Technical field
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The invention belongs to technical field of animal remedy preparation, relate to the preparation method of ivermectin, be specifically related to a kind of with Avrmectin B 2For raw material, by reduction, take off Avrmectin B 223-position sulphonyl hydrazone prepare the method for ivermectin.
Background technology
Ivermectin (Ivermectin) is the antibiotics parasiticide veterinary drug of a kind of wide spectrum, efficient and low toxicity, be used widely, in some field also with the medicine of conducting oneself.Industrial, ivermectin is usually by Avrmectin B at present 1a/1bThrough the conversion of rhodium catalyst shortening, obtain ( Pure & Appl. Chem. , Vol. 62, and No. 7, pp. -).
Avrmectin (Avermectin) is the secondary metabolite that is produced by Avid kyowamycin (Sterptomyces avermitills).Industrial utilization carrys out the scale operation Avrmectin to the fermentation culture of Avid kyowamycin.Avrmectin is that the mixture of 8 components is present in the mycelium of fermented liquid, and 8 components are: Avermectin A 1a, A 1b, A 2a, A 2b, B 1a, B 1b, B 2a, B 2b( Natural Product Reports , ,Pp. 87-121).Through filtering, discarding filtrate, filter cake can obtain mainly containing Avrmectin B with desugar after solvent extraction, concentrated, crystallization 1aAnd B 1bElaboration.The Avrmectin of existing market is with B 1aFor main component, B wherein 1aBe not less than 85%, B 1bBe no more than 15%.&#;
The fermentation of Avid kyowamycin also produces a large amount of B 2Component (comprises B 2aAnd B 2b), be not utilized always.The present invention is exactly with Avrmectin B 2Component is the novel method for preparing ivermectin that raw material is developed.Shown in 1 (Avermectin B in formula 1 2a/2b )B 2aAnd B / 2bMolecular structure, the macrolide with sec-butyl on the C25 position is B 2a, content should be B greater than the lactone with sec.-propyl on 85%, C25 position usually 2b, content usually should be less than 10%.The suitable starting raw material of the present invention is the mixture of these two kinds of lactones, needn't separate.
Merck company ( Tetrahedron Letters, , Vo1.23, No.23, pp -) once reported to adopt and sloughed Avrmectin B 2The method that on component 23-position, the thiocarbonyl group carbonic ether synthesizes ivermectin, hypertoxic tributyl tin hydrogen (Bu has been used in reaction 3SnH) provide hydroperoxyl radical, total recovery is only 10%, is not suitable for suitability for industrialized production.
The method of the method disclosed in the present and Merck company is fully different, and the present invention is with Avrmectin B 2Component is raw material, adopts protection, and oxidation becomes hydrazone, and the novel method (shown in 1) that hydrazone deprotection four-step reaction prepares ivermectin is taken off in reduction, every step reaction yield all greater than this 90%, total recovery reaches 67-72%.Be suitable for suitability for industrialized production.
Summary of the invention
The novel method that the purpose of this invention is to provide a kind of preparation of Ivermectin HCL, to enlarge Avrmectin B 2Utilize scope, improve product yield, be suitable for suitability for industrialized production, reduce the cost of Ivermectin HCL, improve the economic benefit of veterinary drug enterprises.
The preparation method of ivermectin of the present invention, with Avrmectin B 2Component is raw material, and preparation process is as follows:
(1) in inert solvent, under organic bases exists, allyl chlorocarbonate and Avrmectin B 2Reaction generates 4 " and 5-position allyl carbonate protect Avrmectin B 24 " and two hydroxyls of 5-position; Temperature of reaction is-40&#;40 oC, the reaction times is 1&#;10 hour, the amount of described organic bases is Avrmectin B 22&#;6 times of mole number, the amount of allyl chlorocarbonate is Avrmectin B 22&#;6 times of mole number;
(2) under organic bases exists, with dimethyl sulfoxide (DMSO) and oxygenant by in step (1), generate 4 " and the Avrmectin B that protects of 5-position 223-position hydroxyl oxidize be the ketone carbonyl, temperature of reaction is-40&#;30 &#;, reaction times 3&#;20h, the amount of described oxygenant is 4 " and the Avrmectin B of 5-position protection 21&#;6 times of mole number; With phosphoric acid and alkali conditioned reaction liquid that concentration is 1&#;5%, arrive final pH value to 6&#;8, divide the phase of anhydrating, the decompression precipitation obtains Avrmectin B 223-position ketone compound;
(3) in alcoholic solution, the Avrmectin B that generates in organic sulfonyl hydrazide and step (2) 2The ketone compound reaction of 23-position generates Avrmectin B 223-position sulphonyl hydrazone; Temperature of reaction: 20&#;80 &#;, reaction times: 1&#;24h, the consumption of described organic sulfonyl hydrazide are Avrmectin B 21&#;6 times of 23-position ketone compound mole number;
(4) in inert solvent, under palladium catalyst exists, with hydroborate, be reductive agent, add under the condition of alcohol, Avrmectin B is sloughed in reduction 2The sulphonyl hydrazone of 23-position, slough 4 simultaneously " and the protection of 5-position, through crystallization, obtain ivermectin; Temperature of reaction is 0&#;60 oC, the reaction times is 1&#;20 hour, the consumption of hydroborate is Avrmectin B 20.5&#;3 times of 23-position sulphonyl hydrazone mole number; Institute's method state add alcohol consumption be the 2-20% of inert solvent volume;
The reaction of described step (1)&#;(4) all under normal pressure, in the atmosphere of rare gas element.
Inert solvent in step (1) and step (4) is methylene dichloride, ethylene dichloride, chloroform, 2-butyl acetate, dimethyl sulfoxide (DMSO) or dimethyl formamide.In step (1), organic bases is pyridine, DMAP, Trimethylamine 99, triethylamine, Tributylamine or tetramethyl-Edamine.Preferred tetramethyl-Edamine.Oxygenant in step (2) is oxalyl chloride, trifluoro-acetic anhydride, phenoxy group phosphoryl chloride or dicyclohexylcarbodiimide (DCC).Organic sulfonyl hydrazide in step (3) is alkyl sulfonyl hydrazine and aromatic base sulfonyl hydrazide.The alkyl sulfonyl hydrazine is specially for C 1-C 10The alkyl sulfonyl hydrazine, comprise sulfonyloxy methyl hydrazine, ethyl sulfonyl hydrazide, sulfonyl propyl hydrazine or butyl sulfonyl hydrazide.The aromatic base sulfonyl hydrazide is adjacent toluene sulfonyl hydrazide, a toluene sulfonyl hydrazide, p-toluene sulfonyl hydrazide, benzol sulfohydrazide, naphthalene sulfonyl hydrazine, heterocyclic aromatic base sulfonyl hydrazide, 3-pyridine sulfonyl hydrazide or 4-pyridine sulfonyl hydrazide.Step (4) borohydride reduction agent is BH 3, B 2H 6, (RO) 2BH, NaBH 4, NaBH 3CN or NaB (OAc) 3H.Alcohol in step (3) and step (4) is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol or the trimethyl carbinol, or the mixing solutions of above-mentioned any two kinds of alcohol.In step (4), palladium catalyst is palladium salt, contains palladium complex or contain the many empty carriers of palladium.Palladium salt is palladium or Palladous chloride, and containing palladium complex is Pd 2(dba) 3.Containing the palladium porous support is palladium carbon catalyst, palladium-aluminium oxide catalyst, palladium-silicon oxide catalyst or palladium-molecular sieve catalyst.Triphenylphosphine is the part of palladium catalyst, and except Pd/C, palladium catalyst uses together with triphenylphosphine.
Step (3) generates Avrmectin B 223-position sulphonyl hydrazone is the crystalloid material, is convenient to separation and purification.The process that step (4) is separated is: after reaction finishes, 5% aqueous acetic acid washing reaction liquid, then with the alkali aqueous solution washing, after the desolventizing that then reduces pressure in ethanol crystallization obtain ivermectin.
The concise and to the point process of preparation is as shown in the formula shown in 1, and (1) is first by Avrmectin B 24 " and the 5-position on two hydroxyls with allyl carbonate protection (obtaining structural formula I); (2) hydroxyl oxygen of 23-position is changed into to ketone carbonyl (obtaining structural formula II); (3) with organic sulfonyl hydrazide, the ketone carbonyl of 23-position is converted into to hydrazone (obtaining structural formula II I); (4) hydrazone (obtaining structural formula IV) is taken off in reduction, the while Deprotection obtains ivermectin.
The preferred allyl chlorocarbonate of step (1) protective material, adopt allyl chlorocarbonate, can improve yield, shortens operation steps.The preferred methylene dichloride of inert solvent.The preferred phenoxy group phosphoryl chloride of step (2) oxygenant.Organic bases is preferred tetramethyl-Edamine.Step (3) organic sulfonyl hydrazide preferable methyl sulfonyl hydrazide or p-toluene sulfonyl hydrazide, inexpensive source is many.Alcoholic solution preferred alcohol solution.The preferred 2-butyl acetate of step (4) inert solvent, pure particular methanol, the preferred NaBH of borohydride reduction agent 4, use comparatively safe.The preferred palladium carbon catalyst of palladium catalyst, recyclable reusing.Every step yield is all greater than 90%, and total recovery reaches 67-72%.
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Each step reaction of the present invention all uses control in high pressure liquid chromatography to follow the tracks of reaction, and intermediate and the finished product are all through proton nmr spectra and liquid matter analysis confirmation structure, and with external standard method, has determined content and the composition of the finished product.
The present invention is with Avrmectin B 2Component is raw material, adopts reduction to take off Avrmectin B 223-position sulphonyl hydrazone, slough simultaneously 4 " and the method for the protection protecting group of 5-position synthesize ivermectin.Raw material is extensive, and preparation condition relaxes, and yield is high, has avoided using dangerous higher hydroaluminium such as LiAlH 4Tributyl tin hydrogen Bu with severe toxicity 3SnH, be applicable to suitability for industrialized production.The present invention is with Avrmectin B 2a/2bFor parent is synthetic, prepare ivermectin, expanded the raw material sources of ivermectin, enlarged Avrmectin B 2Utilize scope, reduced the production cost of ivermectin, be conducive to improve the economic benefit of veterinary drug enterprises.
Embodiment
Describe the present invention by the following examples, protection scope of the present invention is not limited only to following instance.
Embodiment 14 ", 5-bis-(allyloxy carbonyl oxygen)-23-deoxidation-(4-Methyl benzenesulfonyl hydrazone group)-Avrmectin B 2Preparation
In rare gas element (argon gas) atmosphere, by 10g Avrmectin B 2(content B 2a93.3%, B 2b3.2%) be dissolved in the 100m1 methylene dichloride, be cooled to-10 &#;, add 4.2g allyl chloroformate and 3.0g tetramethyl-Edamine, stirring reaction 2 hours.Be warming up to 20 &#; and add 8.0g tetramethyl-Edamine, 8.0g methyl-sulphoxide and 8.0g phenoxy group phosphoryl chloride, stirring reaction 10 hours.Add phosphoric acid solution and sodium hydroxide solution, first adjust pH to 2, then transfer to 7&#;8, layering, use the dried over sodium sulfate organic phase, and under reduced pressure except desolventizing.
In rare gas element (argon gas) atmosphere, residuum is dissolved in to 95% ethanol of 80ml, add 2.5g toluene sulfonyl hydrazide (TsNHNH 2), be heated to 50&#;60 oC, and stirring reaction 8 hours, then be cooled to 25 oC, filter, and after vacuum-drying, obtains 12.6g and obtain yellow solid.Liquid matter is analyzed LC-MS [M+H] +, lH NMR (CDCl 3, 200Hz) 7.78(d, 2H), 7.31 (d, 2H), 5.89 (m, 2H), 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), 2.32 (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), 1.60-1.46 (m, 6H), 1.48 (br s, 3H), 1.35 (d, J=6.7,3H), 1.23 (d, J=6.2,3H), 1.16 (d, J=7.0,3H), 1.00 (m, 10H).Analyze LC-MS [M+H] +: ,4 ", 5-bis-(allyloxy carbonyl oxygen)-23-deoxidation-(4-Methyl benzenesulfonyl hydrazone)-Avrmectin B 2aThe M+H calculated value: .
The preparation of embodiment 2 ivermectins.
In rare gas element (argon gas) atmosphere, by gained in example 14 ", 5-bis-(allyloxycarbonyl oxygen)-23-deoxidation-(4-Methyl benzenesulfonyl hydrazone)-Avrmectin B 2(10.2g) join in the 100ml 2-butyl acetate, add 0.2g triphenylphosphine and 0.1g Pd (OAc) 2, be heated to 25 oC divides 3 times and adds 0.5g NaBH 4, after 1 hour, add 10 ml methyl alcohol, 25 oC stirred 5 hours.Be heated to 50 oC continues constant temperature and stirred 8 hours.Add 5% aqueous acetic acid 20ml washing reaction liquid, then use NaHCO 3Solution washing toluene, after the decompression desolventizing in ethanol crystallization obtain the crystallization of 6.5g white ivermectin.With the HPLC external standard method, analyze 22,23-dihydro avermectin B 1Content 98.3% (wherein 22,23-dihydro B 1a96.1%, 22,23-dihydro B 1b2.1%). 1HNMR and 13CNMR further proves conclusively its main component structure 22,23-dihydro B 1a. 1H?NMR?(200?MHz,?CDCl 3):?6.00-5.60?(m,?3H,?H-9,?H-10?and?H-11),?5.50-5.20?(m,?3H,?H-3,?H-19?and?H-1&#;),?5.00?(br.?s,?1H,?H-15),?4.85-4.55?(m,?3H,?H-1&#;?and?H 2-8a),?4.24?(br.?s,?1H,?H-5),?4.10-3.35?(m,?8H,?including?H-2,?H-6,?H-13,?H-17,?H-3&#;,?H-3&#;,?H-5&#;?and?H-5&#;),?3.43?(br.?s,?3H,?OMe),?3.42?(br.?s,?3H,?OMe),?3.35-3.10?(m,?4H,?H-2,?H-25,?H-4&#;?and?H-4&#;),?2.54?(br.?s,?1H,?H-12),?2.45-2.15?(m,?4H,?H 2-16,?H eq-2&#;?and?H eq-2&#;),?2.10-1.05?(m,?20H,?including?H 2-20,?H 2-18,?H 2-22,?H 2-23,?H 2-27,?Me-12,?Me-5&#;?or?Me-5&#;),?1,82?(s,?3H,?Me-4),?1.51?(br.?s,?3H,?Me-14),?1.17?(d,?J?=?7.0?Hz,?3H,?Me-5&#;?or?Me-5&#;),?1.00-0.75?(m,?10H,?including?Me-28,?Me-26?and?Me-24)?ppm.? 13C?NMR?(50.32?MHz,?CDCl 3):?173.6?(C-1),?139.7?(C-8),?137.4?(C-11),?135.7?(C-4),?134.8?(C-14),?124.7?(C-10),?119.5?(C-9),?118.3?(C-3),?118.1?(C-15),?98.3?(C-1&#;),?97.3?(C-21),?94.6?(C-1&#;),?81.7?(C-13),?80.4?(C-7),?80.3?(C-4&#;),?79.2?(C-3&#;),?78.0?(C-3"),?77.3?(C-5?or?C-6),?76.7?(C-5?or?C-6),?76.4?(C-25),?75.8?(C-4"),?68.5?(C-5"),?68.0?(2C,?C-8a?and?C-17?or?C-19),?67.0?(2C,?C-5&#;?and?C-17?or?C-19),?56.3?(OMe),?56.2?(OMe),?45.4?(C-2),?41.0?(C-20),?39.5?(C-12),?36.6?(C-16),?35.5?(C-22),?35.2?(C-26),?34.3?(C-2&#;?or?C-18?or?C-2&#;),?34.1?(C-2&#;?or?C-18?or?C-2&#;),?33.9?(C-2&#;?or?C-18?or?C-2&#;),?31.0?(C-24),?27.9?(C-23),?27.1?(C-27),?20.1?(Me-12),?19.7?(Me-4),?18.2?(C-6&#;),?17.5?(C-6&#;),?17.3?(Me-24),?14.9?(Me-14),?12.2?(Me-26),?11.9?(Me-27)&#;
Embodiment 34 ", 5-bis-(allyloxy carbonyl oxygen base)-23-deoxidation-sulfonyloxy methyl hydrazone group-Avrmectin B 2Preparation
Synthetic method step and example 14 ", 5-bis-(allyloxycarbonyl oxygen)-23-deoxidation-(4-Methyl benzenesulfonyl hydrazone)-Avrmectin B 2Synthetic method is identical, by p-toluene sulfonyl hydrazide (TsNHNH 2) replace to sulfonyloxy methyl hydrazine (MsNHNH 2), obtain 4 ", 5-bis-(allyloxycarbonyl oxygen)-23-deoxidation-sulfonyloxy methyl hydrazone-Avrmectin B 2.Liquid matter is analyzed LC-MS [M+H] +, lH 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), 1.60-1.46 (m, 6H), 1.48 (br s, 3H), 1.35 (d, J=6.7,3H), 1.23 (d, J=6.2,3H), 1.16 (d, J=7.0,3H), 1.00 (m, 10H).Analyze LC-MS [M+H] +: ,4 ", 5-bis-(allyloxycarbonyl oxygen)-23-deoxidation-sulfonyloxy methyl hydrazone-Avrmectin B 2aThe M+H calculated value: .
The preparation of embodiment 4 ivermectins
In rare gas element (argon gas) atmosphere, by gained in example 34 ", 5-bis-(allyloxycarbonyl oxygen)-23-deoxidation-sulfonyloxy methyl hydrazone-Avrmectin B 2(9.8 g) joins in the 100ml 2-butyl acetate, adds 0.2g triphenylphosphine and 0.1g Pd (OAc) 2, be heated to 25 oC, divide and add 0.5g NaBH three times 4, stirring reaction adds 10 ml methyl alcohol, 25 after 1 hour oC stirring reaction 5 hours.Be heated to 50 oC continued stirring reaction 8 hours.Add 5% aqueous acetic acid 20ml washing reaction liquid, then use NaHCO 3The solution washing reaction solution, after the decompression desolventizing in ethanol crystallization obtain the crystallization of 6.7g white ivermectin.With the HPLC external standard method, analyze 22,23-dihydro avermectin B 1Content 97.3% ((wherein 22,23-dihydro B 1a96.0%, 22,23-dihydro B 1b1.3%).
The preparation of embodiment 5 ivermectins
In rare gas element (argon gas) atmosphere, by gained in example 14 ", 5-bis-(allyloxycarbonyl oxygen)-23-deoxidation-(4-Methyl benzenesulfonyl hydrazone)-Avrmectin B 2(10.5 g) joins in the 100ml 2-butyl acetate, adds the 0.2g triphenylphosphine 3With the 0.15g Palladous chloride, be heated to 25 oC divides three times and adds 0.5g NaBH 4, stir after 1 hour and add 10 ml methyl alcohol, 25 oC stirred 5 hours.Continue to be heated to 50 oC, stirring reaction 8 hours.With 5% aqueous acetic acid 20ml washing reaction liquid, then use NaHCO 3The solution washing reaction solution, after the decompression desolventizing in ethanol crystallization obtain the crystallization of 6.9g white ivermectin.With the HPLC external standard method, analyze 22,23-dihydro avermectin B 1Content 98.3% (wherein 22,23-dihydro B 1a95.0%, 22,23-dihydro B 1b1.3%).
The preparation of embodiment 6 ivermectins
In rare gas element (argon gas) atmosphere, by gained in example 14 ", 5-bis-(allyloxycarbonyl oxygen)-23-deoxidation-(4-Methyl benzenesulfonyl hydrazone)-Avrmectin B 2(10.5 g) joins in the 100ml 2-butyl acetate, adds 0.5g 10% palladium/carbon catalyst, is heated to 25 oC divides three times and adds 0.5g NaBH 4, stir after 1 hour and add 10 ml methyl alcohol, 25 oC stirring reaction 5 hours.Continue to be heated to 50 oC, stirring reaction 8 hours.The filtered and recycled palladium/carbon catalyst, with 5% aqueous acetic acid 20ml washing 2-butyl acetate solution, then use NaHCO 3Solution washing, the decompression desolventizing to after in ethanol crystallization obtain the crystallization of 7.1g white ivermectin.With the HPLC external standard method, analyze 22,23-dihydro avermectin B 1Content 97.5% (wherein 22,23-dihydro B 1a96.0%, 22,23-dihydro B 1b1.5%).
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