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Preparation method of ivermectin

A technology for ivermectin and avermectin, which is applied in the preparation of sugar derivatives, chemical instruments and methods, and bulk chemical production, can solve the problems of not being suitable for industrial production, and achieves ease of preparation conditions and high yield , the effect of a wide range of raw materials

Active Publication Date: 2013-11-20
河北威远药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Merck (Tetrahedron Letters, 1982, Vo1.23, No.23, pp 2377-2378) has reported the use of A method for synthesizing ivermectin with a thiocarbonyl carbonate at the 23-position of the component of vermectin B2, the reaction uses highly toxic tributyltin hydrogen (Bu3 SnH) to provide hydrogen radicals, the total yield is only 10%, which is not suitable for industrial production

Method used

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  • Preparation method of ivermectin
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  • Preparation method of ivermectin

Examples

Experimental program
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Effect test

Embodiment 1

[0023]Example 1 4", 5-bis(allyloxycarbonyloxy)-23-deoxy-(4-methylbenzenesulfonylhydrazone)-abamectin B 2 preparation of

[0024]

[0025] In an inert gas (argon) atmosphere, 10 g of abamectin B 2 (content B 2a 93.3%, B 2b 3.2%) was dissolved in 100m1 dichloromethane, cooled to -10°C, added 4.2g allyl chloroformate and 3.0g tetramethylethylenediamine, and stirred for 2 hours. Heat up to 20°C and add 8.0g of tetramethylethylenediamine, 8.0g of dimethyl sulfoxide and 8.0g of phenoxyphosphoryl chloride, and stir for 10 hours. Add phosphoric acid solution and sodium hydroxide solution, first adjust the pH value to 2, then adjust to 7-8, separate layers, dry the organic phase with sodium sulfate, and remove the solvent under reduced pressure.

[0026] In an inert gas (argon) atmosphere, the residue was dissolved in 80ml of 95% ethanol, and 2.5g of tosylhydrazide (TsNHNH 2 ), heated to 50~60 o C, and stirred the reaction for 8 hours, then cooled to 25 o C, filtered, and d...

Embodiment 2

[0027] Example 2 Preparation of ivermectin.

[0028] In an inert gas (argon) atmosphere, the 4", 5-di(allyloxycarbonyl oxygen)-23-deoxy-(4-methylbenzenesulfonylhydrazone)-abamectin B obtained in Example 1 2 (10.2g) into 100ml sec-butyl acetate, add 0.2g triphenylphosphine and 0.1g Pd(OAc) 2 , heated to 25 o C add 0.5g NaBH in 3 times 4 , add 10 ml methanol after 1 hour, 25 o C was stirred for 5 hours. heat up to 50 o C continued to stir at constant temperature for 8 hours. Add 20ml of 5% acetic acid aqueous solution to wash the reaction solution, and then wash with NaHCO 3 Wash the toluene with aqueous solution, and crystallize in ethanol after removing the solvent under reduced pressure to obtain 6.5g white ivermectin crystals. Analysis of 22,23-Dihydroabamectin B by HPLC External Standard Method 1 Content 98.3% (of which 22,23-dihydro B 1a 96.1%, 22,23-Dihydro B 1b 2.1%). 1 HNMR and 13 CNMR further confirmed its main component structure 22,23-dihydro-B 1a...

Embodiment 3

[0029] Example 3 4”, 5-bis(allyloxycarbonyloxy)-23-deoxy-methylsulfonylhydrazone-abamectin B 2 preparation of

[0030]

[0031] 4 ", 5-bis(allyloxycarbonyloxy)-23-deoxy-(4-methylbenzenesulfonylhydrazone)-abamectin B of synthetic method steps and example 1 2 Synthetic method is the same, p-toluenesulfonyl hydrazide (TsNHNH 2 ) replaced by methylsulfonylhydrazide (MsNHNH 2 ), to obtain 4”, 5-di(allyloxycarbonyloxy)-23-deoxy-methylsulfonylhydrazone-abamectin B 2 . Liquid mass analysis LC-MS [M+H] + 1149, l H NMR (CDCl 3 , 200Hz) 5.68 (m, 1H ), 5.45 (m, lH),5.23(m, 4H), 5.02 (m, lH), 4.83 (m, 5H), 4.67 (m, 2H), 4.36 (br d, J = 6.1, lH), 4.00 (m, lH), 3.97 (m, lH), 3.96 (br s, lH), 3.89 (m, 2H), 3.86 (m, lH), 3.75 (m, lH), 3.56 (m, lH), 3.51 (m, lH), 3.43 (s, 3H), 3.45 (s, 3H), 3.22 (m, 2H), 3.25 (m, lH), 2.90 (m, lH), 2.50 ( s, 3H), 2.53 (m, lH), 2.30-2.26 (m, 3H), 2.22 (dd, J = 12.7, 5.0, lH), 2.00-1.90 (m, 2H), 1.88 (br s, 4H), 1.80 (m, 2H), 1.76 (m, lH), 1.60-...

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Abstract

The invention relates to a preparation method of ivermectin. The ivermectin is prepared by taking an abamectin B2 component as a raw material and removing 23-position sulfonyl hydrazone of the abamectin B2 through reduction, and the process comprises the following steps: (1) protecting 4''-position hydroxyl and 5-position hydroxyl of the abamectin B2 with allyl carbonate; (2) oxidizing 23-position hydroxyl of the abamectin B2 into keto carbonyl; (3) converting the 23-position keto carbonyl of the abamectin B2 with organic sulfonyl hydrazine into hydrazone, thus generating the 23-position sulfonyl hydrazone of the abamectin B2; and (4) reducing with hydroborate to remove the 23-position sulfonyl hydrazone of the abamectin B2, and simultaneously removing the 4''-position protecting group and the 5-position protecting group to obtain the ivermectin. The total yield of the reaction is up to 67-72%. According to the invention, the ivermectin is prepared by taking the abamectin B2 component as the raw material, the utilization range of the abamectin B2 is widened, the cost of the ivermectin is reduced, the preparation conditions are mild, the yield is high, and the use of virulent tributyltin hydride Bu3SnH is avoided. Thus, the invention is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation of veterinary drugs, relates to a preparation method of ivermectin, in particular to an avermectin B 2 as raw material, by reducing abamectin B 2 23-position sulfonylhydrazone to prepare the method for ivermectin. Background technique [0002] Ivermectin is a broad-spectrum, high-efficiency and low-toxic antibiotic anti-parasitic veterinary drug, which is widely used, and is also used as human medicine in some fields. Currently in industry, ivermectin is usually composed of abamectin B 1a / 1b Obtained by rhodium catalyst catalytic hydrogenation conversion ( Pure & Appl. Chem. 1990, Vol. 62, No. 7, pp. 1231-1240). [0003] Avermectin is a secondary metabolite produced by Streptomyces avermitills. Industrially, the fermentation of Streptomyces avermitilis is used to produce abamectin on a large scale. Avermectin is a mixture of 8 components present in the mycelium of the fermentation brot...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00
CPCY02P20/55
Inventor 贾善考张庆马国峰聂丰秋贾成国
Owner 河北威远药业有限公司
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