CN111662287B - Preparation of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester - Google Patents
Preparation of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester Download PDFInfo
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- CN111662287B CN111662287B CN202010428368.3A CN202010428368A CN111662287B CN 111662287 B CN111662287 B CN 111662287B CN 202010428368 A CN202010428368 A CN 202010428368A CN 111662287 B CN111662287 B CN 111662287B
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a preparation method of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformate, which mainly solves the technical problem that no industrial synthesis method is available at present. The invention is divided into three steps, the third stepFirstly, reacting a compound 1 in hydrochloric acid to obtain a compound 2, secondly, reacting the compound 2 with ethyl glyoxylate toluene solution in acetonitrile to obtain a compound 3, and thirdly, reacting the compound 3 with Boc anhydride and triethylamine in dichloromethane to obtain a final compound 4, wherein the reaction formula is as follows:
Description
Technical Field
The invention relates to a synthesis method of a compound 5-tert-butyl-4-ethyl-3-methyl-6, 7-dihydro-3H-imidazo [4,5-C ] pyridine-4, 5(4H) -diformyl ester, which is abbreviated as: preparation of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester.
Background
The compound 5-tert-butyl-4-ethyl-3-methyl-6, 7-dihydro-3H-imidazo [4,5-C ] pyridine-4, 5(4H) -diformyl ester (CAS: 1380679-97-9) and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of 5-tert-butyl-4-ethyl-3-methyl-6, 7-dihydro-3H-imidazo [4,5-C ] pyridine-4, 5(4H) -diformyl ester is only reported in documents. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.
Disclosure of Invention
The invention aims to develop a synthetic method of 5-tert-butyl-4-ethyl-3-methyl-6, 7-dihydro-3H-imidazo [4,5-C ] pyridine-4, 5(4H) -diformyl ester, which has the advantages of easily obtained raw materials, convenient operation, easily controlled reaction and higher yield. Mainly solves the technical problem that no industrial synthesis method is available at present.
The technical scheme of the invention is as follows: the invention relates to a synthesis method of 5-tert-butyl-4-ethyl-3-methyl-6, 7-dihydro-3H-imidazo [4,5-C ] pyridine-4, 5(4H) -diformate, which comprises three steps, wherein the first step is to react a compound 1 in hydrochloric acid to obtain a compound 2, the second step is to react the compound 2 with ethyl glyoxylate toluene solution in acetonitrile to obtain a compound 3, and the third step is to react the compound 3 with Boc anhydride and triethylamine in dichloromethane to obtain a final compound 4, wherein the reaction formula is as follows:
the first step of reaction is carried out in 6N hydrochloric acid at the temperature of reflux (100 ℃) for 25 hours; the second step is that the mass percentage concentration of the ethyl glyoxylate in the toluene is 50 percent, the reaction temperature is 80 ℃, and the reaction time is 7 hours; the third step is carried out at room temperature overnight.
The invention discloses an abbreviated Chinese meaning: TLC: thin layer chromatography.
The invention has the beneficial effects that: the reaction process is reasonable in design, adopts easily-obtained and large-scale-production raw material 2-methyl-5-oxylidene-5, 6,7, 8-tetrahydroimidazo [1,5-C ] pyrimidine-2-iodide positive ions, and synthesizes 5-tert-butyl-4-ethyl-3-methyl-6, 7-dihydro-3H-imidazo [4,5-C ] pyridine-4, 5(4H) -diformate through three steps.
Detailed Description
The reaction formula of the invention is as follows:
example (b):
the first step is as follows: compound 1 (569 g, 2.0 mol) was dissolved in 6N hydrochloric acid (5.0L) and stirred at 100 ℃ reflux temperature for 25 hours. TLC (dichloromethane/methanol volume ratio = 10/1) indicated complete consumption of the starting material and concentration of the solvent under reduced pressure gave compound 2 as a yellow solid (235 g, yield: 62%).
1(400 M; D2O)
δ 8.59 (s, 1H), 7.33 (s, 1H), 3.83 (s, 3H), 3.29 (t, J = 7.2 Hz, 2H), 3.08 (t, J = 7.2 Hz, 2H)。
The second step is that: compound 2 (243 g, 1.5 mol) was dissolved in acetonitrile (2.5L), ethyl glyoxylate (50% by weight in toluene, 1.5 mol) was added, the mixture was heated to 80 ℃ under reflux, and stirring was continued for 7 hours. TLC (dichloromethane/methanol volume ratio = 10/1) showed complete reaction of the starting material and the solvent was removed under reduced pressure to yield compound 3 as a yellow solid (157 g, 50% yield).
1(400 M; D2O)
δ 8.73 (s, 1H), 5.74 (s, 1H), 4.28 (dd, 2H), 3.88 (s, 3H), 3.79 (dd, 1H), 3.56 (dd, 1H), 3.02 (dd, 2H), 1.21 (t, J = 7.2 Hz, 3H)。
The third step: compound 3 (194 g, 0.93 mol) and triethylamine (188 g, 1.86 mol) were dissolved in anhydrous dichloromethane (2.0L), Boc anhydride (203 g, 0.93 mol) was added dropwise at 0 deg.C, and stirred at room temperature 25 deg.C overnight for 12 hours. TLC (petroleum ether/ethyl acetate volume ratio = 1/1) showed the starting material was completely reacted. The reaction solution was washed with water (500 mL × 4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 4 (138 g, yield: 48%) as a colorless oil.
1(400 M; CDCl3)
δ 7.34 (s, 1H), 5.68 (s, 1H), 4.20 (dd, 2H), 4.18 (dd, 2H), 3.68 (s, 3H), 3.29 (dd, 1H), 2.65 (dd, 2H), 1.46 (s, 9H), 1.24 (t, 3H)。
Claims (6)
1. A preparation method of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester is characterized in that: the method comprises the following steps of firstly reacting a compound 1 in hydrochloric acid to obtain a compound 2, secondly reacting the compound 2 with ethyl glyoxylate toluene solution in acetonitrile to obtain a compound 3, and thirdly reacting the compound 3 with Boc anhydride and triethylamine in dichloromethane to obtain a final compound 4, wherein the reaction formula is as follows:
2. the process for producing 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformate according to claim 1, wherein: the first reaction step was carried out in 6N hydrochloric acid.
3. The process for producing 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester according to claim 1, wherein: the first step is maintained at 100 ℃ and the reaction is carried out for 25 hours.
4. The process for producing 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformate according to claim 1, wherein: the mass percentage concentration of the ethyl glyoxylate in the toluene in the second step is 50 percent.
5. The process for producing 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformate according to claim 1, wherein: the second step reaction temperature was 80 ℃ and the reaction time was 7 hours.
6. The process for producing 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformate according to claim 1, wherein: and the third step is carried out at room temperature overnight.
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