CN103896961A - Milbemycin oxime compound and preparation method thereof - Google Patents

Milbemycin oxime compound and preparation method thereof Download PDF

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CN103896961A
CN103896961A CN201410113540.0A CN201410113540A CN103896961A CN 103896961 A CN103896961 A CN 103896961A CN 201410113540 A CN201410113540 A CN 201410113540A CN 103896961 A CN103896961 A CN 103896961A
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compound
alkyl
milbemycin oxime
ether
preparation
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曾小东
田孝东
洪学传
虞沂
邓子新
赵昌明
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Wuhan University WHU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings

Abstract

The invention discloses a milbemycin oxime compound and a preparation method thereof. The compound as shown in a general formula (I) in the specification is prepared by the steps of carrying out hydrolysis reaction on avermectin B1a to remove C13-position glycosyl, oxidizing both C5-position hydroxyl and C13-position hydroxyl into keto through oxidation reaction, and finally converting the two kinds of keto into oximido, wherein the structure of the compound is confirmed by virtue of the mass spectrum and nuclear magnetic resonance analysis testing technology. According to the milbemycin oxime compound and the preparation method, the milbemycin oxime compound is prepared by starting materials which are cheap and easily obtained; the preparation method has the characteristics of mild reaction condition, simpleness in operation process, low cost and higher yield.

Description

A kind of milbemycin oxime compounds and preparation method thereof
Technical field
The invention belongs to organic synthesis field, relate to a kind of milbemycin oxime compounds and preparation method thereof.
Background technology
Avrmectin (avermectins) is the 16 ring macrolides compounds that obtained from the tunning of streptomycete (Streptomyces avermitilis MA-4680) in 1976 by Japanese scientist large village intelligence and Merck company of the U.S., a kind of effectively insect, acarid and parasite sterilant, because of its wide spectrum, efficient, low toxicity, non-environmental-pollution, application is in the world more and more extensive.Avrmectin component is more, because Avermectin B1a is difficult in industrial production with B1b separate, so the major ingredient of commercial Avrmectin is the mixture of B1a and B1b, wherein the content of B1a component accounts for 3/4, the content of B1b component accounts for 1/4, is the agricultural insecticide of wide spectrum, efficient, low toxicity.
The hexa-atomic macrocyclic lactone compound of a class ten that mibemycin (Milbemycin) is found from the fermented liquid of streptomycete-Streptomyces hygroscopicus subsp.aureolacrimosus of screening in people such as the green grass or young crops wood (Aoki) by Japanese Sankyo company in 1967, various acarids, Agricultural pests and gardening pest insect (as lepidopterous aphid, larva) are had to good prevention effect, and deadly parasite disease (as heartworm disease) to pet dog class and cat class etc. all there is good therapeutic action.Mibemycin and derivative thereof have active high, ultra-high efficiency, utmost point hypotoxicity, safe and reliable, easy degraded, non-environmental-pollution, a kill insects, do not kill natural enemy, also the characteristic such as composite and rotation medication that is difficult for producing resistance, domestic and international market progressively increases the demand of this product.
Milbemycin oxime (milbemycin oxime) is mibemycin A3 and A4 become oximido derivative at the hydroxyl of C5 position, they are the inside and outside parasite type medicines of a class macrolide antibody-like, it is a kind of pest-resistant medicine that is mainly used as treatment dog class, milbemycin oxime has fabulous effect to treatment and the more common parasitic disease of prevention major part, is commonly used to the disease such as cat, dog that prevention and treatment are caused by nematode, dirofilariasis etc.Milbemycin oxime starts the pest-resistant medicine that application is the commodity released by Taiwan Novartis Co.,Ltd in 1997 times arteries and veins heart (composition is milbemycin oxime) by name first at home, as Canis animals and feline prevention of intestinal entozoa and other parasitic medicine for oral administration, just because of it, Mammals inside and outside parasite is all had and well kills effect, and the dog class to some Avrmectin sensitivities is almost without any side effects, make its using value and Research Prospects more and more be subject to the extensive attention in the world.
The derivative of a lot of Avrmectins has good biological activity, and the key distinction of Avrmectin and mibemycin is that mibemycin is at C 13position does not have glycosyl.At present milbemycin oxime analogue substantially all by mibemycin through chemosynthesis, and many parasites have all produced certain resistance to Avrmectin, mibemycin and milbemycin oxime, by Avermectin B1a chemosynthesis milbemycin oxime analogue also nobody attempt, seek thus new antiparasitic cheap and easy to get agricultural and livestock industry producer mask significant.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of taking Avermectin B1a as synthetic milbemycin oxime compounds of initiator and preparation method thereof.
Milbemycin oxime compounds provided by the present invention, has the structure shown in general formula I:
Figure BDA0000481953630000021
Wherein:
X-Y is CH=CH, CH 2-CH (OH), CH 2-CH 2, CH 2-O or CH 2-NH;
R is hydrogen, halogen, alkyl, alkoxyl group, haloalkyl, alkyl-carbonyl, alkoxy carbonyl, aryl, amino, alkylamino, nitro or hydroxyl;
R 1, R 2for hydrogen, alkyl, alkyl-carbonyl or alkoxy carbonyl.
Described alkyl is C 1～C 4straight chain, side chain or cyclic alkyl, as methyl, ethyl, n-propyl, sec.-propyl, butyl, normal-butyl, cyclohexyl etc.
Described alkoxyl group is C 2～C 6alkoxyl group, as methoxyl group, oxyethyl group etc.
Described haloalkyl is the haloalkyl that 1～5 halogen atom replaces, as trifluoromethyl.
Described alkyl-carbonyl is C 1～C 6alkyl-carbonyl, as formyl radical, ethanoyl, propionyl, isopropyl acyl group, butyryl radicals, isobutyryl, tertiary butyryl radicals etc.
Described alkoxy carbonyl is C 1～C 6alkoxy carbonyl, as methoxycarbonyl, ethoxycarbonyl, isopropyl oxygen carbonyl, butoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl etc.
Described amino is C 1～C 10primary amine or secondary amine that alkyl replaces.
Described alkylamino is C 1～C 6alkylamino, as methylamino-, ethylamino, the third amino, isopropylamino, fourth amino, isobutyl amino, tertiary fourth amino etc.
Described aryl is fragrant heterocyclic radical, mononuclear aromatics base, condensed ring aryl radical or aromatic heterocycle alkyl, as phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, pyrryl, imidazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, indyl, quinolyl etc.
A preparation method for above-mentioned milbemycin oxime compounds, comprises the following steps:
(1) under protection of inert gas, Avermectin B1a is dissolved in tetrahydrofuran (THF), removes diglycosyl obtain compound 1 under-10 DEG C～5 DEG C conditions with mineral acid hydrolysis, wherein, the mol ratio of Avermectin B1a and mineral acid is 1:1～2;
(2) compound 1 is dissolved in halogenated alkane or low-carbon (LC) ethers, under-10 DEG C～5 DEG C conditions, adds mild oxidizer, wherein, compound 1 is 1:2～60 with the mol ratio of mild oxidizer; At 10 DEG C～30 DEG C, carry out oxidizing reaction, by the C of compound 1 5position hydroxyl oxidize becomes ketone group, after reaction finishes, adds water and extracts, and purifying obtains compound 2;
(3) compound 2 is dissolved in alcohol, under-10 DEG C～5 DEG C conditions, oxammonium hydrochloride solution is slowly added drop-wise in the alcoholic solution of compound 2, wherein, the mol ratio of compound 2 and oxammonium hydrochloride is 1:2～40, reaction finishes rear with low-carbon (LC) ether or ester extraction, obtains described milbemycin oxime compounds after purifying.
In the preparation method of above-mentioned milbemycin oxime compounds, described halogenated alkane is methylene dichloride, chloroform or tetracol phenixin; Described low-carbon (LC) ether is C 2～C 10ether compound, as methyl ether, ether, methyl tertiary butyl ether etc.; Described mild oxidizer is superoxide, Manganse Dioxide or pyridinium chlorochromate drone salt; Described alcohol is C 1～C 6alcohol, as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol etc.; Described mineral acid is hydracid, sulfuric acid, nitric acid or phosphoric acid; Described ester is C 2～C 10ester, as methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, butylacetate etc.; The organic phase of the extraction use described in step (2) is halogenated alkane.
More preferably: described mineral acid is sulfuric acid; Described halogenated alkane is methylene dichloride; Described mild oxidizer is pyridinium chlorochromate drone salt; Described alcohol is Virahol; Described low-carbon (LC) ether is ether.
The present invention compared with prior art, has higher, the easy and simple to handle and synthetic low cost and other advantages of yield.
Brief description of the drawings
Fig. 1 is milbemycin oxime analogue synthetic route chart.
Fig. 2 is the one-level mass spectrum of compound 3.
Embodiment
Below in conjunction with accompanying drawing and preferred embodiment, technical scheme of the present invention is further described, should be appreciated that preferred embodiment described herein is only for description and interpretation technical scheme of the present invention, and be not used in limitation of the invention.
Embodiment 1: the preparation of compound 1
First by the dense H of 2.35mL 2sO 4with 2.31mL H 2o mixes, and joins in the THF of 8.5mL, mixes rear formation H 2sO 4/ H 2o/THF mixed solution.222mg (0.25mmol) Avermectin B1a is joined in single necked round bottom flask, under argon shield, add 10mL THF that Avermectin B1a is dissolved, then flask is placed under condition of ice bath, while stirring by the H of preparation 2sO 4/ H 2o/THF mixed solution is slowly added drop-wise in the THF solution of Avermectin B1a, dropwise, be placed in 18 DEG C of environment and react 24h, with the carrying out of thin-layer chromatography (TLC) monitoring reaction, after reacting completely, in agitation condition downhill reaction liquid, add 15mL frozen water, then use methylene dichloride (DCM) extraction three times, by the saturated NaHCO of organic phase merging 3solution and water are respectively washed three times, dry, are spin-dried for, and cross silicagel column separation and obtain target compound 1, and productive rate is 80%.
Compound 1 structure determination data are as follows:
1H?NMR(400MHz,CDCl 3):δ6.18–5.64(m,4H),5.57(d,J=9.2Hz,1H),5.40(d,J=25.7Hz,2H),4.92–4.47(m,2H),4.42–4.26(m,1H),4.08–3.94(m,2H),3.90(s,1H),3.48(d,J=9.6Hz,1H),3.29(s,1H),2.63–2.46(m,2H),2.42–2.17(m,4H),2.04(d,J=14.2Hz,2H),1.89(s,3H),1.84–1.68(m,2H),1.67–1.41(m,7H),1.16(dd,J=28.2,6.7Hz,3H),1.02–0.82(m,10H).
13C?NMR(400MHz,CDCl 3):δ173.6,139.8,138.7,137.8,137.0,136.3,127.8,124.8,120.4,118.1,117.1,95.7,80.3,792,75.2,68.5,68.4,68.367.7,45.7,40.6,40.1,36.5,36.3，34.4,30.6,29.7,27.6,19.9,19.2,16.4,14.6,12.8,12.2.
Embodiment 2: the preparation of compound 2
The compound 1 that 25mg (0.043mmol) embodiment 1 is obtained joins in 25mL single necked round bottom flask, then adding 8mL heavily to steam DCM dissolves, under the condition of ice bath, add 27.6mg (3eq) pyridinium chlorochromate drone salt (PCC), mix formation reaction solution, stirring at room temperature reaction 6h.TLC monitoring reaction is carried out, and after reacting completely, in reaction solution, adds 7mL water, DCM extraction three times, saturated aqueous common salt/water for organic phase (1/1, the v/v) washing merging three times, dry, be spin-dried for, cross silicagel column separator column and obtain target compound 2, productive rate is 91%.
Compound 2 structure determination data are as follows:
1H?NMR(400MHz,CDCl 3):δ6.56(s,1H),6.24(t,J=8.2Hz,1H),6.05(dd,J=14.6,11.3Hz,1H),5.94(d,J=11.3Hz,1H),5.84–5.73(m,1H),5.55(dd,J=9.9,2.5Hz,1H),5.42(ddd,J=16.3,11.3,5.6Hz,1H),4.79(qd,J=14.6,2.2Hz,2H),4.31–4.06(m,1H),3.95–3.75(m,2H),3.74–3.54(m,2H),3.46(dd,J=12.5,5.9Hz,1H),2.61(ddd,J=12.4,7.9,4.8Hz,1H),2.35(s,1H),2.26(ddd,J=30.4,17.8,10.6Hz,2H),2.03(dd,J=10.3,5.2Hz,1H),1.89(s,3H),1.74(dd,J=11.0,3.4Hz,1H),1.69–1.55(m,2H),1.51(dd,J=11.9,5.2Hz,1H),1.48–1.36(m,2H),1.21–1.13(m,3H),1.08(dd,J=15.8,8.0Hz,1H),1.01–0.70(m,10H).
13C?NMR(400MHz,CDCl 3):δ202.7,191.9,172.1,140.0,139.7,138.2,137.5,137.1,136.8,135.0,129.1,128.2,127.4,126.8,125.5,121.0,95.8,82.2,80.5,75.5,69.7,68.7,67.6,46.5,46.0,40.4,36.9,35.2,30.6,27.7,16.4,15.5,12.8,12.2.
Embodiment 3: the preparation of compound 3
The compound 2 of 99mg (0.17mmol) is joined in 10mL single necked round bottom flask, then add 18mL Virahol to dissolve, then add the 4A molecular sieve of 150mg, then flask is placed on ice bath.With the oxammonium hydrochloride of a small amount of dissolve with methanol 244mg (20eq), be slowly added drop-wise in round-bottomed flask magnetic agitation reaction 24h.TLC monitoring reaction is carried out, after reacting completely, with anhydrous diethyl ether/water (1/1, v/v) extraction three times, the organic phase of merging washes with water to pH approaching neutral, dry, filtration is spin-dried for, cross silicagel column separator column and obtain target compound 3, compound 3 is described milbemycin oxime compounds, and productive rate is 65%.
Compound 3 structure determination data are as follows:
HRMS(m/z):calc.611.3332,found611.33319[M+H] +.
1H?NMR(400MHz,CDCl 3):δ6.56(s,1H),6.24(t,J=8.2Hz,1H),6.05(dd,J=14.6,11.3Hz,1H),5.94(d,J=11.3Hz,1H),5.84–5.73(m,1H),5.55(dd,J=9.9,2.5Hz,1H),5.42(ddd,J=16.3,11.3,5.6Hz,1H),4.79(qd,J=14.6,2.2Hz,2H),4.31–4.06(m,1H),3.95–3.75(m,2H),3.74–3.54(m,2H),2.65(dd,J=12.5,5.9Hz,1H),2.61(ddd,J=12.4,7.9,4.8Hz,1H),2.26(ddd,J=30.4,17.8,10.6Hz,2H),2.13(s,1H),2.03(dd,J=10.3,5.2Hz,1H),1.74(dd,J=11.0,3.4Hz,1H),1.71(s,3H),1.69–1.55(m,2H),1.51(dd,J=11.9,5.2Hz,1H),1.48–1.36(m,2H),1.21–1.13(m,3H),1.08(dd,J=15.8,8.0Hz,1H),1.01–0.70(m,10H)。

Claims (5)

1. a milbemycin oxime compounds, is characterized in that: have the structure shown in general formula I:
Figure FDA0000481953620000011
Wherein:
X-Y is CH=CH, CH 2-CH (OH), CH 2-CH 2, CH 2-O or CH 2-NH;
R is hydrogen, halogen, alkyl, alkoxyl group, haloalkyl, alkyl-carbonyl, alkoxy carbonyl, aryl, amino, alkylamino, nitro or hydroxyl;
R 1, R 2for hydrogen, alkyl, alkyl-carbonyl or alkoxy carbonyl.
2. milbemycin oxime compounds according to claim 1, is characterized in that:
Described alkyl is C 1～C 4straight chain, side chain or cyclic alkyl;
Described alkoxyl group is C 2～C 6alkoxyl group;
Described haloalkyl is the haloalkyl that 1～5 halogen atom replaces;
Described alkyl-carbonyl is C 1～C 6alkyl-carbonyl;
Described alkoxy carbonyl is C 1～C 6alkoxy carbonyl;
Described amino is C 1～C 6primary amine or secondary amine that alkyl replaces;
Described alkylamino is C 1～C 6alkylamino;
Described aryl is fragrant heterocyclic radical, mononuclear aromatics base, condensed ring aryl radical or aromatic heterocycle alkyl.
3. a preparation method for the milbemycin oxime compounds described in claim 1 or 2, is characterized in that: comprise the following steps:
(1) under protection of inert gas, Avermectin B1a is dissolved in tetrahydrofuran (THF), removes diglycosyl obtain compound 1 under-10 DEG C～5 DEG C conditions with mineral acid hydrolysis, wherein, the mol ratio of Avermectin B1a and mineral acid is 1:1～2;
(2) compound 1 is dissolved in halogenated alkane or low-carbon (LC) ether, under-10 DEG C～5 DEG C conditions, adds mild oxidizer, wherein, compound 1 is 1:2～60 with the mol ratio of mild oxidizer; At 10 DEG C～30 DEG C, carry out oxidizing reaction, by the C of compound 1 5position hydroxyl oxidize becomes ketone group, after reaction finishes, adds water and extracts, and purifying obtains compound 2;
(3) compound 2 is dissolved in alcohol, under-10 DEG C～5 DEG C conditions, oxammonium hydrochloride solution is slowly added drop-wise in the alcoholic solution of compound 2, wherein, the mol ratio of compound 2 and oxammonium hydrochloride is 1:2～40, reaction finishes rear with low-carbon (LC) ether or ester extraction, obtains described milbemycin oxime compounds after purifying.
4. the preparation method of milbemycin oxime compounds according to claim 3, is characterized in that:
Described halogenated alkane is methylene dichloride, chloroform or tetracol phenixin;
Described low-carbon (LC) ether is C 2～C 10ether compound;
Described mild oxidizer is superoxide, Manganse Dioxide or pyridinium chlorochromate drone salt;
Described alcohol is C 1～C 6alcohol;
Described mineral acid is hydracid, sulfuric acid, nitric acid or phosphoric acid;
Described ester is C 2～C 10ester;
The organic phase of the extraction use described in step (2) is halogenated alkane.
5. according to the preparation method of the milbemycin oxime compounds described in claim 3 or 4, it is characterized in that:
Described mineral acid is sulfuric acid;
Described halogenated alkane is methylene dichloride;
Described mild oxidizer is pyridinium chlorochromate drone salt;
Described alcohol is Virahol;
Described low-carbon (LC) ether is ether.
CN201410113540.0A 2014-03-25 2014-03-25 Milbemycin oxime compound and preparation method thereof Pending CN103896961A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104327094A (en) * 2014-10-30 2015-02-04 湖北宏中药业有限公司 Milbemycin oxime separation and purification method
CN105254644A (en) * 2015-11-04 2016-01-20 湖北宏中药业股份有限公司 Preparation method of milbemycin oxime
CN108640927A (en) * 2018-04-27 2018-10-12 丽珠集团福州福兴医药有限公司 A kind of preparation method of milbemycin oxime

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104327094A (en) * 2014-10-30 2015-02-04 湖北宏中药业有限公司 Milbemycin oxime separation and purification method
CN105254644A (en) * 2015-11-04 2016-01-20 湖北宏中药业股份有限公司 Preparation method of milbemycin oxime
CN108640927A (en) * 2018-04-27 2018-10-12 丽珠集团福州福兴医药有限公司 A kind of preparation method of milbemycin oxime
CN108640927B (en) * 2018-04-27 2021-05-07 丽珠集团福州福兴医药有限公司 Preparation method of milbemycin oxime

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Application publication date: 20140702