2-Ethoxy benzaldehyde

A number of syntheses of pioglitazone have been disclosed (Arita and Mizuno, 1992 Fischer et al., 2005 Les et al., 2004 Meguro and Fujita, 1986, 1987 Momose et al., 1991 Prous and Castaner, 1990 Saito et al., 1998). Two related syntheses (Fischer et al., 2005 Les et al., 2004) of pioglitazone hydrochloride are described in Scheme 8.2. The tosylate of 2-(5-ethylpyridin-2-yl)ethanol (16), formed in situ with tosyl chloride, was displaced by 4-hydroxybenzaldehyde (17) by means of benzyltributylammonium chloride and NaOH to give 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde (20). Condensation of 20 with thiazolidine-2,4-dione in basic medium afforded 5-[-4-[2-(5-ethylpyridin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione (21). Finally, this compound was hydrogenated to provide pioglitazone (2). Alternatively, a nucleophilic aromatic substitution reaction... 

To 100 g of 2-(N-methyl-N-(2-pyridyl)amino)ethanol in 500 ml DMF was added 100 g of 4-fluorobenzaldehyde. The reaction mixture was stirred for 10 min at room temperature and 80 g of potassium tertiary butoxide was added to the reaction mixture. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 5-10°C and under the cold conditions, 1.5 L of water was added and stirred for 15 min. The mixture was extracted with ethyl acetate. The combined organic layer was washed with 3 times 1 L water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 148 g (88%) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzaldehyde. 

N-Methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde was converted into highly crystalline 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione by Knoevenegal condensation with 2,4-thiazolidinedione. 800 g of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzyl]thiazolidine-2,4-dione and 280 g maleic acid were dissolved in 1.3 L of acetone in 5 L three necked round bottom flask. The reaction mixture was heated to 50-55°C and the solution was filtered and slowly cooled to obtain 986 g of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleate, (yield 95% M.P. 120-122°C). 

SYNS BOURBONAL ETHAVAN ETHOVAN 3-ETHOXY-4-HYDROXYBENZALDEHYDE ETHYL-PROTAL FEMA No. 2464 4-HYDROXY-3-ETHOXY-BENZALDEHYDE PROTOCATECHLTC ALDEHYDE ETHYL ETHER QUANTROVANIL VANILLAL VANIROM... 

Ausgehend von 4-(2-Trialkylammonio-ethoxy)-benzaldehyd-halogeniden wird auch die Cycli-sierung in Ethanol beschrieben251. 

Chlnr-2-[4-(2-diethylamino-ethoxy)-phenyl]-l,3-henzortiiazol-Hydrochlorid251 Ein Gemisch aus 26,4 g (0,102 mol) 4-(2-Diethylamino-ethoxy)-benzaldehyd-Hydrochlorid und 23 g (0,145 mol) 2-Amino-4-chlor-thiophenol in 120 m/ Nitrobenzol wird in einem Rundkolben mit Luftkiihler innerhalb 15 min auf eine Innentemp. von 180-200° erhitzt. Man laBt innerhalb 12 h abkiihlen und filtriert. Dabei wird der kri-... 

M ethoxy-benzaldehyd 2-Methoxy-benzoesaure 4-Nitro-1 -m ethoxy-benzol... 

Note also that if another ester, of general formula R-COOCjHj, were used in place of benzaldehyde in the above reaction, a similar complex would be formed, and on acidification would give an unstable p-hydroxy-P-ethoxy ester, which would very readily lose ethanol with the formation of a 3-keto-ester. 

The synthesis of the right-wing sector, compound 4, commences with the prochiral diol 26 (see Scheme 4). The latter substance is known and can be conveniently prepared in two steps from diethyl malonate via C-allylation, followed by reduction of the two ethoxy-carbonyl functions. Exposure of 26 to benzaldehyde and a catalytic amount of camphorsulfonic acid (CSA) under dehydrating conditions accomplishes the simultaneous protection of both hydroxyl groups in the form of a benzylidene acetal (see intermediate 32, Scheme 4). Interestingly, when benzylidene acetal 32 is treated with lithium aluminum hydride and aluminum trichloride (1 4) in ether at 25 °C, a Lewis acid induced reduction takes place to give... 

Ethoxy-3-hydroxybenzaldehyde (isobourbonal) has been prepared in good yield (84%) by ethylation of 3,4-dihydroxybenzaldehyde [Benzaldehyde, 3,4-dihydroxy-] with diethyl sulfate [Sulfuric acid, diethyl ester] in dimethylformamide.2... 

Benzaldehyde, 9, 39 Benzaldehyde, 3,4-dihydroxy-, 48 BENZALDEHYDE, 4-ETHOXY-3-HYDROXY-, 44... 

Benzaldehyde, 4-ethoxy-3-methoxy-, 44 Benzaldehyde, 4-ethoxy-3-methoxy-,... 

A solution of the trimethylsilyl enol ether of propionyl trimethylsilane (5 mmol) (Chapter 12) and benzaldehyde diethyl acetal (5 mmol) in dichloromethane (10ml) was added to a solution of BF3.OEt2 (5 mmol) in dichloromethane (5ml), cooled to —78 C. After being stirred for lh at -78°C and 2h at -30°C, the mixture was quenched with excess saturated sodium hydrogen carbonate solution, and extracted with ether. Concentration and distillation gave the product -ethoxy acylsilane, (4.6mmol, 95%). b.p. 105-106 C/2mmHg. Treatment of this alkoxy... 

Lithium aluminum hydride, in reduction of 3-ethoxy-2-cyclohexenone to 2-cyclohexenone, 40, 14 Lithium ethoxide in condensation of benzaldehyde with tripbenylcin-namylphosphonium chloride to form 1,4-diphenyl-l, 3-butadiene,... 

The presence of electron-donating substituents in the diene enables it to react with simple aldehydes thus both acetaldehyde and benzaldehyde add to 1-methoxy-1,3-butadiene at 50-65 °C under high pressure (20 Kbar) to give dihydropyrans as 70 30 mixtures of cis- and frans-isomers (equation 5)4. The combination of electron-rich diene/electron-poor dienophile makes it possible to perform the reaction under milder conditions. 2-Alkyl-l-ethoxy-1,3-butadienes and diethyl mesoxalate afford dihydropyrans almost quantitatively (equation 6)5. 

Note All compounds with a 5-ethoxy group are obtained in poor yields in this nitrating step, but this step can be used to nitrate other benzaldehydes with great success. 

Tetraphenylporphin (H2TPP) was prepared from pyrrole and benzaldehyde (25). The tetraphenylchlorin contamination was oxidized by use of 2,3-dichloro-5,6-dicyano-p-benzoquinone (26). Octaethylporphin (H2-OEP)was prepared by the method of Paine et al.(27) from 3,4-diethyl-2-ethoxy-carbony1-5-methyl-pyrrole (28). Zinc(II)-tetraphenylporphin (ZnTPP) was prepared by refluxing H2TPP and zinc acetate in dimethyl-formamide (29). ZnTPP was dissolved at a concentration of 10 -10 ... 

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