Method for preparing deuterated internal standard substances of tetracyclines and epimers thereof

A technology of epimers and tetracyclines, which is applied in the field of preparation of deuterated stable isotope internal standard reagents, can solve the problems that restrict the application of tetracycline stable isotope internal standard reagents, complicated operation process, long technical route, etc. The effect of preparation risk, short technical route, and guaranteed abundance

Active Publication Date: 2019-04-05
天津阿尔塔科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current production of tetracycline stable isotope internal standard reagents has a long technical route, complicated operation process and high cost, which seriously restrict the application of tetracycline stable isotope internal standard reagents.

Method used

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  • Method for preparing deuterated internal standard substances of tetracyclines and epimers thereof
  • Method for preparing deuterated internal standard substances of tetracyclines and epimers thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (1R,4aS,11R,11aS,12aR)-1,2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxomethylene-1,4,4a,6,11 , Preparation of 11a, 12, 12a-octahydro-1,11-epoxytetracene-3-carboxamide (IIa):

[0027] Dissolve 4.6 grams of tetracycline (Ia) in 250 milliliters of aqueous solution containing 1 milliliter of concentrated hydrochloric acid, and add 3.5 grams of N-chlorosuccinimide in batches at 25°C, after the addition is complete, stir and react at 25°C 30 min; filter with suction, wash the filter cake with water, dissolve the filter cake in 300 ml of methyl tert-butyl ether, and wash 4 times with 50 ml of water. After the solvent was spin-dried under reduced pressure, 3.2 g of the product as a light yellow solid was directly used in the next reaction with a yield of 74.4%. LCMS(ESI+): m / z=416[M+H] + .

Embodiment 2

[0029] (4aS,5aS,6S,12aS,E)-4-hydrazino-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxomethylene-1,4, Preparation of 4a, 5, 5a, 6, 11, 12a-octahydro-2-carboxamide (IIIa):

[0030] 3.2g (1R, 4aS, 11R, 11aS, 12aR)-1,2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxomethylene-1,4,4a, 6,11,11a,12,12a-octahydro-1,11-epoxytetracene-3-carboxamide (IIa) is dissolved in 25 ml of 95% ethanol solution, 0.46 A solution of 80% hydrazine hydrate in 25 ml ethanol was slowly added dropwise to the reaction mixture. After dropping, keep warm for 18 hours. After spin-drying the solvent, 3.3 g of a reddish-brown solid was directly used in the next reaction. Yield 99.7%. LCMS(ESI+): m / z=430[M+H] + .

Embodiment 3

[0032] (4aS,5aS,6S,12aS)-4-Amino-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxomethylene-1,4,4a,5 , the preparation of 5a,6,11,12a-octahydro-2-carboxamide (IVa):

[0033] 3.3 grams of (4aS, 5aS, 6S, 12aS, E)-4-hydrazino-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxomethylene-1 , 4,4a,5,5a,6,11,12a-octahydro-2-carboxamide (IIIa) was dissolved in a mixed solution of 130 ml of acetone and 100% of water, and 6.6 g of it was added in batches at 25°C Sodium dithionite, control the temperature at about 30°C, after the addition is complete, stir and react at 25°C for 30min. After the reaction, add 3 grams of activated carbon, stir for 10 minutes, then add diatomaceous earth for suction filtration and wash with a 1 / 1 mixed solution of water and acetone. Combine the filtrates, spin dry the acetone and adjust the pH to 4-5, wash the aqueous layer with ethyl acetate, extract with n-butanol, dry over anhydrous sodium sulfate, and then suction filter and spin dry to obtain 1.3 g of crude ...

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Abstract

The invention discloses a method for preparing deuterated internal standard substances of tetracyclines and epimers thereof. According to the method, a demethylated primary amine intermediate is obtained through three-step reaction including cyclization, ring-opening reaction and reduction reaction, and deuterated paraformaldehyde is subjected to reductive amination to obtain a deuterated internalstandard reagent of tetracyclines finally. Compared with a traditional method for preparing stable isotope labeled tetracycline internal standard reagents through fermentation or total synthesis, themethod has advantages of short steps, simplicity and convenience in operation, high yield, low cost, high quality and the like. In addition, product purity and the atom deuterated ratio are both 98%or above.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a preparation method of deuterated stable isotope internal standard reagents of aureomycin, tetracycline, oxytetracycline and epimers thereof among tetracycline antibiotics. Background technique [0002] Tetracycline antibiotics are a class of broad-spectrum antibiotics produced by actinomycetes, including aureomycin, oxytetracycline, tetracycline and semi-synthetic derivatives methacycline, doxycycline, dimethylaminotetracycline, etc. Contain naphthalene basic skeleton. Widely used in infections caused by various bacteria and Rickettsia, Chlamydia, Mycoplasma, etc. Tetracycline antibiotics are broad-spectrum antibiotics commonly used in veterinary medicine. They are widely used in the prevention and treatment of animal diseases, and are often used as animal growth promoters. However, while these drugs are effective, they also have relatively large toxic and side eff...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C237/48C07B59/00
CPCC07B59/001C07B2200/05C07B2200/07C07C231/12C07C249/16C07D311/78C07C2603/46C07C237/48C07C251/86
Inventor 张磊郝明锋韩世磊徐浩
Owner 天津阿尔塔科技有限公司
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