed for 30 minutes. After cooling to room temperature, the reaction medium is taken up in 200 mL of EtOAc, washed successively with water (2*100 mL), with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 1.16 g of tert-butyl 6-chloropyridine-3-carboxylate are obtained in the form of a yellow oil, which is used without further purification in the following step.Yield=86%1H NMR, d6-DMSO, 400 MHz, delta (ppm): 8.8 (s, 1H); 8.2 (d, 1H); 7.3 (d, 1H); 1.5 (s, 9H).
1,1-Di-tert-butoxy-N,N-dimethylmethanamine (5.0 mL, 21 mmol) was added slowly dropwise via addition funnel to a refluxing mixture of hexadecanedioic acid (2.2 g, 7.7 mmol) in toluene (15 mL). After refluxing overnight, the mixture was concentrated and absorbed to 10 grams of silica gel and purified by flash chromatography (0 to 100% ethyl acetate/hexanes) to furnish 16-(tert-butoxy)-16-oxohexadecanoic acid (2) as a white solid (1.3 g, 3.8 mmol, 49% yield). LCMS m/z 365 (MH+).
47.6%
In toluene;Reflux;
Hexadecanedioic acid (4.5 g, 15.71 mmol) was suspended in Toluene (28.1 ml) and the mixture was heated to reflux. 1,1 -di-tert-butoxy-N,Ndimethylmethanamine (10.10 ml, 42.1 mmol) was added drop-wise over 30 mm. Themixture was reflux overnight. The solvent was removed in vacuo at 50C and the crude material was suspended in CH2C12/EtOAc (75 mL. 1:1) ans stirred for 15 mm. The solids were removed by filtration and washed with CH2C12 (25 mL). The filtration was evaporated in vacuo. The resulting material was suspended in CH2C12 (6 mL), cooled with ice for 10 mins, and filtered. The solvent was removed invacuo to leave crude product which was purified by flash chromatography (silic gel,EtOAc/Hexane) to get 16-(tert-butoxy)-16-oxohexadecanoic acid (2.56 g, 7.47 mmol,47.6 % yield). Analysis condition D: Retention time = 5.04 mm; ESI-MS(+) m/z269.3 [M - OC(CH3)3]; ?H NMR (500MHz, METHANOL-d4) oe 2.33 - 2.18 (m, 4H),1.66 - 1.54 (m, 4H), 1.50 - 1.43 (m, 9H), 1.40 - 1.25 (m, 20H).
33%
Hexadecadioic acid (40.0 g, 140 mmol) was suspended in toluene (250 ml) and the mixture was heated to reflux. lambda/,lambda/-dimethylformamide di-tert-butyl acetal (76.3 g, 375 mmol) was added drop-wise over 4 hours. The mixture was refluxed overnight. The solvent was removed in vacuo at 50 0C, and the crude material was suspended in DCM/AcOEt (500 ml, 1 :1 ) and stirred for 15 mins. The solids were collected by filtration and triturated with DCM (200 ml). The filtrated were evaporated in vacuo to give crude mono-tert-butyl hexadecandioate, 30 grams. This material was suspended in DCM (50 ml), cooled with ice for 10 mins, and filtered. The solvent was removed in vacuo to leave 25 gram crude mono- tert-butyl hexadecandioate, which was recrystallized from heptane (200 ml) to give mono- tert-butyl hexadecandioate, 15.9 g (33 %).1H-NMR (CDCI3) delta: 2.35 (t, 2H), 2.20 (t, 2H), 1.65-1.55 (m, 4H), 1.44 (s, 9H), 1.34- 1.20 (m, 20 H).
33%
In toluene;Reflux;
Hexadecandioic acid (40.0 g, 140 mmol) was suspended in toluene (250 ml) and the mixture was heated toreflux. N,N-Dimethylformamide di-tert-butyl acetal (76.3 g, 375 mmol) was added drop-wise over 4 hours. The mixturewas refluxed overnight. The solvent was removed in vacuo at 50 C, and the crude material was suspended in dichloromethane/ethyl acetate (500 ml, 1:1) and stirred for 15 mins. The solids were collected by filtration and triturated withdichloromethane (200 ml). The filtrated were evaporated in vacuo to give crude mono-tert-butyl hexadecandioate, 30grams. This material was suspended in dichloromethane (50 ml), cooled with ice for 10 mins, and filtered. The solventwas removed in vacuo to leave 25 gram crude mono-tert-butyl hexadecandioate, which was recrystallized from heptane(200 ml) to give mono-tert-butyl hexadecandioate, 15.9 g (33 %). Alternatively to recrystallization, the mono-ester canbe purified by silica chromatography with ethyl acetate/heptane. 1H-NMR (CDCl3) delta: 2.35 (t, 2H), 2.20 (t, 2H), 1.65-1.55(m, 4H), 1.44 (s, 9H), 1.34-1.20 (m, 20 H).
33%
In toluene; for 4h;Reflux;
The hexadecanedioic acid (20.0 g, 69.8 mmol) was suspended in toluene (125 ml) according to the process for the preparation of tert-butyl hexadecanedioate disclosed in No. 4 of Novo Nordisk Company Patent No. CN1829738.The mixture was heated to reflux. N,N-dimethylformamide di-tert-butyl acetal (38.2 g, 187.5 mmol) was added dropwise over 4 hours and the mixture was refluxed overnight. Remove the solvent in vacuo at 50C,It was suspended in DCM/AcOEt (250 ml, 1:1) and stirred for 15 minutes. The solid was collected by filtration, resuspended by the addition of DCM (50 ml), and the filtrate was collected by filtration, distilled under reduced pressure, and the resulting product was suspended in DCM (25 ml) pre-cooled to 0C.The temperature was reduced to 4C, and the solvent was distilled off under reduced pressure. Recrystallization from n-heptane (100 ml) gave 7.9 g (33%) of mono-tert-butyl hexadecanedioate, which was not suitable for industrial scale-up.
Preparation of Hexadecanedioic Acid mono-tert-butyl Ester This compound was prepared from hexadecanedioic acid and dimethylformamide-di-tert-butyl acetal according to the general procedure reported in the literature: U. Widmer, Synthesis 1983, 135.
In toluene; at 20 - 70℃; for 5.5h;Molecular sieve;
4-lodobenzoic acid (10 g, 40.3 mmol) was dissolved in dry toluene (100 ml, dried over mol. sieves). The solution was heated to 70 C under a flow of nitrogen. A solution of lambda/,lambda/-dimethylformamide di-tert-butyl acetal (24.6 g, 121 mmol) in toluene (25 mL) was added over ca. 30 min. The reaction was mixed for 16 h. At some point the heating unit failed, so the reaction cooled from 70 C to rt. The solution was heated to 70 C for and mixed for 5 h. The sample was concentrated under vacuum, and AcOEt (400 ml) was added. The solution was then washed with 1 :1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCI (75 mL each). The organic phase was dried (MgSO4) and concentrated under vacuum to yield light brown oil. HPLC-MS m/z: 327 (M+23).1H-NMR (CDCI3, 400 MHz) delta 7.77 (d, 2H), 7.69 (d, 2H), 1.58 (s, 9H).
A suspension of <strong>[54916-66-4]5-bromo-2-methoxy-3-pyridine carboxylic acid</strong> (9.3 g, 40 mmol) in toluene (100 ml) was treated with N,N-dimethylformamide di-t-butylacetal (16.3 g, 80 mmol) and the mixture heated at 80 C. for 2 hours. The mixture was cooled and the solvents evaporated. The residue was dissolved in ethyl acetate and washed with water (×2). The organic phase was dried and evaporated to give the title compound (D23). 1H NMR CDCl3 ppm delta 1.58 (9 h, s), 4.01 (3H, s), 8.14 (1H, s), 8.3 (1H, s).
PREPARATION 32; ferf-butyl 2-chloro-6-(pyrazin-2-ylamino)isonicotinate; a) iert-Butyl 2,6-dichloroisonicotinate; To a solution of 2,6-dichloroisonicotinic acid (2 g, 10.4 mmol) in toluene (50 mL) N,N- dimethylformamide di-fert-butil acetal (15 mL, 62.5 mmol) was added under nitrogen atmosphere and mixture heated at 80C overnight. Ethyl acetate was added and organic layer was washed with water and brine, dried (MgS04), filtered and concentrated to yield the title compound (2.34 g, 87%) as a solid.LRMS (m/z): 249 (M+1)+.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.60 (s, 9 H) 7.74 (s, 2 H)
87%
In toluene; at 80℃;Inert atmosphere;
To a solution of 2,6-dichloroisonicotinic acid (2 g, 10.4 mmol) in toluene (50 mL) N,N dimethylformamide di-tert-butil acetal (15 mL, 62.5 mmol) was added under nitrogen atmosphere and mixture heated at 80 Ethyl acetate was added and organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated to yield the title compound (2.34 g, 87%) as a solid.LRMS (m/z): 249 (M+1)+.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.60 (s, 9 H) 7.74 (s, 2 H)
In toluene; at 80℃; for 3h;
a) A suspension of 2,6-dichloroisonicotinic acid (5.23 g, 27.24 mmol) in toluene (100 ml.) is heated to 800C and then slowly treated with N,N-dimethylformamide di-tert. butylacetal (19.94 g, 98.0 mmol). The mixture becomes slightly yellow and clear. Heating and stirring is continued for 3 h before the solution is cooled to rt, diluted with ether and washed with sat. aq. Na2CO3-solution. The org. extract is dried over MgSO4, filtered and the solvent is <n="40"/>evaporated to give 2,6-isonicotinic acid tert.-butyl ester (6.97 g) which solidifies as beige fine needles. 1 H NMR (CDCI3): delta 1.60 (s, 6 H), 7.73 (s, 1 H).
In toluene; at 20 - 80℃; for 28h;
2,6-Dichloro-isonicotinic acid (11.2 g, 57.1 mmol) is suspended in toluene (150 mL) at 800C and then treated with N,N-dimethylformamide di-tert. -butyl acetal (50 mL, 209 mmol). The dark mixture is stirred at 800C for 12 h, then at rt for 16 h. The dark solution is diluted with diethyl ether (400 mL), washed with sat. aq. NaHCOs <n="55"/>solution (3x100 ml_), dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in heptane to give 2,6-dichloro-isonicotinic acid tert. -butyl ester (14.2 g) as a brownish oil which slowly solidifies; LC-MS: tR = 1.05 min; 1H NMR (D6-DMSO): £ 1.56 (s, 9 H), 7.85 (s, 2 H).
In toluene; at 80℃;
A suspension of 2,6-dichloroisonicotinic acid (5.23 g, 27.24 mmol) in toluene (100 mL) is heated to 80 C. and then slowly treated with N,N-dimethylformamide di-tert. butylacetal (19.94 g, 98.0 mmol). The mixture becomes slightly yellow and clear. Heating and stirring is continued for 3 h before the solution is cooled to rt, diluted with ether and washed with sat. aq. Na2CO3-solution. The org. extract is dried over MgSO4, filtered and the solvent is evaporated to give 2,6-isonicotinic acid tert.-butyl ester (6.97 g) which solidifies as beige fine needles. 1H NMR (CDCl3): delta 1.60 (s, 6H), 7.73 (s, 1H).
In toluene; at 20 - 80℃; for 28h;
a) 2,6-Dichloro-isonicotinic acid (11.2 g, 57.1 mmol) is suspended in toluene (150 mL) at 80 C. and then treated with N,N-dimethylformamide di-tert.-butyl acetal (50 mL, 209 mmol).The dark mixture is stirred at 80 C. for 12 h, then at rt for 16 h. The dark solution is diluted with diethyl ether (400 mL), washed with sat. aq. NaHCO3 solution (3×100 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:ethyl acetate to give 2,6-dichloro-isonicotinic acid tert.-butyl ester (14.2 g) as a brownish oil which slowly solidifies; LC-MS: tR=1.05 min; 1H NMR (D6-DMSO): delta 1.56 (s, 9H), 7.85 (s, 2H).
In toluene; at 20 - 80℃; for 28h;
a) 2,6-Dichloro-isonicotinic acid (11.2 g, 57.1 mmol) is suspended in toluene (150 mL) at 80 C. and then treated with N,N-dimethylformamide di-tert.-butyl acetal (50 mL, 209 mmol). The dark mixture is stirred at 80 C. for 12 h, then at rt for 16 h. The dark solution is diluted with diethyl ether (400 mL), washed with sat. aq. NaHCO3 solution (3*100 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in heptane to give 2,6-dichloro-isonicotinic acid tert.-butyl ester (14.2 g) as a brownish oil which slowly solidifies; LC-MS: tR=1.05 min; 1H NMR (D6-DMSO): delta 1.56 (s, 9H), 7.85 (s, 2H).
In toluene; at 20 - 80℃; for 28h;
2,6-Dichloro-isonicotinic acid (11.2 g, 57.1 mmol) is suspended in toluene (150 mL) at 800C and then treated with N,N-dimethylformamide di-tert.-butyl acetal (50 mL, 209 mmol).The dark mixture is stirred at 800C for 12 h, then at rt for 16 h. The dark solution is diluted with diethyl ether (400 mL), washed with sat. aq. NaHCO3 solution (3x100 mL), dried overNa2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:ethyl acetate to give 2,6-dichloro-isonicotinic acid tert. -butyl ester (14.2 g) as a brownish oil which slowly solidifies; LC-MS: tR = 1.05 min; 1H NMR (D6-DMSO): £1.56 (s, 9 H), 7.85 (s, 2 H).
This monomer was generated in situ (during library synthesis) from 4-aza-oxindole and dimethylformamide di-t-butylacetal in DMF.Monomer 9 and Monomer 10 were generated in situ by preparing stock solutions of the corresponding aza-oxindole. For example, 20.1 mg of 4-aza-oxindole was dissolved in 4.0 mL of ethanol. Both of the precursors for monomers 9 and 10 were transferred (0.20 ml/well) to a 96-well dry heating block (vwrBRAND Dry Block Heater, cat No.13259-066) according to the map below where M represents the monomer and A represents the amine. The ethanol was evaporated off at 50 C. until it was clear that there was no solvent remaining. DMF (0.20 mL) was added followed by the addition of dimethylformamide di-t-butylacetal (0.003 mL) and this remained at room temperature for 1 h.
Monomer 9: 3-Dimethylaminomethylene-<strong>[5654-97-7]7-azaoxindole</strong> This monomer was generated in situ (during library synthesis) from <strong>[5654-97-7]7-azaoxindole</strong> and dimethylformamide di-t-butylacetal in DMF.
In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;
This monomer was generated in situ (during library synthesis) from 7-aza-oxindole and dimethylformamide di-t-butylacetal in DMF.Monomer 9 and Monomer 10 were generated in situ by preparing stock solutions of the corresponding aza-oxindole. For example, 20.1 mg of 4-aza-oxindole was dissolved in 4.0 mL of ethanol. Both of the precursors for monomers 9 and 10 were transferred (0.20 ml/well) to a 96-well dry heating block (vwrBRAND Dry Block Heater, cat No.13259-066) according to the map below where M represents the monomer and A represents the amine. The ethanol was evaporated off at 50 C. until it was clear that there was no solvent remaining. DMF (0.20 mL) was added followed by the addition of dimethylformamide di-t-butylacetal (0.003 mL) and this remained at room temperature for 1 h.
To a stirred solution of trans-<strong>[20595-30-6]3-fluorocinnamic acid</strong> (4.34g, 26.1mmol) in toluene [(40ML)] at [110C] was added N,N-dimethylformamide di-tert-butyl acetal [(25ML,] [104MMOL)] dropwise over 30 min. The resulting mixture was stirred at, reflux for a further 4h. The mixture was then cooled to room temperature and washed with water [(50ML),] saturated aqueous sodium hydrogen carbonate solution (2 x 100mL) and brine [(LOOML),,] dried [(MGSO4)] and evaporated. The crude product was purified by Bond Elut (isohexane then 2% ethyl acetate in isohexane) to give the sub-title compound as a liquid (3.7g, 64%).
N, N-DIMETHYLFORMAMIDE-DI-TERT.-BUTYL-ACETAL (19 mL, 80 MMOL) is added during 40 min to a hot (65C, flask temperature) suspension of 2-chloro-6-methyl-isonicotinic acid (3.40 g, 19. 8 MMOL) in dry toluene (100 mL). The clear orange solution is stirred at 80C for 48 h, cooled to r. t. and diluted with toluene (100 mL). The solution is washed with water (2 x 40 mL), sat. aq. NAHCO3 (3 x 30 mL) and sat. aq. NACF (25 mL), dried (NA2SO4), filtered and evaporated. The residue is purified by FC (SI02, CH2CI2-MeOH) to provide the title compound.
In chloroform; for 4.5h;Heating / reflux;
A solution of 5.0 g (29 mmol) of 2-chloro-6-methyl-isonicotinic acid in 50 ml of chloroform is heated to reflux. 14 ml (58 mmol, 2 eq) of di-tert-butoxymethyl-dimethyl-amine are added dropwise over 30 min. After a reaction time of 1.5 h and 3.5 h, further portions of di-tert- butoxymethyl-dimethyl-amine (each time 14 ml, 58 mmol, 2 eq) are added. After a reaction time of 4.5 h, the reaction mixture is cooled to rt and diluted with EtOAc. The organic layer is washed with aq sodium bicarbonate and then brine, dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give the product in the form of a white solid.Rf (DCM/methanol = 95:5): 0.36.MS (LC / MS): 172/174 = [M + H - tert-butylf.1H-NMR (400 MHz, CDCI3): 7.65 (s, 1H), 7.60 (s, 1H), 2.63 (s, 3H), 1.63 (s, 9H).
In toluene; at 80℃; for 92h;
a) A suspension of 2-chloro-6-methyl-isonicotinic acid (7.0 g, 40.9 mmol) in toluene (100 mL) is heated to 800C and then slowly treated with N,N-dimethylformamide di-tert. butylacetal (21.2 g, 104.3 mmol). The mixture becomes clear. Heating and stirring is continued for 20 h before another portion N,N-dimethylformamide di-tert. butylacetal (8.32 g, 40.9 mmol) is added. Stirring is continued at 80C for 72 h. The reaction mixture is cooled to rt, diluted with ether and washed with sat. aq. Na2CO3-solution. The org. extract is dried over MgSO4, filtered and the solvent is carefully evaporated. The crystalline material that formed is collected, carefully washed with cold heptane and dried to give 2-chloro-6- methyl-isonicotinic acid tert.-butyl ester (6.29 g) as colourless fine needles; LC-MS: tR = 1.01 min, [M+1]+ = 228.11 ; 1H NMR (CDCI3): delta 7.61 (s, 1 H), 7.56 (s, 1 H), 2.59 (s, 3H), 1.29 (s, 9H).
In chloroform; for 5h;Heating / reflux;Product distribution / selectivity;
A solution of 5.0 g (29 mmol) <strong>[25462-85-5]2-Chloro-6-methyl-isonicotinic acid</strong> in 50 ml chloroform is heated to reflux temperature. 14 ml (58 mmol, 2 eq) Di-tert-butoxymethyl-dimethyl-amine are added dropwise over 30 min. After 1.5 h and 3.5 h reaction time another portion of di-tert-butoxymethyl-dimethyl-amine (each time 14 ml, 58 mmol, 2 eq) is added. After 4.5 h the reaction mixture is cooled to rt, diluted with EtOAc, washed with aqueous bicarbonate and brine and dried over magnesium sulfate. The product is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give a white solid.Rf: (DCM/methanol=95:5): 0.36MS (LC/MS): 172/174=[M+H-tBu]+ 1H-NMR (400 MHz, CDCl3): 7.65 (s, 1H), 7.60 (s, 1H), 2.63 (s, 3H), 1.63 (s, 9H).; Building block A6: 2-But-3-enyl-6-methyl-isonicotinic acid hydrochloridea) <strong>[25462-85-5]2-Chloro-6-methyl-isonicotinic acid</strong> tert-butyl esterA suspension of 5.00 g (29.1 mmol) 2-chloro-6-methyl-isonicotinic acid in chloroform is heated to reflux and 14.0 ml (58.3 mmol, 2 eq) N,N-dimethylformamide-di-tert-butylacetal are added over a period of 30 min. After 1.5 h and 3.5 h another portion of each time 5 ml (20.8 mmol, 0.7 eq) N,N-dimethylformamide-di-tert-butylacetal is added. After 4.5 h the mixture is cooled to rt, diluted with EtOAc, washed with aq. bicarbonate and brine, dried over sodium sulfate and the solvents are evaporated at reduced pressure. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give the product in the form of a white solid.MS (LC/MS): 172=[M+H-tBu]+ 1H-NMR (400 MHz, CDCl3): 7.65 (s, 1H), 7.60 (s, 1H), 2.63 (s, 3H), 1.63 (s, 9H).
In toluene; at 65 - 80℃; for 48.6667h;
a) N,N-dimethylformamide-di-tert.-butyl-acetal (19 mL, 80 mmol) is added during 40 min to a hot (65 C., flask temperature) suspension of 2-chloro-6-methyl-isonicotinic acid (3.40 g, 19.8 mmol) in dry toluene (100 mL). The clear orange solution is stirred at 80 C. for 48 h, cooled to rt and diluted with toluene (100 mL). The solution is washed with water (2×40 mL), sat. aq. NaHCO3 (3×30 mL) and sat. aq. NaCl (25 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, DCM-MeOH) to give 2-chloro-6-methyl-isonicotinic acid tert-butyl ester.
In toluene; at 20 - 80℃; for 75 - 92h;Product distribution / selectivity;
A suspension of 2-chloro-6-methyl-isonicotinic acid (7.0 g, 40.9 mmol) in toluene (100 mL) is heated to 80C and then slowly treated with N,N-dimethylformamide di- tert. butylacetal (21.2 g, 104.3 mmol). The mixture becomes clear. Heating and stirring is continued for 20 h before another portion N,N-dimethylformamide di-tert. butylacetal (8.32 g, 40.9 mmol) is added. Stirring is continued at 800C for 72 h. The <n="39"/>reaction mixture is cooled to rt, diluted with diethyl ether and washed with sat. aq. Na2CO3-solution. The org. extract is dried over MgSO4, filtered and the solvent is carefully evaporated. The crystalline material that forms is collected, carefully washed with cold heptane and dried to give 2-chloro-6-methyl-isonicotinic acid tert- butyl ester (6.29 g) as colourless fine needles; LC-MS: tR = 1.01 min; [M+1]+ = 228.11 ; 1H NMR (CDCI3): delta 7.61 (s, 1 H), 7.56 (s, 1 H), 2.59 (s, 3H), 1.29 (s, 9H); <strong>[25462-85-5]2-Chloro-6-methyl-isonicotinic acid</strong> (7.55 g, 44.0 mmol) is suspended in toluene (150 mL) at 800C and then treated with N,N-dimethylformamide di-tert. -butyl acetal (50 mL, 209 mmol). The mixture is stirred at 80C for 3 h, then at rt for 72 h. The clear solution is diluted with diethyl ether (250 mL), washed with sat. aq. NaHCO3 solution (4x50 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:ethyl acetate to give 2-chloro- 6-methyl-isonicotinic acid tert. -butyl ester (8.57 g) as a brownish oil which slowly solidifies; LC-MS: tR = 0.99 min; [M+H]+ = 213.24 (-15); 1H NMR (D6-DMSO): £1.56 (s, 9 H), 2.54 (s, 3 H), 7.59 (s, 1 H), 7.66 (s, 1 H).
In toluene; at 80℃;
A suspension of 2-chloro-6-methyl-isonicotinic acid (7.0 g, 40.9 mmol) in toluene (100 mL) is heated to 80 C. and then slowly treated with N,N-dimethylformamide di-tert. butylacetal (21.2 g, 104.3 mmol). The mixture becomes clear. Heating and stirring is continued for 20 h before another portion N,N-dimethylformamide di-tert. butylacetal (8.32 g, 40.9 mmol) is added. Stirring is continued at 80 C. for 72 h. The reaction mixture is cooled to rt, diluted with ether and washed with sat. aq. Na2CO3-solution. The org. extract is dried over MgSO4, filtered and the solvent is carefully evaporated. The crystalline material that formed is collected, carefully washed with cold heptane and dried to give 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (6.29 g) as colourless fine needles; LC-MS: tR=1.01 min, [M+1]+=228.11; 1H NMR (CDCl3): delta 7.61 (s, 1H), 7.56 (s, 1H), 2.59 (s, 3H), 1.29 (s, 9H).
In toluene; at 20 - 80℃; for 75h;
a) <strong>[25462-85-5]2-Chloro-6-methyl-isonicotinic acid</strong> (7.55 g, 44.0 mmol) is suspended in toluene (150 mL) at 80 C. and then treated with N,N-dimethylformamide di-tert.-butyl acetal (50 mL, 209 mmol). The mixture is stirred at 80 C. for 3 h, then at rt for 72 h. The clear solution is diluted with diethyl ether (250 mL), washed with sat. aq. NaHCO3 solution (4×50 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:ethyl acetate to give 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (8.57 g) as a brownish oil which slowly solidifies; LC-MS: tR=0.99 min, [M+H]+=213.24 (-15); 1H NMR (D6-DMSO): delta 1.56 (s, 9H), 2.54 (s, 3H), 7.59 (s, 1H), 7.66 (s, 1H).
In toluene; at 80℃; for 92h;Product distribution / selectivity;
a) A suspension of 2-chloro-6-methyl-isonicotinic acid (7.0 g, 40.9 mmol) in toluene (100 mL) is heated to 80 C. and then slowly treated with N,N-dimethylformamide di-tert. butylacetal (21.2 g, 104.3 mmol). The mixture becomes clear. Heating and stirring is continued for 20 h before another portion N,N-dimethylformamide di-tert. butylacetal (8.32 g, 40.9 mmol) is added. Stirring is continued at 80 C. for 72 h. The reaction mixture is cooled to rt, diluted with diethyl ether and washed with sat. aq. Na2CO3-solution. The org. extract is dried over MgSO4, filtered and the solvent is carefully evaporated. The crystalline material that forms is collected, carefully washed with cold heptane and dried to give 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (6.29 g) as colourless fine needles; LC-MS: tR=1.01 min; [M+1]+=228.11; 1H NMR (CDCl3): delta 7.61 (s, 1H), 7.56 (s, 1H), 2.59 (s, 3H), 1.29 (s, 9H).
In toluene; at 20 - 80℃; for 75h;
<strong>[25462-85-5]2-Chloro-6-methyl-isonicotinic acid</strong> (7.55 g, 44.0 mmol) is suspended in toluene (150 mL) at 800C and then treated with N,N-dimethylformamide di-tert.-butyl acetal (50 mL, 209 mmol). The mixture is stirred at 800C for 3 h, then at rt for 72 h. The clear solution is diluted with diethyl ether (250 mL), washed with sat. aq. NaHCOs solution (4x50 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:ethyl acetate to give 2-chloro-6-methyl-isonicotinic acid tert.-butyl ester (8.57 g) as a brownish oil which slowly solidifies; LC-MS: tR = 0.99 min, [M+H]+ = 213.24 (-15); 1H NMR (D6-DMSO): £ 1.56 (s, 9 H), 2.54 (s, 3 H), 7.59 (s, 1 H), 7.66 (s, 1 H).
In toluene; at 65 - 80℃; for 48h;
[N, N-DIMETHYLFORMAMIDE-DI-TERT.-BUTYL-ACETAL] (19 mL, 80 [MMOL)] is added during 40 min to a hot [(65C,] flask temperature) suspension of 2-chloro-6-methyl- isonicotinic acid (3.40g, 19.8 [MMOL)] in dry toluene (100 mL). The clear orange solution is stirred at [80C] for 48 h, cooled to r. t. and diluted with toluene (100 mL). The solution is washed with water (2 x 40 mL), sat. aq. [NAHCO3] (3 x 30 mL) and sat. aq. NaCI (25 mL), dried [(NA2SO4),] filtered and evaporated. The residue is purified by FC [(SIO2,] [CH2CI2-MEOH)] to provide the title compound.
(i) <strong>[16732-64-2]4-Bromo-1H-indole-2-carboxylic acid</strong> tert-butyl ester To 7 g <strong>[16732-64-2]4-Bromo-1H-indole-2-carboxylic acid</strong> in 150 ml toluene, 28 ml Di-tert-butoxymethyl-dimethyl-amine were added dropwise at 80 C. The reaction mixture was heated under reflux for additional 12 h. After removal of the solvents under reduced pressure the residue was dissolved in 200 ml DCM and washed with sat. aqueous NaHCO3 solution (2*50 ml). he organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluding with n-heptane/ethyl acetate 9:1. The fractions containing the product were collected and concentrated under reduced pressure. Yield: 6.5 g MS (ESI+): m/e=297.
In toluene; at 80℃; for 12h;
(i) <strong>[16732-64-2]4-Bromo-1H-indole-2-carboxylic acid</strong> tert-butyl ester To 7 g <strong>[16732-64-2]4-Bromo-1H-indole-2-carboxylic acid</strong> in 150 ml toluene, 28 ml Di-tert-butoxymethyl-dimethyl-amine were added dropwise at 80 C. The reaction mixture was heated under reflux for additional 12 h. After removal of the solvents under reduced pressure the residue was dissolved in 200 ml DCM and washed with sat. aqueous NaHCO3 solution (2*50 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluding with n-heptane/ethyl acetate 9:1. The fractions containing the product were collected and concentrated under reduced pressure. Yield: 6.5 g. MS (ESI+): m/e=297.
(1) A mixture composed of <strong>[2434-03-9]4,5-dibromo-2-furancarboxylic acid</strong> (20.00 g), DMF di-tert-butylacetal (71.08 ml) and toluene (100 ml) was stirred for 2 hours at 90C. The reaction solution was diluted with toluene and washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane = 1/20), thereby giving 20.10 g of tert-butyl 4,5-dibromo-2-furancarboxylate.(2) Tert-butyllithium (1.51 M pentane solution: 30.48 ml) was added dropwise to a diethyl ether (100 ml) solution of the above-obtained tert-butyl ester compound (10.00 g) at -78C. After confirming the completion of the reaction at -78C, the reaction solution was poured into saturated aqueous ammonium chloride solution (200 ml), diluted with diethyl ether (100 ml), and mixed with 2 M hydrochloric acid. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%?10% ethyl acetate/hexane gradient), thereby giving 1.81 g of the desired compound.
a) A solution of (4-NITRO-LH-PYRAZOL-L-YL) acetic acid (2.0 g, 11.7 mmol) in toluene (40 ml) was heated to 80C and then N, N-dimethylformamide di-tert-butyl acetal (7.0 g, 34.5 mmol) was added dropwise over 1 hour. The reaction mixture was heated at 80C for a further 20 minutes and then allowed to cool to room temperature. The mixture was concentrated and the residue purified by silica gel chromatography eluting with 50% methyl tert-butyl ether in iso-hexane to give tert-butyl (4-NITRO-1H-PYRAZOL-1-YL) acetate (2.21 g, 83% yield) as a colourless solid: LH-NMR (CDC13) : 8. 25 (s, 1H), 8.10 (s, 1H), 4. 83 (s, 2H), 1.52 (s, 9H).
3-[(dimethylamino)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide;
3-[(Dimethylamino)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one This monomer was generated in situ (during library synthesis) from <strong>[32501-05-6]1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one</strong> and dimethylformamide di-t-butylacetal in DMF.
With methanesulfonic acid; sodium hydrogencarbonate; In methanol; ethanol; water; N,N-dimethyl-formamide;
Example 3A 4-[(2-Oxo-1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzenesulfonamide Dimethylformamide di-tert-butyl acetal (180 mg, 0.89 mmol) was added to a solution of 1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-2-one (70 mg, 0.52 mmol) in 0.25 ml DMF, and the reaction mixture was slowly warmed to 100 C. The cooled solution was then diluted with 5 ml of ethanol. Sulfanilamide (172 mg, 1.00 mmol) and methanesulfonic acid (60 mg, 0.63 mmol) were added, and the reaction mixture was stirred at reflux for 2 hours. The cooled solution was diluted with 4 ml of water, treated with NaHCO3 (70 mg, 0.83 mmol) and stirred 10 min. The resulting solid was filtered, washed with water and ethanol, and then suspended in boiling methanol and filtered upon cooling. Inorganics were removed by filtration through a short silica gel column, eluding with DMF. The resulting solution was diluted with an equal volume of ice water, and the suspension was refrigerated overnight. The solid was isolated by filtration and dried to give 36 mg (21%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) (4:1 ratio of Z:E isomers): delta (Z) 11.07 (s, 1H), 10.76 (d, J=12.4 Hz, 1H), 8.67 (d, J=12.5 Hz, 1H), 7.92 (d, J=5.1 Hz, 1H), 7.84 (d, J=7.3 Hz,
36 mg (21%)
With methanesulfonic acid; sodium hydrogencarbonate; In methanol; ethanol; water; N,N-dimethyl-formamide;
EXAMPLE 3 4-[(2-oxo-1,2-Dihydro-3H-pyrrolo[2,3-b]pyridin-3-ylidene)methyl]amino}benzenesulfonamide Dimethylformamide di-tert-butyl acetal (180 mg, 0.89 mmol) was added to a solution of 1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-2-one (70 mg, 0.52 mmol) in 0.25 ml DMF, and the reaction mixture was slowly warmed to 100 C. The cooled solution was then diluted with 5 ml of ethanol. Sulfanilamide (172 mg, 1.00 mmol) and methanesulfonic acid (60 mg, 0.63 mmol) were added, and the reaction mixture was stirred at reflux for 2 h. The cooled solution was diluted with 4 ml of water, treated with NaHCO3 (70 mg, 0.83 mmol) and stirred 10 min. The resulting solid was filtered, washed with water and ethanol, and then suspended in boiling methanol and filtered upon cooling. Inorganics were removed by filtration through a short silica gel column, eluding with DMF. The resulting solution was diluted with an equal volume of ice water, and the suspension was refrigerated overnight. The solid was isolated by filtration and dried to give 36 mg (21%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) (4:1 ratio of Z:E isomers): delta (Z) 11.07 (s, 1H), 10.76 (d, J=12.4 Hz, 1H), 8.67 (d, J=12.5 Hz, 1H), 7.92 (d, J=5.1 Hz, 1H), 7.84 (d, J=7.3 Hz, 1H), 7.77 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 7.25 (s, 2H), 6.93 (dd, J=7.3, 5.1 Hz, 1H); (E) 10.79 (s, 1H), 9.70 (d, J=13.4 Hz, 1H), 8.23 (d, J=7.3 Hz, 1H). ESI-MS m/z 315 (M-H). Anal. Calcd. for C14H12N4O3S. 0.5 H2O: C, 51.68; H, 4.03; N, 17.03. Found: C, 51.75; H, 3.95; N, 17.26.
3-dimethylaminomethylene-1,3-dihydropyrrolo[2,3-b]pyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide;
3-[(Dimethylamino)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-one This compound was prepared in situ (during library synthesis) from <strong>[5654-97-7]1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one</strong> and dimethylformamide di-t-butylacetal in DMF.
Example 20 Preparation of 4-[(dimethylamino)methylene]-3-(1.3-thiazol-2-yl)-2-pyrazolin-5-one, (Compound 296) To a solution of the pyrazolone (VIa), (250 mg, 1.5 mmol) in dry THF (12 mL) was added N,N-dimethylformamide di-tert-butyl acetal (0.319 g, 1.05 equiv) and the reaction mixture was heated under reflux for 15 min. TLC (10% methanol-chloroform) showed complete conversion of the pyrazolone (Rf=0.08) to a new product (Rf=0.17). Concentration of the reaction gave compound 296 as a solid. 1H-HMR (d6-DMSO) delta11.26 (s, 1H, enolic), 8.69 (s, 1H, =CH), 7.86 (s, 1H), 7.67 (s, 1H), 3.79 (s, 3H), 3.33 (s, 3H); electrospray MS, m/z 223 [M+1]+base peak; HPLC Rt=5.01 min. versus Rt=4.06 min. for the pyrazolone (VIa), (method A).
5-Bromo-2-(dimethylamino-methyleneamino)-3-methyl-benzoic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.61 g (49%)
In toluene;
EXAMPLE 234 5-Bromo-2-(dimethylamino-methyleneamino)-3-methyl-benzoic acid tert-butyl ester A mixture of 5.0 g (21.7 mmol) of the product of Example 132 and 20.8 ml (86.9 mmol) of N,N-dimethylformamide di-t-butylacetal in 30 ml of toluene was heated to reflux for 2 hr. The reaction mixture was cooled to room tenperature, washed with water and brine, dried over MgSO4 and concentrated in vacuo to provide 3.61 g (49%) of the desired product as an yellow oil. Electrospray Mass Spec 341(M+H).
3.61g (49%)
In toluene;
Example 234 5-Bromo-2-(dimethylamino-methyleneamino)-3-methyl-benzoic acid tert-butyl ester A mixture of 5.0g (21.7 mmol) of the product of Example 132 and 20.8ml (86.9 mmol) of N,N-dimethylformamide di-t-butylacetal in 30ml of toluene was heated to reflux for 2 hr. The reaction mixture was cooled to room temperature, washed with water and brine, dried over MgSO4 and concentrated in vacuo to provide 3.61g (49%) of the desired product as an yellow oil. Electrospray Mass Spec 341(M+H).
Intermediate 16 4-Carboxymethylsulfanyl-3-chloro-benzoic acid tert-butyl ester a) 3-Chloro-4-fluoro-benzoic acid tert-butyl ester4-Bromo-3-chloro-benzoic acid (1.3 g) was slurried in toluene (3 mL) and (di-tert- butoxymethyl)dimethylamine (9 mL) was added. The reaction mixture was heated to 115 0C for 16 h. The mixture was evaporated, the residue was partitioned between sodium bicarbonate solution and ethyl acetate, the organic phase was dried and evaporated to give the subtitle compound (1.3 g). LC-MS std RT 2.85 <n="34"/>1HNMR delta(cDCB) 1.60 (9H3 s), 7.17 (IH, t), 7.85 - 7.93 (IH3 m), 8.01 - 8.07 (IH, m).
Example 40A 6-Fluoro-nicotinic acid tert-butyl ester To a stirred and refluxed solution of 6-fluoro-nicotinic acid (0.092 g, 6.52 mmol) in benzene and 2-methyl-propan-2-ol (2:1, 15:7 mL) was added dropwise N,N-dimethylformamide di-tert-butyl acetal (8.2 mL, 29.6 mmol). The reaction mixture was refluxed for 3 hours, cooled to room temperature and partitioned between aqueous NaHCO3 and dichloromethane. The organic layer was washed with water and brine, dried (MgSO4), filtered, concentrated under reduced pressure and purified by flash chromatography with 15% to 30% ethyl acetate in hexane to provide the titled compound. MS (CI) m/z 197 (M+1)+; 1H NMR (300 MHz, CDCl3) delta ppm 8.82(d, 1H), 8.38(m, 1H), 6.98(d, 1H), 1.64 (s, 9H).
Description 13: 1 H-Pvrazole-4-carboxylic acid ter-butyl ester A stirred suspension of 1 H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (1. 12g) in dry toluene (20ml) was heated at 70°C for 15min under an atmosphere of nitrogen. To the hot suspension was added a solution of N, N-dimethylformamide-di-tert-butyl acetal (8ml) in dry toluene (8ml). The resultant solution was heated at 78°C for 21 hrs. After cooling, the mixture was diluted with ethyl acetate (100ml) and washed with saturated aqueous brine solution (5x25mi). The organic phase was dried over magnesium sulphate, filtered, and evaporated to dryness to give a gum. The gum was purified by flash column chromatography on silica gel (60g of Merck 9385) and eluted with dichloromethane/methanol 50: 1. The required fractions were combined and evaporated to dryness to give the title compound as a gum which solidified upon standing (0.481g). Mpt. 96-97 °C
To eicosanedioic acid (3 g, 8.76 mmol) was added toluene (25 mL) and N, N dimethylformamide di-tert-butylacetal (2.1 mL, 8.76 mmol). The mixture is heated to 95C for 30 minutes, the mixtures is filtered and evaporated to an oil, which is redisolved in dichloromethane and washed with water. The organic phase is dried and evaporated to give 722 mg (21 %) of the title compound, which was subsequently used without any further purification.
722 mg (21%)
In dichloromethane; toluene;
Building Block 1 Eicosanedioic Acid Mono-Tert-Butyl Ester: To eicosanedioic acid (3 g, 8.76 mmol) was added toluene (25 mL) and N,N dimethylformamide di-tert-butylacetal (2.1 mL, 8.76 mmol). The mixture is heated to 95 C. for 30 minutes, the mixtures is filtered and evaporated to an oil, which is redisolved in dichloromethane and washed with water. The organic phase is dried and evaporated to give 722 mg (21%) of the title compound, which was subsequently used without any further purification. 1H NMR (CDCl3): delta10.90 (br s, 1H), 2.35 (t, 2H), 20 (t, 2H), 1.60 (m, 4H), 1.45 (s, 9H); 1.40-1.20 (m, 28H)
In N,N-dimethyl-formamide; toluene; at 90℃; for 10h;
Synthesis of tert-butyl imidazo[1,5-a]pyridine-6-carboxylate 3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tertbutyl)acetal are added to 570 mg (3.52 mmol) of <strong>[256935-76-9]imidazo[1,5-a]pyridine-6-carboxylic acid</strong> [described in Bioorg. Med. Chem. Lett., (2002), 12(3), 465-470] in a mixture of 5 ml of dimethylformamide and 5 ml of toluene and the mixture is heated at 90 C. for 6 hours. 3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tert-butyl)acetal are again added to the reaction medium and the mixture is heated at 90 C. for a further 4 hours. The reaction medium is poured onto water and extracted with ethyl acetate. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by filtration through a bed of silica, elution being carried out with a mixture of dichloromethane and methanol (98/2). After evaporation, 580 mg of a beige powder are obtained. Melting point: 77 C.; 1H NMR (d6-DMSO): 1.59 (9H, s), 7.71 (1H, d), 7.36 (1H, s), 7.58 (1H, d), 8.56 (1H, s), 9.03 (1H, s).
A solution of 10.0 g (53.3 mmol) 2-Chloro-6-methoxy-isonicotinic acid in 60 ml DMF is heated to 100 C. for 4 h, then to 80 C. for another 44 h. In total 99 ml (410 mmol, 7.8 eq) N,N-dimethylformamide di-tert-butylacetal is added in 12 portions over time. After cooling to rt the mixture is diluted with EtOAc, washed with aq. bicarbonate and brine, and dried over sodium sulfate. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give the product in the form of a white solid.MS (LC/MS): 188=[M+H-tBu]+ 1H-NMR (300 MHz, CDCl3): 7.37 (s, 1H), 7.16 (s, 1H), 3.97 (s, 3H), 1.59 (s, 9H).
A solution of 10.0 g (63.4 mmol) 2-chloro-isonicotinic acid in 100 ml chloroform is heated to reflux temperature. In total 91.2 ml (380 mmol, 6 eq) N,N-dimethylformamide di-tert-butylacetal is added in 3 portions of each 30.4 ml at the start, after 1 h and after 2 h. After cooling to rt the mixture is diluted with EtOAc, washed with aq. bicarbonate and brine, and dried over sodium sulfate. The residue is purified by chromatography on silica (flashmaster, hexane to hexane/EtOAc 95/5) to give 7.6 g (35.6 mmol, 56percent) of the product as white solid.MS (LC/MS): 158=[M+H-tBu]+ 1H-NMR (300 MHz, CDCl3): 8.55 (d, 1H), 7.85 (s, 1H), 7.76 (d, 1H), 1.64 (s, 9H).
33%
In toluene; at 90℃; for 20.0h;
a) To a solution of 2-chloroisonicotinic acid (5.00 g, 31.7 mmol) in toluene is added N,Ndimethylformamide di-tert. butylacetal (17.9 g, 79.3 mmol). The mixture is stirred at 90°C for 20 h. The mixture is concentrated, filtered and the filtrate is diluted with EA and washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting heptane:EA 5:1 to give tert. butyl 2-chloroisonicotinate (2.23 g, 33percent) as a colourless oil; LC-MS: tR = 0.98 mm, [M+1+CH3CN] = 255.31.
The carboxylic acid (10 g, 60.9 mmol) and Me2NCH(OtBu)2 (25 g) were heated in toluene (300 ml_) for 5 hours (85 0C). More Me2NCH(OtBu)2 (25 g) was added, and the reaction was heated at 85 0C for 14 hours. The solution was partitioned between EtOAc and sat. NaHCO3(aq.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solution residue was filtered through a plug of SiO2 rinsing with CH2CI2. This afforded 4.7 g (35 %) of the tert-butyl ester as a solid.
Example 9; Preparation of Compound 125; Step 1: <n="123"/>; To a solution of the indole 9A (1.6 g, 6.9 mmol) in toluene (5.0 mL) was added N,N- dimethylformamide di-tert butyl acetal (5 mL), and heated to 90 0C for 12h, cooled to room temperature, another aliquot of JV,N-dimethylforrnamide di-tert butyl acetal (5 mL) was added and the reaction mixture was heated to 90 0C for 12h, cooled to room temperature, diluted with ethyl acetate (10.0 mL), washed with water (2 X 10.0 mL), brine, dried over MgSO4, filtered and concentrated to yield compound 9B (1.2 g, 60%) as a white solid. 1H nuMR (400 MHz, CDC13): delta 9.17 (s, IH), 7.97 (s, IH), 7.51 (s, 2H), 7.21 (s, IH), 1.63 (s, 9H).; Example 10; Preparation of Compound 44; Step 1: 1OA 1 0B; To a solution of the indole 1OA (1.6 g, 6.9 mmol) in Toluene (5.0 mL) was added N,N- dimethylformamide di-tert butyl acetal (5 mL), and heated to 90 0C for 12h, cooled to room temperature, another aliquot of lambdazetaN-dimethylformamide di-tert butyl acetal (5 mL) was added and the reaction mixture was heated to 90 0C for 12h, cooled to room temperature, diluted with ethyl acetate (10.0 mL), washed with water (2 X 10.0 mL), brine, dried over MgSO4, filtered and concentrated to yield the product 1OB (1.2 g, 60%) as a white solid.
60%
In toluene; at 20 - 90℃; for 24.0h;
Example 5; Preparation of Compound 167; <n="149"/>Step 1:; To a solution of the indole 5A (1.6 g, 6.9 mmol) in toluene (5.0 mL) was added N,N- dimethylformamide di-tert butyl acetal (5 mL), and heated to 900C for 12h, cooled to room temperature, another aliquot of N,JV-dimethylformamide di-tert butyl acetal (5 mL) was added and the reaction mixture was heated to 90 0C for 12h, cooled to room temperature, diluted with ethyl acetate (10.0 mL), washed with water (2 X 10.0 mL), brine, dried over MgSO4, filtered and concentrated to yield compound 5B (1.2 g, 60%) as a white solid. 1H nuMR (400 MHz, CDC13): delta 9.17 (s, IH), 7.97 (s, IH), 7.51 (s, 2H), 7.21 (s, IH), 1.63 (s, 9H).; Example 9; Preparation of Compound 77; Step 1:; 9A 9B; To a solution of <strong>[496946-78-2]5-(trifluoromethyl)indole-2-carboxylic acid</strong>, 9A (1.6 g, 6.9 mmol) in toluene (5.0 mL) at room temperature was added N,N-dimethylforrnamide d-tert-bxxtyl acetal (5.0 mL). The mixture was allowed to stir at 90 C for 12 hours, and then was cooled to room temperature. Another aliquot of N,N-dimethylformamide di-tert butyl acetal (5 mL) was added. The reaction mixture was heated to 900C for another 12 hours, cooled to room temperature, and was diluted with ethyl acetate (10 mL). The mixture was washed with water (2 X 10 mL), and brine respectively. The separated organic layer was dried over MgSO4, filtered and concentrated to yield the product 9B (1.2 g, 60% yield). 1H nuMR (400 MHz, CDCl3): 59.17 (s, IH), 7.97 (s, IH), 7.51 (s, 2H), 7.21 (s, IH), 1.63 (s, 9H).
Intermediate 54-6 :tert-Butyl 2-(4-bromophenyl)acetate CAS 33155-58-7N,N-Dimethylformamide di-tert-butyl acetal (29.8 mL, 124.44 mmol) was added portionwise over 10 minutes to a stirred solution of 4-bromophenylacetic acid (13.38 g, 62.22 mmol) in toluene (400 mL) at 85 0C. The resulting solution was stirred at 85 0C for 4 hours and allowed to cool to ambient temperature. The reaction mixture was evaporated afford crude product which was purified by flash silica chromatography, elution gradient 0 <n="158"/>to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (10.29 g, 61.0 %) as a colourless oil.1H NMR (400 MHz, CDCl3) delta 1.43 (9H, s), 3.46 (2H, s), 7.14 (2H, d), 7.44 (2H, d); m/z (EI+) 270 M+.
To a 2L high pressure vessel were added 4-fluoro-3-nitrobenzoic acid (25 g, 135 mmol), dimethylformamide di-t-butylacetal (162 ml, 675 mmol), and toluene (200 ml). The vessel was sealed and heated to 1000C for 20 hours. The mixture was cooled to ambient temperature. The mixture was transferred to 100 mL of EtOAc and 100 ml of IN HCl and the layers were separated. The organic layer was washed with IN HCl, water, and brine, dried over MgSO4, filtered through a medium frit filter, and concentrated. The crude was purified on silica gel (EtOAc in hexanes gradient) to provide 5. Ig of the title compound were obtained as light yellow solid (16%).
Tert-butyl 4-bromo-3-hydroxybenzoate. To a solution of <strong>[14348-38-0]4-bromo-3-hydroxybenzoic acid</strong> (1.0 g, 4.6 mmol) in toluene (100 mL) was added di-tert-butoxy-N,N-dimethylmethanamine (935 mg, 4.6 mmol). Then the mixture was stirred at 85 C overnight. The reaction mixture was poured into water (50 mL) and ethyl acetate (50 mL), the organic phase was washed with water (30 mL), dried over anhydrous sodium sulfate, evaporated and purified by column chromatography to give tert-butyl 4-bromo-3-hydroxybenzoate (1.0 g, 79.4%) as a white solid. LRMS (M+ H+) m/z: calcd 273.00; found 273.
79.4%
In toluene; at 85℃;
Tert-butyl 4-bromo-3-hydroxybenzoate To a solution of <strong>[14348-38-0]4-bromo-3-hydroxybenzoic acid</strong> (1.0 g, 4.6 mmol) in toluene (100 mL) was added di-tert-butoxy-N,N-dimethylmethanamine (935 mg, 4.6 mmol). Then the mixture was stirred at 85 C. overnight. The reaction mixture was poured into water (50 mL) and ethyl acetate (50 mL), the organic phase was washed with water (30 mL), dried over anhydrous sodium sulfate, evaporated and purified by column chromatography to give tert-butyl 4-bromo-3-hydroxybenzoate (1.0 g, 79.4%) as a white solid. LRMS (M+H+) m/z: calcd 273.00. found 273.
In toluene; at 80℃; for 2h;
Step 2; Reference: lrich Widmer, Synthesis, 1983, 135-136, Dissolve 1betaa2 (4,55 g, 20.97 mmol} in anhydrous toluene (20 mL) and heat to 80C, Add dimethylfomnamide di-t-butylacetat (10 mL, 427 rnniol) portionwise over about a 2 h period. Cool the mixture to RT, Evaporate the volatiles and purify the residue with flash chromatography (EtGAcLambdaekappaanes) to give 16a3.
A solution of <strong>[619-12-5]4-formyl-3-hydroxybenzoic acid</strong> (1 g, 6.0 mmol) was dissolved in tetrahydrofuran (10 ml) and heated under reflux. Then N,N-dimethylformamide di-tert-butyl acetal was added dropwise (5.77 ml, 24.0 mmol) and the mixture was stirred at the temperature for 1.5 h. The cooled solution was concentrated under reduced pressure and the residue chromatographed on silica gel with cyclohexane/ethyl acetate as the eluent (gradient=1 hour from 0% ethyl acetate to 5% ethyl acetate).Yield: 1.13 g (84% of theory).HPLC-MS: logP=3.11; mass (m/z): 223.1 (M+H)+; 1H NMR (CD3CN) 1.58 (s, 9H), 7.48 (s, 1H), 7.57 (d, 1H), 7.76 (d, 1H).
6.95 g
In tetrahydrofuran; for 1.5h;Reflux;
A solution of <strong>[619-12-5]4-formyl-3-hydroxybenzoic acid</strong> (6.19 g, 37.3 mmol) in 56 mL of anhydrous THF washeated to reflux, 1,1-di-tert-butoxy-N,N-dimethylmethanamine (35.7 mL, 149 mmol) was addeddropwise and the mixture was stirred at reflux for 1.5 hr. After cooled the reaction to RT, the reaction solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography (100% heptane - 5% ethyl acetate/heptane) to give tert-butyl 4-formyl-3- hydroxybenzoate (6.95 g). LCMS retention time = 1.39 minutes (LC method 3); MS (m+1) = 223.1.1H NMR (400 MHz, DMSO-d5) 51.54 (s, 9H), 7.41 (ddd, J= 8.1, 1.4, 0.6 Hz, IH), 7.54 (d, J= 1.4 Hz, IH), 7.72 (d, J= 8.1 Hz, IH), 10.31 -10.37 (m, IH), 11.00 (s, IH).
In tetrahydrofuran; toluene; at 85℃; for 0.5h;Inert atmosphere;
<strong>[25503-90-6]1-acetylpiperidine-4-carboxylic acid</strong> (2.97 g), suspended in 25 ml of a THF/toluene mixture and heated to 85 C. in a nitrogen stream. N,N dimethylformamide di-t-butyl acetal (25 ml, 6 eq) is added drop by drop and heating is maintained for 30 min. The mixture is evaporated to dryness and the residue is taken up with ethyl acetate. The organic phase is washed with water, with a saturated NaCl solution, dried over Na2SO4, filtered and evaporated to dryness. Yellow oil p=3.45 g (yield 88%). HPLC Atlantis T3 10-90 gradient of CH3CN (0.1% TFA/H2O (0.1% TFA) in 15 min Rt=10.3 min. ESI (+) (M+H)+=228 NMR (DMSO d6) delta (ppm): 1.20-1.80 (13H, m), 2.10 (3H, s), 2.40 (1H, m). 2.60-3.20 (4H, m), 3.60-4.30 (4H, m).
A suspension of <strong>[871-70-5]octadecanedioic acid</strong> (15 g, 47.7 mmol) in Toluene (191 ml) was brought to reflux in 3 neck 1 L round bottom flask. When all of the acid was in solution, 1,1 -di-tert-butoxy-N,N-dimethylmethanamine (22.87 ml, 95 mmol) wasadded dropwise over 30 minutes. The reaction mixture was heated under reflux overnight. The reaction was stopped after 20 total hours of heating. The reaction mixture was cooled to room temperature resulting in precipitation of solids. The mixture was filtered by vacuum filtration. The resulting white solid was suspended in 200 ml dichloromethane and stirred for 15 minutes. The remaining solids wereremoved via vacuum filtration. The collected solids were again suspended in dichloromethane and stirred for 15 minutes. After a second filtration the combined filtrates were concentrated in vacuo and the resulting white powder was dried undervacuum. 18-(tert-butoxy)-18-oxooctadecanoic acid (10.14 g, 27.4 mmol, 57.4 % yield) was isolated as a white solid. ?H NMR (400MHz, CHLOROFORM-d) oe 2.35(t, J=7.5 Hz, 2H), 2.21 (t, J=7.5 Hz, 2H), 1.70 - 1.52 (m, 4H), 1.45 (s, 9H), 1.36 -1.22 (m, 24H).
In n-heptane; dichloromethane; toluene;
N,N-Dimethylformamide di-tert-butylacetal (35.2 ml, 147 mmol) was added dropwise to a solution of <strong>[871-70-5]octadecanedioic acid</strong> (15.4 g, 49.0 mmol) in toluene (250 ml) which was kept at 95 C. The reaction mixture was kept at 95 C. for 16 hours. It was cooled to room temperature. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (150 ml). The solvent was removed in vacuo. The residue was dissolved in dichloromethane (150 ml). The solvent was removed in vacuo. The residue was dissolved in dichloromethane (150 ml). The solvent was removed in vacuo. The residue was dissolved in dichloromethane (85 ml). The insoluble material was removed by filtration. The solvent was removed in vacuo from the filtrate. The residue was dissolved in dichloromethane (18 ml). Heptane (180 ml) was added. The formed precipitation was removed by filtration. The solvent was removed in vacuo. Heptane (150 ml) was added. A precipitation was formed. This was isolated by filtration and dried in vacuo. The solvent was removed in vacuo from the mother liquor. The formed solid was isolated by filtration and dried in vacuo. The two batches of isolated solids were combined and dissolved in the smallest possible amount of refluxing dichloromethane. The solution was cooled to room temperature. Heptane (10 times the volume of dichloromethane) was added. The mixture was kept at 0 C. The formed precipitation was isolated by filtration, washed with heptane (30 ml) and dried in vacuo to give 4.19 g of <strong>[871-70-5]octadecanedioic acid</strong> mono-tert-butyl ester. 1H-NMR (DMSO-d6) 1.23 (m, 24H); 1.39 (s, 9H); 1.47 (m, 4H); 2.16 (m, 4H).
tert-butyl α-(2-trifluoromethylphenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
In toluene; at 80℃; for 2h;
A solution of <strong>[3038-48-0][2-(trifluoromethyl)phenyl]acetic acid</strong> (3.06 g, 15.0 mmol) in toluene (30 mL) was heated to 80C, 1,1-di-tert-butoxy-N,N-dimethylmethaneamine (14.4 g, 60.0 mmol) was added and the mixture was stirred at 80C for 2 hr. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The obtained extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100 - 30/70) to give tert-butyl [2-(trifluoromethyl)phenyl]acetate (3.16 g, 81%). To a solution of tert-butyl [2-(trifluoromethyl)phenyl]acetate (3.10 g, 11.9 mmol) in DMF (36 mL) was added sodium hydride (60% oil, 524 mg, 13.1 mmol), and the mixture was stirred at room temperature for 30 min. 1-Chloro-3-iodopropane (1.34 mL, 12.5 mmol) was added, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100 - 30/70) to give tert-butyl 5-chloro-2-[2-(trifluoromethyl)phenyl]pentanoate (3.63 g, 91%). A solution of tert-butyl 5-chloro-2-[2-(trifluoromethyl)phenyl]pentanoate (3.56 g, 9.83 mmol) in TFA (10 mL) was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, ethyl acetate was added, and the mixture was extracted with 1 M aqueous sodium hydroxide solution. The extract was acidified with 6 M hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (2.74 g, 99%). 1H NMR (CDCl3) delta: 1.55 - 1.75 (1 H, m), 1.76 - 2.04 (2 H, m), 2.16 - 2.34 (1 H, m), 3.50 (2 H, t, J=6.3 Hz), 4.06 (1 H, t, J=7.3 Hz), 7.31 - 7.45 (1 H, m), 7.46 - 7.62 (2 H, m), 7.67 (1 H, d, J=7.7 Hz).
To a solution of <strong>[7697-23-6]2-fluoro-4-methylbenzoic</strong> acid (2.62 g) in toluene (34 ml) were added N,N-dimethylformamide di-tert-butylacetal (16.3 ml), the mixed solution was stirred for 1 hour at 100 C. The solution was returned to room temperature, and water was added to the solution, which was then extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=0 to 20%) to give tert-butyl 2-fluoro-4-methylbenzoate (2.87 g) as a pale yellow oily substance. 1H NMR (600 MHz, CHLOROFORM-d) delta ppm 1.59 (s, 9H), 2.37 (s, 3H), 6.89-7.77 (m, 3H)
4-benzyl 1,2-di-tert-butyl piperazine-1,2,4-tricarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
In toluene; at 80℃; for 2h;Inert atmosphere;
Stage 1. 4-Benzyl 1 ,2-di-teit-butyl piperazine-1 ,2,4-tricarboxylate 4-[(Benzyloxy)carbonyl]- 1 -(teit-butoxycarbonyl)piperazi ne-2-carboxyl ic acid (1.0 g,2.74 mmol) was dissolved in toluene (10 mL) and heated to 80C under a nitrogen atmosphere. DMF di teit-butyl acetal was then added dropwise (2.6 mL, 11 mmol) and stirring continued for 2 hrs. The reaction mixture was cooled and partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Mg504, concentrated in vacuo and the residue was purified by automated column chromatography (0-100% EtOAc/heptane) to give the title compound as a colourless oil (1.08 g, 94%).LCMS: m/z 443 [M+Na].
Step 1: 5-Chloro-1H-indole-3-carboxylic acid tert-butyl ester (XXVIII) 25 ml (104 mmol) of N,N-dimethylformamide di-tert-butyl acetal are added to a solution containing 5.0 g (26 mmol) of <strong>[10406-05-0]5-chloro-1H-indole-3-carboxylic acid</strong> in 200 ml of benzene. The reaction medium is stirred for 12 h and then another portion of the acetal (25 ml) is added. After a further 12 h of stirring, the medium is concentrated, diluted with DCM and then washed with a saturated NaHCO3 solution (3*). 5.7 g of expected product are obtained after evaporation of the solvents. Yield=87%. LC-MS tR(method A): 1.05 min; MS (ES) m/z: 196.1 (M-tBu+H+).
Intermediate 12 5-Bromothiazole-4-carboxylic acid (2.17g, 10.4mmol) was dissolved in dry dioxan (170ml_) and heated at 100C. To this, Lambda/,/V-dimethyl-formamide di-tert-butyl acetal (13.68g, 67.28mmol) was added drop wise and the mixture stirred at 100C for 1 hour. The mixture was cooled to room temperature and stirred for 18 hours. The volatile solvents were removed in vacuo and the residue partitioned between water and diethyl ether. The organic layer was washed with saturated NaHC03, dried with Na2S04, filtered and concentrated in vacuo to dryness. The residue was purified by chromatography on silica eluting with 0-20% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 12 (2.8g) as a yellow solid. 1 H NMR (CDCIs) delta: 8.76 (1 H, s), 1 .63 (9H, s) LCMS (Method 2) Rt 3.23 min; m/z(M+H)+ 265
Ethyl 5-nitro-1-benzofuran-2-carboxylate (2.0 g, 8.54 mmol) was suspended in a mixed solvent of methanol (3.2 mL) and THF (3.2 mL), then a 4 mol/L aqueous solution of sodium hydroxide (3.2 mL) was added thereto, and the mixture was stirred at 70C for 1 hour. A 1 mol/L aqueous solution of hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate twice. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and filtered, and then the solvent was concentrated under reduced pressure to obtain a crude product. The obtained crude product was dissolved in DMF (20 mL), then 1,1-di-tert-butoxy-N,N-dimethylmethaneamide (13.9 g, 68.32 mmol) was added, and the mixture was stirred at 80C for 11 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and filtered, and then the organic layer was concentrated under reduced pressure to obtain a crude product. Chloroform (10 mL) was added to the obtained crude product, and the crystal was filtered out to obtain the title compound (1.76 g, 78%). 1H NMR (CDCl3, 300 MHz) delta 12.43 (s, 1H), 8.13-8.11 (m, 1H), 7.61-7.59 (m, 1H), 7.34 (s, 1H), 2.11-1.98 (m, 4H), 1.64-1.59 (m, 9H).
A mixture of <strong>[586-30-1]3-hydroxy-4-methylbenzoic acid</strong> (10.0 g, 65.8 mmol) and 1,1-di- ieri-butoxy-NN-dimethylmethanamine (63 mL, 0.26 mmol) in THF (200 mL) was heated at reflux for 4 h and then concentrated. The residue was purified by chromatography column (Si02, petroleum ether:ethyl acetate = 100: 1) to give tert-butyl 3-hydroxy-4-methylbenzoate as a yellow solid. NMR (400 MHz, CDC13): delta 7.47-7.44 (m, 2H), 7.15-7.12 (m, 1H), 5.41 (s, 1H), 2.27 (s, 3H), 1.57 (s, 9H).
General procedure: [0567] A solution of the corresponding carboxylic acid (1eq.) in toluene (0.15-0.05M) was heated to 60-100 C., andN,N-dimethylformamide di-tert-butyl acetal (4 eq.) wasadded dropwise. The reaction mixture was stirred at 60-100C. for 1-5 h and cooled to RT, and ethyl acetate was added.The organic phase was washed with saturated aqueoussodium bicarbonate solution and with saturated aqueoussodium chloride solution, dried (sodium sulphate), filteredand concentrated under reduced pressure. The crude productwas used for the next step without purification.
1000 mg
In toluene; at 20 - 100℃;
General procedure: General Method 10A: Preparation of tert-butyl esters Asolution of the corresponding carboxylic acid (1 eq.) in toluene (0.15-0.05M)was heated to 60-100 C, and N,N-dimethylformamide di-tert-butyl acetal (4 eq.)was added dropwise. The reaction mixture was stirred at 60-100 C for 1-5 h andcooled to RT, and ethyl acetate was added. The organic phase was washed withsaturated aqueous sodium bicarbonate solution and with saturated aqueous sodiumchloride solution, dried (sodium sulphate), filtered and concentrated underreduced pressure. The crude product was used for the next step withoutpurification.
To a suspension of 2-chloro-3-nitrobenzoic acid (1.278 g, 6.340 mmol) in toluene (12 mL) under nitrogen was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (4.223 ml, 15.85 mmol). The reaction was heated at 80C overnight. The mixture was cooled to room temperature and concentratedin vacuo. The residue was purified by silica gel column chromatography with 20% ethyl acetate/hexanes to give the title compound (1.3 12 g, 80.3 %) as yellow oil. LCMS m/z = 258.2 [M+Hf; ?H NMR (400 MHz, CDC13) oe ppm 1.61 (s, 9H), 7.44 (t, J= 7.9 Hz, 1H), 7.80 (dd, J= 7.7 and 1.6 Hz, 1H), 7.83 (dd, J= 8.0 and 1.7 Hz, 1H).
A suspension of Compound 44 (4.52 g, 31.4 mmol) in 1,1-di-tert-butoxy-N,N-dimethylmethanamine (75 ml, 314 mmol) was stirred at 80° C. for 3 hours, and a saturated aqueous solution of ammonium chloride was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated sodium bicarbonate solution and brine and then dried with anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The obtained solid residue was suspended in cold hexane, and then filtered to obtain Compound 45 (5.22 g, 83percent) as a white solid. Compound 45; 1H-NMR (DMSO-d6) delta: 1.06-1.47 (m, 13H), 1.76-1.85 (m, 4H), 2.06 (tt, J=11.80, 3.22 Hz, 1H), 3.28-3.40 (m, 1H), 4.55 (d, J=4.27 Hz, 1H).
tert-butyl 5-nitropyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene; at 60 - 100℃;
General procedure: [0497] A solution of the appropriate carboxylic acid (1 eq.) in toluene (0.15-0.05 M) was heated to 60 to 100° C., and N,N-dimethylformamide di-tert-butyl acetal (4 eq.) was added dropwise. The reaction mixture was stirred at 60 to 100° C. for ito 5 hand cooled to RT, and ethyl acetate was added. The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was used in the next stage without purification.; [0513] According to General Method 10A, 1000mg (5.95mmol) of <strong>[30651-24-2]5-nitropyridine-2-carboxylic acid</strong> were reacted.The crude product was used in the next stage withoutpurification. Yield: 600 mg (45percent of theory)10514] HPLC [Method 1]: R=0.89 mm,10515] ?H-NMR (400 MHz, DMSO-d5): oe [ppm]=9.44 (d,1H), 8.73 (dd, 1H), 8.22 (d, 1H), 1.58 (s, 9H).
tert-butyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.04 g
In toluene; for 1h;Reflux;
6-Bromopyrazolo [1,5-a] pyridine-3-carboxylic acid (2 g),1,1-di-tert-butoxy-N,N-dimethylmethanamine (24.87 ml), and toluene (30 ml)And the mixture was stirred under heating reflux for 1 hour.The mixture was concentrated.The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.04 g).
(S)-tert-butyl 2-(benzyloxycarbonylamino)-2-cyclohexylacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.6%
In toluene; at 110℃; for 16h;Inert atmosphere;
To a solution of <strong>[69901-75-3](S)-2-(benzyloxycarbonylamino)-2-cyclohexylacetic acid</strong> (400 mg, 1.37 mmol) in toluene (10 mL) was added di-tert-butoxy-N, N-dimethylmethanamine (1.2 g, 5.90 mmol). The resulting mixture was stirred at 110 C for 16 h under N2 atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by flash column chromatography with MeOH/DCM (1 : 10, v/v) to afford the title compound (246 mg, 51.6%) as a colorless oil. LCMS (ESI, m/z): [M+H]+ = 347.3.
Into the reaction vessel was added pyridine (50 mL) and <strong>[5985-24-0]dimethyl 4-hydroxyisophthalate</strong> (3.6 g, 17 mmol). The mixture was stirred at reflux for 17h andconcentrated. The residue was acidified with 1M HC1 (50 mL) and extracted with EtOAc (3OmL x 3). The organic phase was dried over Na2504, concentrated, and dissolved in DCM (10 mL). 1,1 -Di-tert-butoxy-N,N-dimethylmethanarnine (10.45 g, 51 .40 mmol) was then added and the reaction was stirred at rt for 12h. After diluted with EtOAc (30 mL), the organic phase was washed with sat NaHCO3 (20 mL x 3), dried over Na2SO4, andconcentrated to produce 1A (2.62 g, 10.40 mmol, 60.7percent yield) as a white solid which was used for next step without further purification. LCMS Anal. Calc?d for C13H1605 252.10,found [M+H] 253.1; 1H NMR (500MHz, chloroform-d) 8 11.56 (s, 1H), 8.58-8.46 (m, 1H), 8.16 - 8.08 (m, 1H), 7.02 (s, 1H), 3.93 (s, 3H), 1.66 (s, 9H).
Compound 33b (7.2 g, 35.4 mmol) was added in a dropwise fashion to a solution of 33a (2 g, 7.1 mmol) in toluene (100 mL) at 85 C under argon. After 1 hr at 85 C, the reaction mixture was cooled to rt, and quenched with water (20 mL). The organic layer was separated, washed with saturated NaHC03 and brine. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (EtO Ac/Hexanes 0 ~ 30%) to afford the product as colorless oil (1.8 g, 80%): 'HNMR (300MHZ, CDCl3) 8.33 (d, 1H, J = 1.8 Hz), 8.04 (dd, 1H, J = 1.8 & 8.4 Hz), 7.46 (d, 1H, J = 8.1 Hz), 4.35 (q, 2H, J = 6.9 Hz), 1.59 (s, 9H), 1.31 (t, 3H, J = 6.9 Hz).
In tetrahydrofuran; for 24h;Inert atmosphere; Reflux;
<strong>[345-16-4]5-Fluorosalicylic acid</strong> (10.5 g, 66.9 mmol) in THF (110 mL) under Ar was heated to reflux. N,N-Dimethylformamide di-tert-butyl acetal (50.0 mL, 208 mmol) was added through the condenser in three portions every 30 min. The reaction mixture was stirred at reflux for an additional 23 h. The reaction was diluted with water and extracted two times with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated. Column chromatography (0-70% DCM/Hexane) afforded the title compound (10.1 g, 71%). ESI-MS m/z 213 (MH)+.
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