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Synthetic method of tigecycline

A synthesis method and technology of tigecycline, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of high cost and low yield, and achieve easy control of conditions, simple operation, and wide application foreground effect

Active Publication Date: 2009-06-10
SHANGHAI LAIYI BIOMEDICAL RES & DEV CENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] This method has high cost and low yield
[0019] In summary, according to the traditional synthetic method to synthesize tigecycline, minocycline must be synthesized first, however, in the synthesis process of minocycline, various unfavorable factors cannot be avoided

Method used

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  • Synthetic method of tigecycline
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  • Synthetic method of tigecycline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 , the preparation of sancycline (I)

[0035] According to the method of the U.S. Patent (US3160661) of the people such as Jerry Robert Daniel McCormick, 6-demeclotetracycline is carried out catalytic hydrogenation, obtains product (I), specifically as follows:

[0036] Take 4.6g of 6-demeclotetracycline, dissolve it in a mixture of 100mL of water and dimethylformamide DMF (1:1), adjust the pH value to 1.8 with concentrated hydrochloric acid, add 3.0g of 5% Pd-C, and then Add 0.5mL of perchloric acid dropwise, place in a hydrogen reactor, pass through hydrogen, and stir for 2h at a pressure of 1.5atm.

[0037] The reaction solution was filtered to remove the catalyst, the filtrate was adjusted to pH 3.0 with ammonia water, extracted with 100 mL of n-butanol, the organic phase was washed once with the same volume of saturated NaCl, then dried with anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain 3.0 g Yellow powder (I).

[0038] Mass ...

Embodiment 2

[0039] Example 2 , 7, the preparation of 9-dinitroshancycline (II)

[0040] According to the method of the U.S. Patent (US3397230) of Robert Winterbottom et al., product (I) is carried out nitration reaction, obtains product (II), specifically as follows:

[0041] Take 60mL of concentrated sulfuric acid and stir in an ice-water bath to lower the temperature to about 0°C. Take 4.0 g of compound (I) and slowly add it to concentrated sulfuric acid, controlling the temperature not to exceed 20°C. After the addition is complete, stir until the temperature drops below 10°C. Weigh 4.0gKNO 3 , added to the reaction solution in three batches, and stirred at this temperature for 15 min after addition, and thin layer chromatography TLC showed that the reaction was complete. The reaction solution was slowly poured into 600 mL of frozen anhydrous diethyl ether, a precipitate was precipitated, left to stand, and filtered with suction to obtain 5.5 g of light red solid (II).

[0042] T...

Embodiment 3

[0043] Example 3 , the preparation of 7-nitro-9-aminocycline (III)

[0044] According to Nagaraj R.Ayyangar, Uttam R.Kalkote et al's method (Bull.Chem.Soc.Jpn., 1983,56,3159-3164), the product (II) is selectively reduced to obtain the product (III), specifically as follows:

[0045] Take 2.0 g of compound (II), add 25 mL of 60% hydrazine hydrate, and stir to dissolve. Stirring at room temperature for 6h, TLC showed that the reaction was complete. Under an ice-water bath, the pH value of the reaction solution was adjusted to about 5 with 3N HCl, and the same volume of n-butanol was added for extraction. The organic phase was separated, washed twice with the same volume of water, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain 1.5 g of reddish-brown solid (III).

[0046] The obtained compound (III) was subjected to mass spectrometry (ESI, Q-Tofmicro YA019), MS: 475 (M+1).

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Abstract

The invention discloses a method for synthesizing tigecycline. The method comprises: 6-demeclocycline is subjected to catalytic hydrogenation, nitration, selective deoxidization, amino prevention reaction, catalytic deoxidization, and a deprotection to form 9-amino minocycline hydrochloride; the 9-amino minocycline hydrochloride reacts with tert-butylamine acetyl chloride hydrochloride to form tigecycline. The invention uses 6-demeclocycline as a starting material, without synthesizing minocycline as the intermediate. The novel method has simple operation, easily controllable conditions, low requirements on equipment, low pollution, and great application prospect.

Description

technical field [0001] The invention belongs to the field of chemical industry, and in particular relates to a synthesis method of tigecycline. Background technique [0002] Tigecycline (tigecycline), chemical name: (4S, 4aS, 5aR, 12aS)-4,7-bis(dimethylamino)-9-[(tert-butylamino)acetamido]-3,10, 12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, also known as 9-tert-butylglycerol Aminoamido minocycline or Dingglyminocycline, which was approved by the FDA in June 2005, is the first glycylcycline antibiotic approved for marketing. The molecular structure is as follows: [0003] [0004] The synthetic method of traditional tigecycline is obtained by the structural transformation of minocycline, and its intermediate process involves several links such as the preparation of minocycline, the generation of side chain, condensation (Bioorganic & Medicinal Chemistry Letters1999, 9, 1459-1462), as follows: [0005] [0006] or: [0007] ...

Claims

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Application Information

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IPC IPC(8): C07C237/26C07C231/14
CPCY02P20/55
Inventor 邵昌王涛杨志钧袁建勇陈鹏叶伟东罗敏玉戈梅
Owner SHANGHAI LAIYI BIOMEDICAL RES & DEV CENT
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