Quinhydroxy ketone glycine ester hydrochloride and preparation method thereof

Abstract

The invention discloses a quinhydroxy ketone alanine ester hydrochloride and a preparation method thereof. The preparation method comprises the following steps: quinhydroxy ketone is reacted with N-(tert-butoxycarbonyl)-alanine in the presence of a catalyst N,N'-diisopropylcarbodiimide, and N-(tert-butoxycarbonyl)-alanine quinhydroxy ketone is obtained; then under the effect of trifluoroacetic acid, quinhydroxy-ketone alanine ester is obtained; and finally by reacting with hydrochloric acid, quinhydroxy ketone alanine ester hydrochloride is obtained. The product obtained by the method is good in water-solubility and high in conversion rate of the product hydrolyzing into quinhydroxy-ketone in vivo.

Description

technical field

[0001] The invention relates to the field of veterinary medicine, in particular to the synthesis of a quinoxaline compound. Background technique

[0002] Since the first quinoxaline compound was synthesized in 1965, many such compounds such as olaquindox, acetylmethaquine, quinolone, and quinolone have been used in animal husbandry and have achieved huge economic benefits. benefit.

[0003] Quinoxaline compounds have poor water solubility and are generally used in premix dosage forms, which seriously affects their application in animal breeding. In order to solve the problem of its water solubility and meet the requirements of clinical medication, the current methods mainly use organic solvents or add solubilizers such as sodium salicylate, such as 10% sodium salicylate to be added in 2% acetylmethaquine injection. dissolve. Unfortunately, both organic solvents and solubilizers have certain toxicity, which can cause toxic side effects, reduce the safety of...

Examples

Embodiment 1

[0008] Embodiment 1 Preparation of quinolone of tert-butoxycarbonylalanine

[0009] In a 500ml round bottom flask, add quinolone 6.4 g, dimethylformamide 12 ml, stir until completely dissolved, add N,N′-diisopropylcarbodiimide 15 ml, tert-butoxycarbonylalanine 3.8 g, reacted at room temperature with magnetic stirring. React for 1 hour, concentrate under reduced pressure, add ethyl acetate and water for extraction, discard the water layer, wash the ethyl acetate layer with saturated sodium bicarbonate and saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and recover acetic acid Ethyl ester, ethyl acetate-petroleum ether recrystallized to obtain 8.3 g of light yellow solid, yield 83.4%, mp: 153-154°C.

Embodiment 2

[0010] Embodiment 2 Preparation of quinolone glycinate

[0011] In a 1000ml round bottom flask, add 49 g of quinolone tert-butoxycarbonylalanine, 350 ml of dichloromethane, and 350 ml of trifluoroacetic acid, and react under magnetic stirring in an ice-salt bath. React for 30 minutes, concentrate under reduced pressure, remove the solvent, extract with ethyl acetate and water, discard the water layer, wash with saturated sodium bicarbonate and saturated sodium chloride respectively, add anhydrous sodium sulfate to dry, concentrate under reduced pressure, and recover acetic acid Ethyl ester, 17 g of yellow solid was obtained, yield 50.1%, mp: 137-140°C.

[0012] IR(cm-1): 1672.9, 1701.3, 1741.5 (C=O);

[0013] 1H NMR(400MHz, CDCl3) δ: 8.65 (d, J =7.96Hz, 1H), 8.59 (d, J =9.56Hz, 1H), 7.88 (dt, Ar-H, 2H), 7.73 (dd, Ar- H, 2H), 7.46 (t, 1H), 7.30 (t, 1H), 7.17 (dd, Ar-H, 2H), 5.14 (d, J =6.52, 1H), 4.45 (m, 1H), 2.57 ( s, 3H), 1.42 (d, J =7.28Hz, 3H), 1.31 (m, 9H)

Embodiment 3

[0014] Embodiment 3 Preparation of quinolone glycinate hydrochloride

[0015] In a 1000ml round bottom flask, add 48 g of quinolone alanine and 600 ml of methanol. Concentrated hydrochloric acid was added dropwise under stirring, and the pH was adjusted to 2 to start the reaction. React for 2 hours, concentrate under reduced pressure, and distill off methanol to obtain a dark green solid, yield 4.75 g, yield: 90.5%, mp: 198-201°C.

technical field

[0001] The invention relates to the field of veterinary medicine, in particular to the synthesis of a quinoxaline compound. Background technique

[0002] Since the first quinoxaline compound was synthesized in 1965, many such compounds such as olaquindox, acetylmethaquine, quinolone, and quinolone have been used in animal husbandry and have achieved huge economic benefits. benefit.

[0003] Quinoxaline compounds have poor water solubility and are generally used in premix dosage forms, which seriously affects their application in animal breeding. In order to solve the problem of its water solubility and meet the requirements of clinical medication, the current methods mainly use organic solvents or add solubilizers such as sodium salicylate, such as 10% sodium salicylate to be added in 2% acetylmethaquine injection. dissolve. Unfortunately, both organic solvents and solubilizers have certain toxicity, which can cause toxic side effects, reduce the safety of...

Examples

Embodiment 1

[0008] Embodiment 1 Preparation of quinolone of tert-butoxycarbonylalanine

[0009] In a 500ml round bottom flask, add quinolone 6.4 g, dimethylformamide 12 ml, stir until completely dissolved, add N,N′-diisopropylcarbodiimide 15 ml, tert-butoxycarbonylalanine 3.8 g, reacted at room temperature with magnetic stirring. React for 1 hour, concentrate under reduced pressure, add ethyl acetate and water for extraction, discard the water layer, wash the ethyl acetate layer with saturated sodium bicarbonate and saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and recover acetic acid Ethyl ester, ethyl acetate-petroleum ether recrystallized to obtain 8.3 g of light yellow solid, yield 83.4%, mp: 153-154°C.

Embodiment 2

[0010] Embodiment 2 Preparation of quinolone glycinate

[0011] In a 1000ml round bottom flask, add 49 g of quinolone tert-butoxycarbonylalanine, 350 ml of dichloromethane, and 350 ml of trifluoroacetic acid, and react under magnetic stirring in an ice-salt bath. React for 30 minutes, concentrate under reduced pressure, remove the solvent, extract with ethyl acetate and water, discard the water layer, wash with saturated sodium bicarbonate and saturated sodium chloride respectively, add anhydrous sodium sulfate to dry, concentrate under reduced pressure, and recover acetic acid Ethyl ester, 17 g of yellow solid was obtained, yield 50.1%, mp: 137-140°C.

[0012] IR(cm-1): 1672.9, 1701.3, 1741.5 (C=O);

[0013] 1H NMR(400MHz, CDCl3) δ: 8.65 (d, J =7.96Hz, 1H), 8.59 (d, J =9.56Hz, 1H), 7.88 (dt, Ar-H, 2H), 7.73 (dd, Ar- H, 2H), 7.46 (t, 1H), 7.30 (t, 1H), 7.17 (dd, Ar-H, 2H), 5.14 (d, J =6.52, 1H), 4.45 (m, 1H), 2.57 ( s, 3H), 1.42 (d, J =7.28Hz, 3H), 1.31 (m, 9H)

Embodiment 3

[0014] Embodiment 3 Preparation of quinolone glycinate hydrochloride

[0015] In a 1000ml round bottom flask, add 48 g of quinolone alanine and 600 ml of methanol. Concentrated hydrochloric acid was added dropwise under stirring, and the pH was adjusted to 2 to start the reaction. React for 2 hours, concentrate under reduced pressure, and distill off methanol to obtain a dark green solid, yield 4.75 g, yield: 90.5%, mp: 198-201°C.

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