CN111217828A - Preparation method of lepithromycin and intermediate thereof - Google Patents
Preparation method of lepithromycin and intermediate thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of lepimectin shown in formula V and an intermediate thereof, which takes tianweimycin as a starting material, respectively performs acid hydrolysis reaction, protects a group on a 5-hydroxyl, and then performs SN reaction with 2-methoxyimino phenylacetic acid2And finally, removing the 5-hydroxyl protecting group to obtain the compound shown in the formula V. The method has the advantages of low cost, high purity, high yield and suitability for industrial production.
Description
Technical Field
The invention relates to the field of pesticides, and particularly relates to a preparation method of lepinomycin and an intermediate thereof.
Background
Lepimectin (lepimectin), having a structural formula shown in formula V, is another successful 16-membered macrolide antibiotic developed by Sanko Japan and registered in Japan in 2006. The product contains two effective components of the leporicin A3 and the leporicin A4, wherein the content of the leporicin A3 is less than or equal to 20 percent, and the content of the leporicin A4 is more than or equal to 80 percent. The leporicin is mainly applied to agricultural pest control, targets are lepidoptera and homoptera pests, such as prodenia litura, plutella xylostella, cotton bollworm, mealybug and the like, and the main action modes are stomach toxicity and contact killing. Compared with other avermectins, the lepimetin has the advantages of being free from temperature influence, more stable and quick-acting. If the spodoptera littoralis is treated for 6 hours, symptoms are presented, the spodoptera littoralis quickly dies, and 100% of insecticidal activity is presented.
Leporicin a 3: r is CH3(ii) a Leporicin a 4: r ═ C2H5
The toxicity test of the lepimetin shows that the LD is acute toxicity for rats through oral administration, skin and inhalation50Respectively is 1210mg/Kg of the total weight of the components,>2000mg/Kg，>5.15mg/L, belonging to low-toxicity pesticide. Compared with similar medicines of avermectin (avermectin), emamectin (emamectin) and milbemycin (milbemycin), the lepimetin has lower toxicity and higher safety. In addition, as a novel pesticide, compared with milbemycin and abamectin, the lepimectin has higher insecticidal activity on certain targets, has less dosage and has no cross resistance with abamectin and other pesticides. Therefore, the lepimetin is a variety with great development potential.
The initial starting material for the prior art process for the preparation of lepimetin is milbemycin, as disclosed in patent EP0675133B1, which has the following general reaction formula:
specifically, the method uses 15-hydroxy-5-keto-milbemycin A4 as a raw material, obtains 13- (α -methoxyiminophenylacetyloxy) -5-keto-milbemycin A4 by catalytic rearrangement and esterification of cuprous iodide, then obtains a product 13- (α -methoxyiminophenylacetyloxy) milbemycin A4 by reducing 5-site ketone, wherein 15-hydroxy-5-keto-milbemycin A4 is prepared by referring to the method disclosed in EP0147852, the method uses milbemycin A4 as a starting raw material, respectively obtains 15-site epoxidation reaction, 5-site hydroxy protecting group and azide epoxy 865 by reaction, finally removes 5-hydroxy protecting group to obtain 15-hydroxy-milbemycin A4, the 15-hydroxy-milbemycin A5 is oxidized by a conventional oxidant (such as manganese dioxide and the like) to obtain 15-hydroxy-5-keto-milbemycin A634, the disadvantages of 1, long technological route, low linear preparation unit, low cost relative to the industrial preparation of milbemycin A5-keto-milbemycin A12, and large yield of the industrial preparation of milbemycin A2, the product obtained by the industrial preparation method uses the initial raw material of α -methoxyiminophenyl-phenyl-ketomilbemycin A3613, the initial raw material is prepared by the method, the method uses the method, the method uses the method for preparing milbemycin A4, the method uses the method, the.
In conclusion, in order to accelerate the popularization and application of the lepistamycin, a preparation process of the lepistamycin, which has the advantages of short production route, low cost and high yield and is suitable for industrial mass production, needs to be found.
Disclosure of Invention
One object of the present invention is to provide an intermediate compound of formula III for the preparation of a lepimetin:
wherein: r is methyl or ethyl, G is a hydroxyl protecting group, preferably a silyl protecting group or an allyloxycarbonyl protecting group.
In a preferred embodiment of the present invention, the silyl ether protecting group is selected from tert-butyldimethylsilyl group, trimethylsilyl group, tert-butyldiphenylsilyl group, or triisopropylsilyl group.
It is an object of the present invention to provide a process for the preparation of a compound of formula III:
reacting a compound of formula II with a hydroxy protecting agent to obtain a compound of formula III:
wherein R and G are as defined in formula III.
In a preferable embodiment of the invention, the hydroxyl protective agent is selected from tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane or allyl chloroformate, and the molar ratio of the hydroxyl protective agent to the compound of the formula II is (3-5): 1.
According to the preferable scheme of the invention, the temperature of the reaction of the compound of the formula II and the hydroxyl protective agent is-15-30 ℃, and the preferable temperature is-15-30 DEG C
The reaction time is 3-8 hours at the temperature of-10-25 ℃.
One of the objects of the present invention is to provide an intermediate compound of formula II for preparing a lepimetin:
wherein R is methyl or ethyl.
One of the objects of the present invention is to provide a process for the preparation of a compound of formula II, said process comprising subjecting a compound of formula I to a hydrolysis reaction in an organic solvent under acidic conditions to obtain a compound of formula II:
wherein R is methyl or ethyl.
In a preferred embodiment of the present invention, the organic solvent is selected from methanol, isopropanol, n-butanol or acetone, the acidic solution under acidic conditions is selected from a sulfuric acid solution with a mass fraction of more than 90%, a hydrochloric acid solution with a mass fraction of more than 30% or an acetic acid solution with a mass fraction of more than 38%, and the volume ratio of the organic solvent to the acidic solution is 80: 20-99: 1, and more preferably 90: 10-95: 5.
According to the preferable scheme of the invention, the temperature of the hydrolysis reaction is-10-100 ℃, more preferably 20-80 ℃, and the reaction time of the hydrolysis reaction is 3-15 hours.
One of the objects of the present invention is to provide a process for the preparation of compounds of formula V, based on the compounds of formulae II and III provided above and their preparation:
the method comprises the following steps:
(a) the compound of formula III is reacted with 2-methoxyiminophenylacetic acid via SN2The reaction affords compounds of formula IV:
(b) removing the hydroxyl protecting group G from the compound of the formula IV under the action of a catalyst to obtain a compound V:
wherein: r and G are as defined in formula III.
In a preferred embodiment of the present invention, the SN is2The reaction is a Mitsunobu reaction.
In a preferred embodiment of the present invention, the azo reagent of the Mitsunobu reaction is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, di-p-chlorobenzyl azodicarboxylate or N, N' -tetramethylazodicarboxamide, and the phosphine compound of the Mitsunobu reaction is selected from triphenylphosphine, tributylphosphine, or trimethylphosphine; the azo reagent comprises a phosphine compound and the compound shown in the formula III, wherein the molar ratio of the phosphine compound to the compound shown in the formula III is (3-7): (3-7): 1.
In a preferred embodiment of the present invention, the solvent of the Mitsunobu reaction is selected from one or two of benzene, toluene, tetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide and dichloromethane, and the temperature of the Mitsunobu reaction is-15 to 10 ℃, and more preferably-5 to 0 ℃.
According to the preferable scheme of the invention, the catalyst in the step (b) is p-toluenesulfonic acid or sodium borohydride, the molar ratio of the catalyst to the compound of the formula IV is (1-5): 1, more preferably (1-2): 1, the reaction temperature in the step (b) is-15-10 ℃, and the reaction time in the step (b) is 2-4 hours.
In a preferred embodiment of the present invention, step (a) further comprises the following steps:
(c) and carrying out hydrolysis reaction on the compound of the formula I in an organic solvent under acidic conditions to obtain a compound of a formula II:
(d) reacting a compound of formula II with a hydroxy protecting agent to obtain a compound of formula III:
wherein R and G are as defined in formula III.
In a preferable embodiment of the present invention, the organic solvent in step (c) is selected from methanol, isopropanol, n-butanol or acetone, the acid solution under acidic conditions in step (c) is selected from a sulfuric acid solution with a mass fraction of more than 90%, a hydrochloric acid solution with a mass fraction of more than 30% or an acetic acid solution with a mass fraction of more than 38%, and the volume ratio of the organic solvent to the acid solution is 80: 20-99: 1, and more preferably 90: 10-95: 5.
According to the preferable scheme of the invention, the temperature of the hydrolysis reaction in the step (c) is-10-100 ℃, more preferably 20-80 ℃, and the time of the hydrolysis reaction is 3-15 hours.
In a preferable embodiment of the invention, the hydroxyl protecting agent in the step (d) is selected from tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane or allyl chloroformate, and the molar ratio of the hydroxyl protecting agent to the compound of the formula II is (3-5): 1.
According to the preferable scheme of the invention, the reaction temperature of the compound in the formula II in the step (d) and the hydroxyl protective agent is-15-30 ℃, preferably-10-25 ℃, and the reaction time is 3-8 hours.
The invention aims to provide application of a compound shown in a formula III or a compound shown in a formula II in preparation of the lepinomycin shown in a formula V.
It is an object of the present invention to provide a process for the preparation of compounds of formula II, formula III and a process for the preparation thereof, as provided above, and further to provide a preferred process for the preparation of compounds of formula V, comprising the steps of:
(1) and hydrolyzing the compound shown in the formula I in a mixed solvent of methanol and concentrated sulfuric acid to obtain a compound shown in the formula II:
(2) reacting a compound of formula II with a hydroxy protecting agent in a dichloromethane solvent to obtain a compound of formula III:
(3) carrying out Mitsunobu reaction on the compound shown in the formula III and 2-methoxyimino phenylacetic acid in a mixed solvent of toluene and tetrahydrofuran to obtain a compound shown in the formula IV:
(4) in a methanol solvent, removing a hydroxyl protecting group G from the compound shown in the formula IV under the action of p-toluenesulfonic acid or sodium borohydride to obtain the lepinomycin shown in the formula V:
wherein R in the steps (1) to (4) is methyl or ethyl, and G is a silyl ether protecting group.
The invention has the advantages that:
the invention takes a compound (i.e. the tianweimycin) with 13-site carbon as alpha single configuration as an initial raw material for the first time, and respectively carries out acid hydrolysis and 5-site hydroxyl group protection, and then 13-site hydroxyl group and 2-methoxyimino phenylacetic acid pass through SN2the method comprises the following steps of reacting, and finally removing a 5-hydroxyl protecting group to obtain a compound (namely the lepimetin) with a single beta-configuration 13-carbon structure, wherein the prior art uses milbemycin with a lower fermentation unit or a derivative thereof as a starting material to prepare the lepimetin, and not only is high in cost, but also has a long process route, and the invention uses the tianweimycin as the starting material and can obtain the lepimetin only by 4 steps of reaction, wherein the fermentation unit of the tianweimycin is high, so that the production cost of the lepimetin is reduced, the reaction route is shortened, the production process is simplified, the structures of 13-carbon structures of a starting material, an intermediate and a final product are kept in a single configuration after the reaction of each step, and therefore, the operation requiring chiral resolution after the reaction is finished is avoided, the operation is simplified, the industrial production is facilitated, the yield of the product is improved, and the yield of the invention can reach 45%.
Some of the terms referred to in the present invention are defined as follows:
SN2reaction: and (3) bimolecular nucleophilic substitution reaction, wherein an attack group attacks from the back of a leaving group, and if the attacked atom has chirality, the stereochemistry of the reacted chiral atom is subjected to configuration inversion.
The leporicin is a mixture of leporicin A3 and leporicin A4.
The ivermectin refers to ivermectin A shown as a formula I-1
And ivermectin B of the formula I-2
A mixture of (a).
TBDMS refers to tert-butyldimethylsilyl group.
v/v refers to the volume ratio.
w/v refers to weight to volume ratio.
Detailed Description
The above-described aspects of the present invention will be described in further detail with reference to specific embodiments. This is not to be construed as limiting the invention.
Refer to the patent CN106459885A, and the method for separating the tianweimycin A and the tianweimycin B, to prepare the raw material tianweimycin of the invention, wherein the content of tianweimycin B is 85%, the content of tianweimycin A is 11%, the purity of HPLC (mobile phase is acetonitrile: water is 90:10, v/v) is 96%;
the reagents (analytically pure) required by the invention are purchased from national medicine group reagent limited company; silica gel (100-200 mesh) was purchased from Qingdao oceanic plant; high performance liquid chromatography (Agilent 1100, Zorbax SB-C18,5 μm,250x 9.4mmi. d), Agilent, Palo Alto, CA, USA; a rotary evaporator (Digital water bath SB-1000) was purchased from EYELA, Japan; superconducting nuclear magnetic resonance apparatus (Bruber AVANCE-400) available from Bruker, Rheinstetten, Germany.
EXAMPLE 12 Synthesis of Methoxyiminophenylacetic acid
50g (0.030mol) of ethyl benzoylformate was dissolved in 350mL of methanol solution containing 33g of methoxyamino hydrochloride, and the mixture was refluxed at 80 ℃ for 8 hours, checked by TLC for completion of the reaction, extracted with ethyl acetate (3X 100mL), concentrated and subjected to silica gel column chromatography (elution system methanol: chloroform: 1:9 (v/v)) to obtain 53.6g of ethyl 2-methoxyiminophenylacetate in 91% yield.
Dissolving 53.6g of ethyl 2-methoxyiminophenylacetate in 500mL of a mixed solution of tetrahydrofuran and water (v: v ═ 1:1), slowly adding 15mL of lithium hydroxide monohydrate, stirring at 25 ℃ for 5 hours, adding 10M hydrochloric acid to neutralize to neutrality, extracting with ethyl acetate (3X 300mL), washing the organic layer with water and saturated brine, drying over anhydrous sodium sulfate, distilling under reduced pressure to dryness, and separating with silica gel column chromatography (the elution system is ethyl acetate: petroleum ether ═ 2:3(v/v) to obtain 47.92g of 2-methoxyiminophenylacetic acid, ESI-MS: M/z180.36[ M + H: 180.36 ]]+The yield was 96.4% and the HPLC purity was 95%.
EXAMPLE 2 preparation of Compound of formula II-1
20g (0.024mol) of the compound of formula I-1 (ivermectin A) was added to 250mL of methanol and 95% sulfuric acid (90:10, v/v)) Stirring the mixed solution at 25 ℃ for 15h under the protection of nitrogen, then adding 100mL of ice water into the reaction solution for dilution, extracting the dichloromethane for 3 times (3X 100mL), washing an organic layer with saturated sodium bicarbonate solution and water respectively, combining the organic layers, drying the organic layers by anhydrous sodium sulfate, filtering, distilling under reduced pressure at 45 ℃, and separating by silica gel column chromatography, wherein an elution system is ethyl acetate, petroleum ether is 1:3(v/v), and 12.5g of the compound of the formula II-1 is obtained, and ESI-MS: m/z 545.2[ M + H ]]+The yield thereof was found to be 96%.
EXAMPLE 3 preparation of the Compound of formula III-1
Dissolving 10g (0.0184mol) of the compound shown in the formula II-1 in 75mL of dry dichloromethane, adding 6.25g (0.0918mol) of imidazole, stirring at 25 ℃ until all raw materials are dissolved, adding 11g (0.073mol) of tert-butyldimethylchlorosilane, continuously stirring at 25 ℃ for 3h, concentrating the reaction product to be dry, and performing silica gel column chromatography gradient elution by using ethyl acetate and petroleum ether as an elution system, wherein the petroleum ether is 1:6-1:3(v/v), so as to obtain 11.8g of the compound shown in the formula III-1, and ESI-MS: m/z 659.4[ M + H ]]+The yield thereof was found to be 97.4%.
EXAMPLE 4 preparation of Compound of formula V-1 (Lepidomycin A3)
Dissolving 11.6g (0.0607mol) of 2-methoxyiminophenylacetic acid, 10g (0.0152mol) of the compound of formula III-1 and 9.25g (0.0457mol) of tributylphosphine in 200mL of mixed solution of toluene and tetrahydrofuran (5:1, v/v), dropwise adding 8g (0.0459mol) of diethyl azodicarboxylate at 15 ℃, returning to 10 ℃ after dropwise adding, stirring for reaction for 8h, diluting with diethyl ether or n-hexane, filtering to remove triphenylphosphine oxide, concentrating the filtrate under reduced pressure, and carrying out column chromatography on a crude product of silica gel to obtain 6.1g of the compound of formula IV-1, ESI-MS: m/z 820.4[ M + H ]]+The yield thereof was found to be 48.9%.
2g (0.0030mol) of the compound of formula IV-1 was added to 120mL of a methanol solution of 0.83% (w/V) p-toluenesulfonic acid (1.0g, 0.0058mol) at-15 deg.C, the reaction was stirred at 10 deg.C for 2h, washed with a saturated sodium bicarbonate solution, extracted with ethyl acetate (3X 50mL), the organic layers were combined, washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and then chromatographed on a silica gel column using ethyl acetate, n-hexane ═ 1:5(V/V) to give the compound of formula V-1, i.e., lepinomycin A32.0g, yield 94.5%, and HPLC purity 97.3% (mobile phase acetonitrile: water ═ 90: 10). The physicochemical properties and characterization data of the lerpin mycin A3 are as follows:
appearance: a white powder;
melting point: 150-152 ℃;
ESI-MS m/z 706.34[M+H]+；
1H NMR(400MHz,CDCl3)δppm：3.28(1H,br,s,H-2),5.40(1H,s,H-3),4.30(1H,d,J＝6.0Hz,H-5),3.97(1H,d,J＝6.3Hz,H-6),5.81(2H,m,H-9,H-10),5.40(1H,m,H-11),2.63(1H,m,H-12),5.20(1H,br d,J＝10.2Hz,H-13),5.55(1H,dd,J＝11.3,2.5Hz,H-15),2.33(1H,m,H-16a),2.44(1H,m,H-16b),3.63(1H,m,H-17),0.90(1H,q,J＝11.9Hz,H-18a),1.73(1H,m,H-18b),5.40(1H,m,H-19),1.36(1H,t,J＝12.2Hz,H-20a),2.03(1H,dd,J＝12.2,4.2Hz,H-20b),1.51(1H,m,H-22a),1.69(1H,m,H-22b),1.51(2H,m,H-23),1.36(1H,m,H-24),3.31(1H,m,H-25),1.88(3H,br s,H-26),4.65(1H,d,J＝12.1Hz,H-27a),4.71(1H,d,J＝12.1Hz,H-27b),1.10(3H,d,J＝6.0Hz,H-28),1.55(3H,br s,H-29),0.84(3H,d,J＝6.4Hz,H-30),1.17(3H,d,J＝6.0Hz,H-31),7.33-7.52(5H,H-phenyl),3.97(3H,s,OCH3)。
EXAMPLE 5 preparation of the Compound of formula II-2
Adding 10g (0.0118mol) of the compound of formula I-2 (ivermectin B) into 150mL of a mixed solution of methanol and 95% sulfuric acid (90:10, v/v), stirring at 80 ℃ for 3h under the protection of nitrogen, adding 60mL of ice water into the reaction solution, diluting with dichloromethane (3X 100mL), washing the organic layer with a saturated sodium bicarbonate solution and water respectively, combining the organic layers, drying over anhydrous sodium sulfate, filtering, and decompressing at 45 DEG CDistilling, separating by silica gel column chromatography, and eluting with ethyl acetate and petroleum ether at a ratio of 1:3(v/v) to obtain 6.46g of compound of formula II-2, ESI-MS: m/z 559.1[ M + H ]]+The yield thereof was found to be 98%.
EXAMPLE 6 preparation of the Compound of formula III-2
Dissolving 5g (0.0089mol) of the compound shown in the formula II-2 in 50mL of dry dichloromethane, adding 2.5g (0.0367mol) of imidazole, stirring until all raw materials are dissolved, adding 6.75g (0.0448mol) of tert-butyldimethylsilyl chloride, stirring at 10 ℃ for 8h, concentrating the reaction product to be dry, and performing silica gel column chromatography gradient elution by using ethyl acetate and petroleum ether as an elution system, wherein the petroleum ether is 1:6-1:3(v/v), so as to obtain 5.90g of the compound shown in the formula III-2, and ESI-MS: m/z 673.2[ M + H ]]+The yield thereof was found to be 98%.
EXAMPLE 7 preparation of Compound of formula V-2 (Lepidomycin A4)
Dissolving 3.2g (0.0167mol) of 2-methoxyiminophenylacetic acid, 5.90g (0.0087mol) of a compound of a formula III-2 and 12g (0.0457mol) of triphenylphosphine in 200mL of mixed solution of toluene and tetrahydrofuran (5:1, v/v), dropwise adding 10g (0.0574mol) of diethyl azodicarboxylate at 0 ℃, recovering to 10 ℃ after dropwise adding, stirring for reaction for 3h, diluting with diethyl ether or n-hexane, filtering to remove triphenylphosphine oxide, concentrating the filtrate under reduced pressure, and carrying out silica gel column chromatography on a crude product, wherein an elution system is ethyl acetate and n-hexane is 10:90(v/v), so that 43.58g of a compound of a formula IV-2, ESI-MS are obtained: m/z 834.4[ M + H ]]+The yield thereof was found to be 49%.
2g (0.0024mol) of the compound of formula IV-2 is added into 120mL of a methanol solution of 1% (w/V) p-toluenesulfonic acid (1.2g, 0.007mol) under the condition of ice-water bath, the mixture is reacted for 2h under the condition of 10 ℃, a saturated sodium bicarbonate solution is washed, ethyl acetate is extracted (3X 50mL), organic layers are combined and washed by water and saturated saline water in sequence, anhydrous magnesium sulfate is dried, filtered, concentrated under reduced pressure and separated by silica gel column chromatography, and the elution system is ethyl acetate, namely n-hexane, 1:5(V/V), so that the compound of formula V-2, namely the lepinomycin A41.69g is obtained, the yield is 97.9%, and the HPLC purity is 98.6% (mobile phase is acetonitrile, water, namely 90: 10). The physicochemical properties and characterization data of the lerpin mycin A4 are as follows:
appearance: a white powder;
melting point: 152-154 ℃;
ESI-MS m/z 719.99[M+H]+；m/z 743.23[M+Na]+；
1H NMR(400MHz,CDCl3)δppm：3.27(1H,br,s,H-2),5.40(1H,s,H-3),4.30(1H,d,J＝5.9Hz,H-5),3.96(1H,d,J＝6.2Hz,H-6),5.82(2H,m,H-9,H-10),5.40(1H,m,H-11),2.62(1H,m,H-12),5.20(1H,br d,J＝10.5Hz,H-13),5.53(1H,dd,J＝11.5,2.5Hz,H-15),2.31(1H,m,H-16a),2.42(1H,m,H-16b),3.62(1H,m,H-17),0.90(1H,q,J＝11.9Hz,H-18a),1.72(1H,m,H-18b),5.40(1H,m,H-19),1.36(1H,t,J＝12.2Hz,H-20a),2.03(1H,dd,J＝12.2,4.2Hz,H-20b),1.51(1H,m,H-22a),1.69(1H,m,H-22b),1.51(2H,m,H-23),1.36(1H,m,H-24),3.07(1H,t,J＝8.2Hz,H-25),1.87(3H,br s,H-26),4.65(1H,d,J＝14.6Hz,H-27a),4.71(1H,d,J＝14.6Hz,H-27b),1.10(3H,d,J＝6.4Hz,H-28),1.55(3H,br s,H-29),0.83(3H,d,J＝6.4Hz,H-30),1.38(1H,m,H-31a),1.69(1H,m,H-31b),1.00(3H,t,J＝7.2Hz,H-32),7.33-7.52(5H,H-phenyl),3.97(3H,s,OCH3)。
EXAMPLE 8 preparation of Lepidomycin
Adding 5g of ivermectin into a mixed solution of 75mL of methanol and 95% sulfuric acid (90:10, v/v), stirring for 10h at 25 ℃ under the protection of nitrogen, adding 40mL of ice water for dilution, extracting with dichloromethane (3X 80mL), washing an organic layer with a saturated sodium bicarbonate solution and clear water, combining the organic layers, drying with anhydrous sodium sulfate, filtering, distilling at 45 ℃ under reduced pressure, and separating by silica gel column chromatography, wherein an elution system is ethyl acetate and petroleum ether is 1:3(v/v), so that 3.23g of a mixture of the compound of the formula II-1 and the compound of the formula II-2 is obtained, and the yield is 98%.
Dissolving 2g of a mixture of the compound of the formula II-1 and the compound of the formula II-2 in 25mL of dry dichloromethane, adding 1.1g of imidazole, stirring at 25 ℃ until all raw materials are dissolved, adding 1.65g (0.011mol) of tert-butyldimethylchlorosilane, stirring at 25 ℃ for 3h, concentrating the reaction product to be dry, and performing gradient elution by silica gel column chromatography, wherein the elution system is ethyl acetate and petroleum ether which are 1:6-1:3(v/v), so as to obtain 2.36g of a mixture of the compound of the formula III-1 and the compound of the formula III-2, and the yield is 98%.
Dissolving 9.55g (0.05mol) of 2-methoxyimino-phenylacetic acid, 2.2g of a mixture of a compound of a formula III-1 and a compound of a formula III-2 and 4.2g (0.021mol) of tributylphosphine in 150mL of a mixed solution of toluene and tetrahydrofuran (5:1, v/v), dropwise adding 3.5g (0.02mol) of diisopropyl azodicarboxylate at 0 ℃, stirring and reacting at 0 ℃ for 5h after dropwise adding, diluting with diethyl ether, filtering to remove triphenylphosphine oxide, concentrating the filtrate under reduced pressure, and carrying out silica gel column chromatography on a crude product, wherein an elution system is ethyl acetate and n-hexane is 10:90(v/v), so as to obtain 1.33g of a mixture of the compound of the formula IV-1 and the compound of the formula IV-2 with the yield of 48.7%.
1g of a mixture of the compound of the formula IV-1 and the compound of the formula IV-2 was added to 1% (w/v) of 60mL of p-toluenesulfonic acid in methanol, reacted at 0 ℃ for about 2.5 hours, washed with a saturated sodium bicarbonate solution, extracted with ethyl acetate (3X 50mL), the organic layers were combined, washed with water and a saturated saline solution in this order, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography, wherein the elution system was ethyl acetate, n-hexane ═ 1:5(v/v), delevelin 0.84g, yield was 97%, and HPLC purity was 97%.
EXAMPLE 9 preparation of Lepidomycin
Adding 50g of ivermectin into a mixed solution of 750mL of methanol and 95% sulfuric acid (99:1, v/v), stirring for 8h at 50 ℃ under the protection of nitrogen, adding 500mL of ice water for dilution, extracting with dichloromethane (3X 500mL), washing an organic layer with a saturated sodium bicarbonate solution and clear water, combining the organic layers, drying with anhydrous sodium sulfate, filtering, distilling at 45 ℃ under reduced pressure, and separating by silica gel column chromatography, wherein an elution system is ethyl acetate and petroleum ether is 1:3(v/v), so that 29.5g of a mixture of the compound of the formula II-1 and the compound of the formula II-2 is obtained, and the yield is 90%.
20g of the mixture of the compound of the formula II-1 and the compound of the formula II-2 is dissolved in 1000mL of dry dichloromethane, 11g (0.162mol) of imidazole is added and stirred at 25 ℃ until all the raw materials are dissolved, 16.2g (0.108mol) of tert-butyldimethylsilyl chloride is added and stirred at 25 ℃ for 8h, the reaction product is concentrated to be dry and separated by silica gel column chromatography, and the elution system is ethyl acetate and petroleum ether which are 1:6-1:3(v/v), so that 14.98g of the mixture of the compound of the formula III-1 and the compound of the formula III-2 is obtained, and the yield is 94%.
5.68g (0.03mol) of 2-methoxyimino-phenylacetic acid, 10g of a mixture of the compound of the formula III-1 and the compound of the formula III-2 and 9.0g (0.044mol) of tributylphosphine are dissolved in 150mL of a mixed solution of toluene and tetrahydrofuran (5:1, v/v), 9.2g (0.046mol) of diisopropyl azodicarboxylate is added dropwise at the temperature of-5 ℃, after the dropwise addition is finished, the mixed solution is returned to the temperature of 5 ℃ and stirred for reaction for 8 hours, diluted by ether, filtered to remove tributylphosphine oxide, the filtrate is concentrated under reduced pressure, and a crude product is subjected to silica gel column chromatography, wherein an elution system is ethyl acetate and n-hexane is 10:90(v/v), so that 5.0g of the mixture of the compound of the formula IV-1 and the compound of the formula IV-2 is obtained, and the yield.
The mixture of 5g of the compound of formula IV-1 and the compound of formula IV-2 was added to 60mL of a 2% (w/v) solution of p-toluenesulfonic acid (1.2g, 0.007mol) in methanol, reacted at-15 ℃ for about 4 hours, washed with a saturated sodium bicarbonate solution, extracted with ethyl acetate (3 × 100mL), the organic layers were combined, washed with water and a saturated saline solution in this order, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column, wherein the elution system was ethyl acetate, n-hexane ═ 1:5(v/v), delevelin 4.0g, yield 92.7%, and HPLC purity was 97%.
EXAMPLE 10 preparation of Lepidomycin
Adding 5g of ivermectin into a mixed solution of 75mL of methanol and 36% hydrochloric acid (80:20, v/v), stirring for 15h at 20 ℃ under the protection of nitrogen, adding 200mL of ice water for dilution, extracting with dichloromethane (3X 50mL), washing an organic layer with a saturated sodium bicarbonate solution and clear water, combining the organic layers, drying with anhydrous sodium sulfate, filtering, distilling at 45 ℃ under reduced pressure, and separating by silica gel column chromatography, wherein an elution system is ethyl acetate and petroleum ether is 1:3(v/v), so that 3.0g of a mixture of the compound of the formula II-1 and the compound of the formula II-2 is obtained, and the yield is 91%.
Placing 3.0g of the mixture of the compound of the formula II-1 and the compound of the formula II-2 in a dry three-neck flask, adding 5mL of dichloromethane for dissolution, adding 0.65g (0.0056mol) of tetramethylethylenediamine at-15 ℃ under the protection of nitrogen, slowly dropwise adding 2.0g (0.0166mol dissolved in 2mL of dichloromethane) of allyl chloroformate, stirring, reacting for 3h, adding 50mL of 2% phosphoric acid solution for terminating the reaction, extracting with dichloromethane (3X 50mL), drying with anhydrous sodium sulfate, filtering, distilling at 45 ℃ under reduced pressure, and performing silica gel column chromatography gradient elution by using ethyl acetate and petroleum ether as eluent, wherein the petroleum ether is 1:5-1:3(v/v), so as to obtain 3.1g of the mixture of the compound of the formula III-3 and the compound of the formula III-4 with the yield of 90%.
Dissolving 1.8g (0.009mol) of 2-methoxyimino-phenylacetic acid, 3g (0.0047mol) of a mixture of a compound of formula III-3 and a compound of formula III-4 and 6.1g (0.023mol) of triphenylphosphine in 50mL of a mixture of dimethylformamide and tetrahydrofuran (3:1, v/v), dropwise adding 4.1g (0.023mol) of diethyl azodicarboxylate at 0 ℃, recovering to 10 ℃ after dropwise adding, stirring for reaction for 8h, diluting with diethyl ether, filtering to remove triphenylphosphine oxide, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography on a crude product, wherein the elution system is ethyl acetate and n-hexane is 10:90(v/v), so as to obtain 1.3g of a mixture of the compound of formula IV-3 and the compound of formula IV-4 with the yield of 35%.
1.3g of the mixture of the compound of formula IV-3 and the compound of formula IV-4 is dissolved in 100mL of methanol, and 60mg (0.0016mol) of sodium borohydride is added thereto at 0 ℃, and the reaction is stirred for about 4 hours and checked by TLC. The mixture was washed with a saturated solution of sodium hydrogencarbonate, extracted with ethyl acetate (3 × 80mL), and the organic layers were combined, washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to gradient elution with a silica gel column chromatography in which ethyl acetate, n-hexane, was 1:5 to 1:3(v/v) to separate 1.12g of delevelin, yield 96%, and HPLC purity 96%.
Equivalents and scope
Some non-limiting preferred embodiments of the invention have been described above. Various changes and modifications may be made by those skilled in the art to the description without departing from the true scope of the invention as defined by the appended claims. Such changes and modifications are to be considered within the scope of the present invention.
Claims (20)
1. A compound of formula III:
wherein: r is methyl or ethyl, G is a hydroxyl protecting group, preferably a silyl protecting group or an allyloxycarbonyl protecting group.
2. The compound of formula III according to claim 1, wherein the silyl-based protecting group is selected from tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl.
3. A process for the preparation of a compound of formula III as defined in claim 1 or 2, wherein a compound of formula II is reacted with a hydroxy protecting agent to give a compound of formula III:
wherein R and G are as defined in claim 1.
4. The method according to claim 3, wherein the hydroxyl protecting agent is selected from tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane or allyl chloroformate, and the molar ratio of the hydroxyl protecting agent to the compound of the formula II is (3-5): 1.
5. The method according to claim 3 or 4, wherein the reaction temperature of the compound of formula II and the hydroxyl protecting agent is-15-30 ℃, preferably-10-25 ℃, and the reaction time is 3-8 hours.
6. A compound of formula II:
wherein R is methyl or ethyl.
7. A process for preparing a compound of formula II according to claim 6, said process comprising subjecting a compound of formula I to a hydrolysis reaction in an organic solvent under acidic conditions to obtain a compound of formula II:
wherein R is methyl or ethyl.
8. The method according to claim 7, wherein the organic solvent is selected from methanol, isopropanol, n-butanol or acetone, the acidic solution under acidic conditions is selected from a sulfuric acid solution with a mass fraction of more than 90%, a hydrochloric acid solution with a mass fraction of more than 30% or an acetic acid solution with a mass fraction of more than 38%, and the volume ratio of the organic solvent to the acidic solution is 80: 20-99: 1, preferably 90: 10-95: 5.
9. The method according to claim 7 or 8, wherein the temperature of the hydrolysis reaction is-10 to 100 ℃, preferably 20 to 80 ℃, and the time of the hydrolysis reaction is 3 to 15 hours.
10. A process for preparing a lepimectin of formula V:
the method is characterized by comprising the following steps:
(a) the compound of formula III is reacted with 2-methoxyiminophenylacetic acid via SN2The reaction affords compounds of formula IV:
(b) removing the hydroxyl protecting group G from the compound of the formula IV under the action of a catalyst to obtain a compound of a formula V:
wherein: r and G are as defined in claim 1.
11. The method of claim 10, wherein the SN is the SN2The reaction is a Mitsunobu reaction.
12. The process according to claim 11, wherein the azo reagent of the Mitsunobu reaction is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, di-p-chlorobenzyl azodicarboxylate or N, N' -tetramethylazodicarboxamide, the phosphine compound of the Mitsunobu reaction is selected from triphenylphosphine, tributylphosphine or trimethylphosphine; the azo reagent comprises a phosphine compound and the compound shown in the formula III, wherein the molar ratio of the phosphine compound to the compound shown in the formula III is (3-7): (3-7): 1.
13. The method according to claim 11 or 12, wherein the solvent of the Mitsunobu reaction is selected from one or two of benzene, toluene, tetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide and dichloromethane, and the temperature of the Mitsunobu reaction is-15 to 10 ℃, preferably-5 to 0 ℃.
14. The method according to claim 10, wherein the catalyst in step (b) is p-toluenesulfonic acid or sodium borohydride, the molar ratio of the catalyst to the compound of formula IV is (1-5): 1, preferably (1-2): 1, the reaction temperature in step (b) is-15-10 ℃, and the reaction time in step (b) is 2-4 hours.
15. The method of claim 10, wherein step (a) is preceded by the steps of:
(c) and carrying out hydrolysis reaction on the compound of the formula I in an organic solvent under acidic conditions to obtain a compound of a formula II: :
(d) reacting a compound of formula II with a hydroxy protecting agent to obtain a compound of formula III:
wherein R and G are as defined in claim 1.
16. The method according to claim 15, wherein the organic solvent in step (c) is selected from methanol, isopropanol, n-butanol or acetone, the acidic solution under acidic conditions in step (c) is selected from a sulfuric acid solution with a mass fraction of more than 90%, a hydrochloric acid solution with a mass fraction of more than 30% or an acetic acid solution with a mass fraction of more than 38%, and the volume ratio of the organic solvent to the acidic solution is 80: 20-99: 1, preferably 90: 10-95: 5.
17. The method according to claim 15 or 16, wherein the temperature of the hydrolysis reaction in the step (c) is-10 to 100 ℃, preferably 20 to 80 ℃, and the time of the hydrolysis reaction is 3 to 15 hours.
18. The method of claim 15, wherein the hydroxyl protecting agent in step (d) is selected from tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane or allyl chloroformate, and the molar ratio of the hydroxyl protecting agent to the compound of formula II is (3-5): 1.
19. The method according to claim 15 or 18, wherein the reaction temperature of the compound of formula II in step (d) with the hydroxyl protecting agent is-15 to 30 ℃, preferably-10 to 25 ℃, and the reaction time is 3 to 8 hours.
20. Use of a compound of formula III according to claim 1 or a compound of formula II according to claim 6 for the preparation of a lepinomycin of formula V.
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