* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 10, p. 1491 - 1508
2
[ 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
3
[ 24424-99-5 ]
[ 619-66-9 ]
[ 65874-27-3 ]
Yield
Reaction Conditions
Operation in experiment
34%
With dmap In tetrahydrofuran
EXAMPLE 32 Compound 32-A: 4-Formyl-benzoic acid tert-butyl ester A suspension of 4-carboxybenzaldehyde (5.2 g, 34.6 mmol) in tetrahydrofuran (130 ml) was treated under argon with di-tert-butyl dicarbonate (15.3 g, 70.0 mmol) and 4-dimethylaminopyridine (1.28 g, 10.0 mmol) and the resulting mixture was stirred at 22° C. for 72 h. After dilution with dichloromethane, the reaction mixture was washed successively with 5percent citric acid, saturated sodium bicarbonate and brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 95:5) yielded 2.43 g (34percent yield) of the title ester as a white solid. 1H-NMR 400 MHz (CDCl3) δ (ppm): 1.61 (9H, s, t-Bu), 7.92 (2H, d, J=8.3 Hz, aromatics), 8.13 (2H, d, J=8.3 Hz, aromatics), 10.09 (1H, s, CH).
28%
With dmap In tetrahydrofuran at 20℃; for 16 h;
Example 1tert-Butyl 4-formylbenzoateTo a 250-mL round-bottom flask was added 4-formylbenzoic acid (5.0 g, 33 mmol), di-tert-butyldicarbonate (14.54 g, 66.6 mmol), N,N-dimethylaminopyridine (0.814 g, 6.66 mmol), and THF (100 mL). The mixture was stirred at rt for 16 h. The solvent was then removed to give a solid. To the residue was added EtOAc (150 mL), sat. NaHCO3 solution (25 mL), and water (25 mL). After separation, the aqueous layer was extracted with EtOAc (2.x.100 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated. Purification via flash chromatography (hexanes to 10percent EtOAc-hexanes) afforded tert-butyl 4-formylbenzoate (1.90 g, 28percent) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 10.10 (s, 1H), 8.14 (d, J=8.3 Hz, 2H), 7.93 (d, J=8.5 Hz, 2H), 1.61 (s, 9H).
Reference：
[1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 7488 - 7489
[3] Patent: US2003/176495, 2003, A1,
[4] Patent: US2011/212969, 2011, A1, . Location in patent: Page/Page column 109
(a) To 4-formylbenzoic acid t-butyl ester (12.27 g) in dichloromethane (250 ml) were added dropwise 50% aqueous sodium hydroxide (5.86 g) and then triethylphosphonoacetate (16.44 g), and the mixture was stirred under nitrogen atmosphere at 25 C. for 40 minutes. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, evaporated to give an oily residue which was then purified by silica gel chromatography to give 3-(4-tert-butyloxycarbonylphenyl)acrylic acid ethyl ester.
PREPARATIVE EXAMPLE 7 t-Butyl 4-(3-iodo-1-ethylpropyl)benzoate [a compound represented by the formula (12) wherein n is 2, R2 is a phenylene group, R3 is H, R4 is Et, R7 is t-Bu and Y is I] t-Butyl p-formylbenzoate (20 g, 97 mmol) was dissolved in ether (300 ml), followed by the dropwise addition of ethylmagnesium bromide.(3M ethereal solution, 33 ml) under cooling with ice. The obtained mixture was stirred. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the obtained mixture was extracted with ether. The organic layer was distilled to remove the solvent. The residue was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:4) to give 22.3 g of t-butyl 4-(1-hydroxypropyl)benzoate.
With ammonium chloride;
PREPARATIVE EXAMPLE 119 Preparation of t-butyl 4-(1-ethyl-3-iodopropyl)benzoate t-Butyl p-formylbenzoate (20 g, 97 mmol) was dissolved in ether (300 ml), followed by the dropwise addition of ethylmagnesium bromide (3M ethereal solution, 33 ml) under cooling with ice. The obtained mixture was stirred to complete a reaction. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the obtained mixture was extracted with ether. The organic phase was distilled to remove the solvent and the obtained residue was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:4) to give 22.3 g of t-butyl 4-(1-hydroxypropyl)benzoate.
4-[2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-4-[2-carboxymethyl-3-(4-phosphonomethyl-phenyl)-propionylamino]-piperidine-1-carboxylic acid 4-carboxy-benzyl ester[ No CAS ]
4-{2-<i>tert</i>-butoxycarbonylmethyl-3-[4-(di-<i>tert</i>-butoxy-phosphorylmethyl)-phenyl]-propionylamino}-4-[2-carbamoyl-1-(3-naphthalen-1-yl-propylcarbamoyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid 4-carboxy-benzyl ester[ No CAS ]
cis-1-[3'-(benzyloxycarbonyl)phenylacetate]-3-(4'-tert-butyldiphenylsilyloxybenzyl)-4-[4'-(tert-butyloxycarbonyl)benzyloxycarbonyl]-2-azetidinone[ No CAS ]
cis-3-benzyl-4-[4'-(tert-butyloxycarbonyl)benzyloxycarbonyl]-1-{3'-[(4''-tert-butyloxycarbonyl)benzyloxycarbonyl]phenylacetate}-2-azetidinone[ No CAS ]
4-({(1R,2R,4R)-1-[(Diisopropylsulfamoyl)-methyl]-7,7-dimethyl-bicyclo[2.2.1]hept-2-ylsulfanylcarbonyl}-trimethylsilanyloxy-methyl)-benzoic acid tert-butyl ester[ No CAS ]
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