CN111217828B - Preparation method of lepistamycin and intermediate thereof - Google Patents
Preparation method of lepistamycin and intermediate thereof Download PDFInfo
- Publication number
- CN111217828B CN111217828B CN201811416685.2A CN201811416685A CN111217828B CN 111217828 B CN111217828 B CN 111217828B CN 201811416685 A CN201811416685 A CN 201811416685A CN 111217828 B CN111217828 B CN 111217828B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- acid solution
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a preparation method of lepinomycin shown in formula V and an intermediate thereof, which takes avilamycin as a starting material, respectively carries out acid hydrolysis reaction, a protecting group is arranged on a 5-site hydroxyl group, and then the lepinomycin and 2-methoxyiminophenylacetic acid are subjected to SN 2 Reaction and final removal ofProtecting the hydroxyl group at the 5-position to provide a compound of 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 lepinomycin A3 and the lepinomycin A4, wherein the content of the lepinomycin A3 is less than or equal to 20 percent, and the content of the lepinomycin 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 A3: r = CH 3 (ii) a Leporicin A4: r = C 2 H 5
The toxicity test of the lepimetin shows that the LD is acute toxicity for rats through oral administration, skin and inhalation 50 Respectively 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 insecticidal activity of the lepithromycin to certain targets is higher, and the dosage is higherLess and no cross resistance with abamectin and other insecticides. Therefore, the lepimetin is a variety with great development potential.
The initial starting material for the prior art process for preparing lepithromycin is milbemycin, as disclosed in patent EP0675133B1, which discloses the following general reaction formula:
specifically disclosed is: taking 15-hydroxy-5-ketone milbemycins A4 as a material, carrying out catalytic rearrangement and esterification by cuprous iodide to obtain 13- (alpha-methoxyimino phenyl acetoxyl) -5-ketone-milbemycins A4, and reducing the 5-ketone into hydroxy to obtain a product 13- (alpha-methoxyimino phenyl acetoxyl) milbemycins A4. Wherein, the 15-hydroxy-5-keto-milbemycins A4 is prepared by a method disclosed in reference EP0147852, the method takes milbemycins A4 as a starting material, and the milbemycins A4 are respectively subjected to epoxidation reaction at 14,15 site, protective group on 5 site hydroxy, and epoxy ring opening reaction with azido acid, finally 5-hydroxy protective group is removed to obtain 15-hydroxy-milbemycins A4, and the 15-hydroxy-5-keto-milbemycins A4 are oxidized by a conventional oxidizing agent (such as manganese dioxide and the like) to obtain 15-hydroxy-5-keto-milbemycins A4. The process has the following disadvantages: 1. the process route is long, the fermentation unit of the milbemycins is low, the cost is relatively high, and the process has great limitation on the industrialization of the lepistamycin and the popularization and application in the pesticide market; 2. the 13-site carbon in the parent nucleus of the obtained final product 13- (alpha-methoxyiminophenylacetoxy) milbemycin A4 exists in a mixed form of alpha configuration and beta configuration, the lepimemycin A4 with the 13-site beta configuration is obtained by a resolution technology, and the lepimemycin A4 is not suitable for industrial mass production; 3. the total yield of the process for preparing 13- (alpha-methoxyiminophenylacetoxy) milbemycins A4 by taking 15-hydroxy-5-keto milbemycins A4 as raw materials is lower and is about 26%, wherein the raw material 15-hydroxy-5-keto milbemycins A4 is also prepared by taking milbemycins A4 as starting raw materials through 5 steps of reaction, so that the total yield of the 13- (alpha-methoxyiminophenylacetoxy) milbemycins A4 prepared by taking milbemycins as the initial raw materials is far lower than 26%.
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 provide a compound of formula III:
wherein R and G are as defined in formula III.
In a preferable embodiment of the invention, 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.
In a preferred embodiment of the present invention, the temperature for the reaction of the compound of formula II with the hydroxyl protecting agent is-15 to 30 ℃, and more preferably, the temperature is-15 to 30 DEG C
The reaction time is 3 to 8 hours at the temperature of minus 10 to 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 acid 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 acid solution is from 80 to 99, more preferably from 10 to 95.
In a preferred embodiment of the present invention, the temperature of the hydrolysis reaction is-10 to 100 ℃, more preferably 20 to 80 ℃, and the reaction time of the hydrolysis reaction is 3 to 15 hours.
An object 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 SN 2 The 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 is 2 The 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 molar ratio of the azo reagent to the phosphine compound to the compound shown in the formula III is (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 ℃.
In a preferred embodiment of the present invention, 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, more preferably (1-2): 1, the reaction temperature in step (b) is-15 to 10 ℃, and the reaction time in step (b) is 2 to 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 an acidic condition 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 preferred 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 from 80 to 99, more preferably from 90 to 95.
In a preferred embodiment of the present invention, the temperature of the hydrolysis reaction in the step (c) is-10 to 100 ℃, more preferably 20 to 80 ℃, and the time of the hydrolysis reaction is 3 to 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.
In a preferred embodiment of the present invention, the reaction temperature of the compound of formula II in step (d) and the hydroxyl protecting agent is-15 to 30 ℃, preferably-10 to 25 ℃, and the reaction time is 3 to 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 SN 2 And finally, removing the 5-hydroxyl protecting group to obtain the compound (namely the lepimetin) with 13-carbon in a beta single configuration. The prior art uses milbemycins or derivatives thereof with lower fermentation units as starting raw materials to prepare the lepimemycin, which has higher cost and longer process route, but the invention uses the tianweimycin as the starting raw material and can obtain the lepimemycin only by 4 steps of reaction; the fermentation unit of the cevicin is higher, so that the production cost of the lepimetin is reduced, the reaction route is shortened, and the production process is simplified, and the configuration of 13-bit carbon of parent nucleus of the raw materials, the intermediate and the final product keeps single configuration after the reaction of each step is finished, so that the operation of chiral resolution after the reaction is finished is avoidedThe operation is simplified, which is not only beneficial to industrialized production, but also improves the yield of the product, and the yield of the invention can reach 45%.
Some of the terms referred to in the present invention are defined as follows:
SN 2 reaction: 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 in 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.
Referring to the fermentation process of patent CN106459885A and the method for separating the tianweimycin A and the tianweimycin B, the raw material tianweimycin of the invention is prepared, wherein the content of the tianweimycin B is 85%, the content of the tianweimycin A is 11%, and the purity of HPLC (mobile phase acetonitrile: water = 90;
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 9.4mm i.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 1 Synthesis of 2-methoxyiminophenylacetic acid
50g (0.030 mol) of ethyl benzoylformate was dissolved in 350mL of methanol solution containing 33g of methoxyamino hydrochloride, the mixture was refluxed at 80 ℃ for 8 hours, the reaction was detected by TLC to be complete, extracted with ethyl acetate (3X 100 mL), and concentrated and then separated by column chromatography on silica gel (elution system methanol: chloroform =1 (v/v), yielding 53.6g of ethyl 2-methoxyiminophenylacetate in 91% yield.
53.6g of ethyl 2-methoxyiminophenylacetate was dissolved in 500mL of a mixed solution of tetrahydrofuran and water (v: v = 1), 15mL of lithium hydroxide monohydrate was slowly added, the mixture was stirred at 25 ℃ for 5 hours, 10M hydrochloric acid was added to neutralize the mixture to neutrality, ethyl acetate was extracted (3X 300 mL), the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, distilled to dryness under reduced pressure, and separated by silica gel column chromatography (elution system: ethyl acetate: petroleum ether =2 (v/v), whereby 47.92g of 2-methoxyiminophenylacetic acid, ESI-MS: M/z 180.36[ M H ]] + The yield was 96.4% and the HPLC purity was 95%.
EXAMPLE 2 preparation of Compound of formula II-1
20g (0.024 mol) of the compound of formula I-1 (tianweicin A) is added to a mixture of 250mL of methanol and 95% sulfuric acid (90, 10, v/v), stirred at 25 ℃ for 15h under nitrogen protection, then 100mL of ice water is added to the reaction solution for dilution, dichloromethane is extracted for 3 times (3X 100 mL), the organic layer is washed with saturated sodium bicarbonate solution and water respectively, the organic layer is combined, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure at 45 ℃, and separated by silica gel column chromatography, and the elution system is ethyl acetate: petroleum ether =1: m/z 545.2[ m ] +H] + The yield thereof was found to be 96%.
EXAMPLE 3 preparation of the Compound of formula III-1
10g (0.0184 mol) of the compound of formula II-1 was dissolved in 75mL of dry dichloromethane, 6.25g (0.0918 mol) of imidazole was added and stirred at 25 ℃ until all starting materials were dissolved, 11g (0.073 mol) of tert-butyldimethylchlorosilane was added and stirring continued at 25 ℃ for 3h, the reaction was concentrated to dryness and eluted by gradient silica gel column chromatography using ethyl acetate: petroleum ether =1: 6-3 (v/v) to give 11.8g of the compound of formula III-1, 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 (0.0607 mol) of 2-methoxyiminophenylacetic acid, 10g (0.0152 mol) of a compound of formula III-1 and 9.25g (0.0457 mol) of tributylphosphine in 200mL of a mixed solution of toluene and tetrahydrofuran (5, 1 v/v), dropwise adding 8g (0.0459 mol) of diethyl azodicarboxylate at-15 ℃, returning to 10 ℃ after dropwise adding, stirring and reacting for 8h, 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: n-hexane =10 (v/v), so as to obtain 6.1g of a compound of formula IV-1, ESI-MS: m/z 820.4[ m ] +H] + The yield thereof was found to be 48.9%.
2g (0.0030 mol) of the compound of formula IV-1 was added to 120mL of a 0.83% (w/V) solution of p-toluenesulfonic acid (1.0 g, 0.0058mol) in methanol 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 50 mL), the organic layers were combined and washed with water and saturated brine in sequence, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and then chromatographed on a silica gel column using ethyl acetate: n-hexane =1 (V/V) to give the compound of formula V-1, i.e., lepinomycin A32.g, yield 94.5%, HPLC purity 97.3% (mobile phase acetonitrile: water = 90. The physical and chemical 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] + ；
1 H NMR(400MHz,CDCl 3 )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,OCH 3 )。
EXAMPLE 5 preparation of the Compound of formula II-2
Adding 10g (0.0118 mol) of the compound of formula I-2 (tianweimycin B) into a mixed solution of 150mL 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 the mixture, extracting the mixture with dichloromethane (3X 100 mL), washing the organic layer with saturated sodium bicarbonate solution and water respectively, combining the organic layers, drying the organic layer with anhydrous sodium sulfate, filtering, distilling at 45 ℃ under reduced pressure, and separating by silica gel column chromatography, wherein the elution system is ethyl acetate, petroleum ether = 13 (v/v), so as to obtain 6.46g of the 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
5g (0.0089 mol) of the compound of formula II-2 was dissolved in 50mL of dry methylene chloride, 2.5g (0.0367 mol) of imidazole was added, stirring was carried out until all the starting materials were dissolved, and 6.75g (0.0448 mol) of tert-butyl acetate was addedButyldimethylchlorosilane was stirred at-10 ℃ for 8h, the reaction was concentrated to dryness, and gradient eluted on a silica gel column with ethyl acetate: petroleum ether =1:3 (v/v) to give 5.90g of the compound of formula III-2, esi-MS: m/z 673.2[ m ] +H] + And the yield thereof was found to be 98%.
EXAMPLE 7 preparation of Compound of formula V-2 (Lepidomycin A4)
Dissolving 3.2g (0.0167 mol) of 2-methoxyiminophenylacetic acid, 5.90g (0.0087 mol) of a compound of formula III-2 and 12g (0.0457 mol) of triphenylphosphine in 200mL of a mixed solution of toluene and tetrahydrofuran (5, v/v), dropwise adding 10g (0.0574 mol) of diethyl azodicarboxylate at 0 ℃, after the dropwise adding is finished, returning to 10 ℃ and 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: n-hexane =10 (v/v), so as to obtain 43.58g of a compound of formula IV-2, ESI-MS: m/z 834.4[ m ] +H] + The yield thereof was found to be 49%.
2g (0.0024 mol) of the compound of formula IV-2 is added to 120mL of a 1% (w/V) solution of p-toluenesulfonic acid (1.2g, 0.007mol) in methanol under ice-water bath conditions, reacted at 10 ℃ for 2h, washed with saturated sodium bicarbonate solution, extracted with ethyl acetate (3X 50 mL), the organic layers are combined and washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and chromatographed on a silica gel column with ethyl acetate: n-hexane =1 (V/V) to give the compound of formula V-2, i.e., the lepinomycin A41.69g, yield 97.9%, HPLC purity 98.6% (mobile phase is acetonitrile: water =90 10). The physical and chemical properties and the characterization data of the lepimetin A4 are as follows:
appearance: white powder;
melting point: 152-154 ℃;
ESI-MS m/z 719.99[M+H] + ；m/z 743.23[M+Na] + ；
1 H NMR(400MHz,CDCl 3 )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,OCH 3 )。
EXAMPLE 8 preparation of Lepidomycin
Add 5g of tianweicin to a mixture of 75mL of methanol and 95% sulfuric acid (90, v/v), stir at 25 ℃ for 10h under nitrogen protection, then add 40mL of ice water for dilution, extract with dichloromethane (3X 80 mL), wash the organic layer with saturated sodium bicarbonate solution and clear water, combine the organic layers, dry over anhydrous sodium sulfate, filter, distill under reduced pressure at 45 ℃, separate by silica gel column chromatography, eluting with ethyl acetate: petroleum ether = 13 (v/v), to give 3.23g of a mixture of the compound of formula II-1 and the compound of formula II-2 in 98% yield.
Dissolving 2g of a mixture of the compound of formula II-1 and the compound of 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 (0.011 mol) of tert-butyldimethylchlorosilane, stirring at 25 ℃ for 3h, concentrating the reaction to dryness, and performing gradient elution by silica gel column chromatography, wherein the elution system is ethyl acetate: petroleum ether = 1.
9.55g (0.05 mol) of 2-methoxyimino-phenylacetic acid, 2.2g of a mixture of the compound of the formula III-1 and the compound of the formula III-2 and 4.2g (0.021 mol) of tributylphosphine are dissolved in 150mL of a mixed solution of toluene and tetrahydrofuran (5.
1g of a mixture of the compound of the formula IV-1 and the compound of the formula IV-2 is added to 1% (w/v) of 60mL of a methanol solution of p-toluenesulfonic acid, reacted at 0 ℃ for about 2.5h, washed with a saturated sodium bicarbonate solution, extracted with ethyl acetate (3X 50 mL), the organic layers are combined, washed with water, saturated brine and dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by silica gel column chromatography, and the elution system is ethyl acetate: n-hexane =1 (v/v), 0.84g of delevelin, yield 97% and HPLC purity 97%.
EXAMPLE 9 preparation of lepomycin
50g of ivermectin is added into a mixed solution of 750mL of methanol and 95% sulfuric acid (99, v/v), stirred for 8h at 50 ℃ under the protection of nitrogen, then added with 500mL of ice water for dilution, extracted by dichloromethane (3X 500 mL), washed by saturated sodium bicarbonate solution and clear water, combined with organic layers, dried by anhydrous sodium sulfate, filtered, distilled under reduced pressure at 45 ℃, separated by silica gel column chromatography, and the elution system is ethyl acetate: petroleum ether =1:3 (v/v), so as to obtain 29.5g of a mixture of the compound of the formula II-1 and the compound of the formula II-2 with the yield of 90%.
Dissolving 20g of the mixture of the compound of the formula II-1 and the compound of the formula II-2 in 1000mL of dry dichloromethane, adding 11g (0.162 mol) of imidazole, stirring at 25 ℃ until all raw materials are dissolved, adding 16.2g (0.108 mol) of tert-butyldimethylsilyl chloride, stirring at 25 ℃ for 8h, concentrating the reaction product to dryness, and separating by silica gel column chromatography, wherein the elution system is ethyl acetate: petroleum ether = 1-6 (v/v), so as to obtain 14.98g of the mixture of the compound of the formula III-1 and the compound of the formula III-2, and the yield is 94%.
5.68g (0.03 mol) 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 (0.044 mol) of tributylphosphine were dissolved in 150mL of a mixture of toluene and tetrahydrofuran (5.
The above 5g mixture of the compound of formula IV-1 and the compound of formula IV-2 was added to 60mL of 2% (w/v) p-toluenesulfonic acid (1.2g, 0.007mol) in methanol, reacted at-15 ℃ for about 4h, washed with saturated sodium bicarbonate solution, extracted with ethyl acetate (3X 100 mL), 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 chromatographed on a silica gel column, eluting with ethyl acetate: n-hexane =1 (v/v), delevelin 4.0g, yield 92.7%, and HPLC purity 97%.
EXAMPLE 10 preparation of Lepidomycin
Add 5g of tianweicin to 75mL of a mixed solution of methanol and 36% hydrochloric acid (80, 20, v/v), stir at 20 ℃ for 15h under nitrogen protection, then add 200mL of ice water for dilution, extract with dichloromethane (3X 50 mL), wash the organic layer with saturated sodium bicarbonate solution and clean water, combine the organic layers, dry over anhydrous sodium sulfate, filter, distill under reduced pressure at 45 ℃, separate by silica gel column chromatography, eluting with ethyl acetate: petroleum ether = 13 (v/v), to obtain 3.0g of a mixture of the compound of formula II-1 and the compound of formula II-2, with a yield of 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 (0.0056 mol) of tetramethylethylenediamine at-15 ℃ under the protection of nitrogen, slowly dropwise adding 2.0g (0.0166 mol 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 50 mL), drying with anhydrous sodium sulfate, filtering, distilling at 45 ℃ under reduced pressure, and eluting with silica gel column chromatography gradient, wherein the elution system is ethyl acetate: petroleum ether =1, 5-1 (v/v), and obtaining 3.1g of the mixture of the compound of the formula III-3 and the compound of the formula III-4, and the yield is 90%.
Dissolving 1.8g (0.009 mol) of 2-methoxyimino-phenylacetic acid, 3g (0.0047 mol) of a mixture of the compound of the formula III-3 and the compound of the formula III-4 and 6.1g (0.023 mol) of triphenylphosphine in 50mL of a mixture of dimethylformamide and tetrahydrofuran (3, v/v), dropwise adding 4.1g (0.023 mol) of diethyl azodicarboxylate at 0 ℃, returning to 10 ℃ after the dropwise addition, 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: n-hexane =10 (v/v), so as to obtain 1.3g of a mixture of the compound of the formula IV-3 and the compound of the formula IV-4 with the yield of 35%.
1.3g of the mixture of the above-mentioned compound of the formula IV-3 and the compound of the formula IV-4 was dissolved in 100mL of methanol, and 60mg (0.0016 mol) of sodium borohydride was added thereto at 0 deg.C, and the reaction was stirred for about 4 hours and checked by TLC. The mixture was washed with a saturated solution of sodium bicarbonate, extracted with ethyl acetate (3 × 80 mL), combined with organic layers, washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, filtered, concentrated and then eluted with a silica gel column chromatography gradient eluting ethyl acetate: n-hexane =1:5-1 (v/v) for separation, delevelin 1.12g, yield 96%, HPLC purity 96%.
Equivalents and scope
Some non-limiting preferred embodiments of the invention have been described above. Various changes and modifications may be effected therein by one skilled in the art without departing from the true scope of the invention as defined by the claims. Such changes and modifications are to be considered within the scope of the present invention.
Claims (29)
1. A compound of formula III:
wherein: r is methyl or ethyl, G is a hydroxyl protecting group.
2. The compound of formula III according to claim 1, wherein G is a silyl ether-based protecting group or an allyloxycarbonyl group.
3. The compound of formula III according to claim 2, wherein the silyl-based protecting group is selected from tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, or triisopropylsilyl.
4. A process for the preparation of a compound of formula III as defined in claim 1,2 or 3, 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.
5. The method of claim 4, 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 formula II is (3-5): 1.
6. The method of claim 5, wherein the compound of formula II is reacted with the hydroxyl protecting agent at a temperature of-15 to 30 ℃ for a time of 3 to 8 hours.
7. The method of claim 6, wherein the reaction temperature of the compound of formula II with the hydroxyl protecting agent is-10 to 25 ℃.
8. A compound of formula II:
wherein R is methyl or ethyl.
9. A process for preparing a compound of formula II according to claim 8, 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.
10. The method according to claim 9, wherein the organic solvent is selected from methanol, isopropanol, n-butanol or acetone, the acidic solution under acidic conditions is selected from sulfuric acid solution with mass fraction greater than 90%, hydrochloric acid solution with mass fraction greater than 30% or acetic acid solution with mass fraction greater than 38%, and the volume ratio of the organic solvent to the acidic solution is 80-99.
11. The method according to claim 10, wherein the volume ratio of the organic solvent to the acid solution is from 90 to 95.
12. The method according to claim 9, 10 or 11, wherein the temperature of the hydrolysis reaction is-10 to 100 ℃ and the time of the hydrolysis reaction is 3 to 15 hours.
13. The process according to claim 12, wherein the temperature of the hydrolysis reaction is 20 to 80 ℃.
14. A process for preparing a lepimectin of formula V:
the method is characterized by comprising the following steps:
(a) A compound of formula III with 2-methoxyIminophenylacetic acid via SN 2 The 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.
15. The method of claim 14, wherein the SN is the SN 2 The reaction is a Mitsunobu reaction.
16. The process according to claim 15, wherein the Mitsunobu-reacted azo reagent is selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, di-p-chlorobenzyl azodicarboxylate or N, N' -tetramethylazodicarboxamide, mitsunobu-reacted phosphine compound is selected from triphenylphosphine, tributylphosphine or trimethylphosphine; the molar ratio of the azo reagent to the phosphine compound to the compound shown in the formula III is (3-7): 1.
17. The method according to claim 15 or 16, 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 ℃.
18. The method of claim 17, wherein the temperature of the Mitsunobu reaction is between-5 and 0 ℃.
19. The method according to claim 14, wherein the catalyst of 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, the reaction temperature of step (b) is-15-10 ℃, and the reaction time of step (b) is 2-4 hours.
20. The process of claim 19, wherein the molar ratio of the catalyst to the compound of formula IV is (1-2): 1.
21. The method of claim 14, 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 an acidic condition 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.
22. The method according to claim 21, wherein 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 sulfuric acid solution with mass fraction of more than 90%, hydrochloric acid solution with mass fraction of more than 30% or acetic acid solution with mass fraction of more than 38%, and the volume ratio of the organic solvent to the acid solution is 80-99.
23. The method according to claim 22, wherein the volume ratio of the organic solvent to the acid solution is from 90 to 95.
24. The method as claimed in claim 21, 22 or 23, wherein the hydrolysis reaction temperature in step (c) is-10 to 100 ℃ and the hydrolysis reaction time is 3 to 15 hours.
25. The process of claim 24, wherein the temperature of the hydrolysis reaction in step (c) is 20 to 80 ℃.
26. The method of claim 21, wherein in step (d), 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 formula II is (3-5): 1.
27. The process of claim 21 or 26, wherein the compound of formula II in step (d) is reacted with the hydroxy protecting agent at a temperature of-15 to 30 ℃ for a time of 3 to 8 hours.
28. The method according to claim 27, wherein the temperature for reacting the compound of formula II with the hydroxyl protecting agent in step (d) is from-10 to 25 ℃.
29. Use of a compound of formula III according to claim 1 or a compound of formula II according to claim 8 for the preparation of a lepinomycin of formula V according to claim 14.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811416685.2A CN111217828B (en) | 2018-11-26 | 2018-11-26 | Preparation method of lepistamycin and intermediate thereof |
| PCT/CN2019/111554 WO2020108146A1 (en) | 2018-11-26 | 2019-10-17 | Preparation method for lepimectin, and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811416685.2A CN111217828B (en) | 2018-11-26 | 2018-11-26 | Preparation method of lepistamycin and intermediate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111217828A CN111217828A (en) | 2020-06-02 |
| CN111217828B true CN111217828B (en) | 2022-11-25 |
Family
ID=70828715
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811416685.2A Active CN111217828B (en) | 2018-11-26 | 2018-11-26 | Preparation method of lepistamycin and intermediate thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111217828B (en) |
| WO (1) | WO2020108146A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111592553B (en) * | 2020-06-23 | 2022-09-02 | 江苏威凌生化科技有限公司 | Method for preparing moxidectin |
| BR112023023856A2 (en) | 2021-05-14 | 2024-01-30 | Syngenta Crop Protection Ag | CONTROL OF INSECT PESTS, MITE AND NEMATODES |
| WO2023203038A1 (en) | 2022-04-19 | 2023-10-26 | Syngenta Crop Protection Ag | Insect, acarina and nematode pest control |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK614084A (en) * | 1983-12-30 | 1985-07-01 | Ciba Geigy Ag | MILBEMYCIM DERIVATIVES AND THEIR PREPARATION AND USE |
| EP0180539A1 (en) * | 1984-09-18 | 1986-05-07 | Ciba-Geigy Ag | 13-Halo- and 13-hydroxymilbemycin |
| JP2622197B2 (en) * | 1990-03-01 | 1997-06-18 | 三共株式会社 | 13-ether substituted milbemycin derivative |
| JPH085894B2 (en) * | 1990-03-01 | 1996-01-24 | 三共株式会社 | Milbemycin ether derivative |
| US5614470A (en) * | 1994-04-01 | 1997-03-25 | Sankyo Company, Limited | 13-substituted milbemycin derivatives, their preparation and their use |
| JP3499097B2 (en) * | 1995-09-22 | 2004-02-23 | 三共アグロ株式会社 | Insecticidal milbemycin derivatives having a substituent containing an oxime group at position 13 |
| JP2004043452A (en) * | 2002-05-17 | 2004-02-12 | Sankyo Lifetech Co Ltd | Macrolactone derivative |
| JP2007254406A (en) * | 2006-03-24 | 2007-10-04 | Sankyo Agro Kk | Milbemycin derivative having oxime group at 13 site, and insecticidal, miticidal or anthelmintic agent containing the derivative as active component |
| JP2008143818A (en) * | 2006-12-08 | 2008-06-26 | Sankyo Agro Kk | Oxime group-containing milbemycin derivative |
-
2018
- 2018-11-26 CN CN201811416685.2A patent/CN111217828B/en active Active
-
2019
- 2019-10-17 WO PCT/CN2019/111554 patent/WO2020108146A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020108146A1 (en) | 2020-06-04 |
| CN111217828A (en) | 2020-06-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111217828B (en) | Preparation method of lepistamycin and intermediate thereof | |
| ES2270226T3 (en) | METHOD FOR OBTAINING CLARITROMYCIN IN NON-PHARMACEUTICAL QUALITY CRYSTALS. | |
| US6069238A (en) | Spirocyclic C-glycosides | |
| CA1216287A (en) | Derivatives of 4'-demethyl-4-epipodophyllotoxin | |
| JPH05255342A (en) | 4a-substituted avermectin derivative | |
| JP2002500229A (en) | Novel aromatic amides, preparation methods and pharmaceutical uses | |
| EP0827965A2 (en) | Synthesis of 9-deoxo- 9a-aza 11,12-deoxy- 9a-methyl-9a-homoerythromycin A 11,12- hydrogenorthoborate dihydrate | |
| US20080167463A1 (en) | Process for Preparation of Gemcitabine Hydrochloride | |
| JP3231765B2 (en) | Method for producing demethyl epipodophyllotoxin | |
| KR100953031B1 (en) | Process for the preparation of ribavirin | |
| CN107226830B (en) | Chemical synthesis method of spinetoram | |
| CA2024235A1 (en) | Epipodophyllotoxin altroside derivatives | |
| CA1306249C (en) | Tylosin derivatives and processes for producing the same | |
| US4794173A (en) | Mycaminosyl tylonolide derivatives | |
| EP0675895B1 (en) | Etoposide derivatives, process for their preparation, their use as a drug and in the preparation of a drug for treating cancer | |
| JPH0631298B2 (en) | Novel anthracycline derivative, antitumor agent, and production method | |
| CA1267890A (en) | Process for preparing milbemycin derivatives and certain compounds employed therein | |
| CN1982301B (en) | A manufacturing process of 2',2'-difluoronucleoside and intermediate | |
| WO1992022544A1 (en) | Method for separation of gibberellin mixtures | |
| CN110003291B (en) | Fluoro glycosyl modified taxol compound and synthesis method and application thereof | |
| CZ20014362A3 (en) | 4'-demycarosyl-8a-aza-8a-homotylosines and process for preparing thereof | |
| WO2004007518A1 (en) | Erythromycin a 9-o-pseudosaccharinyloxime derivatives and process for the preparation of clarithromycin using the same | |
| JPS6152160B2 (en) | ||
| JP3904270B2 (en) | Production method of etoposides | |
| CN117466953A (en) | Preparation method of natural product emmbeloside A |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |