CN113735924A - Preparation method of 23-ketone avermectin B2a/B2B derivative - Google Patents
Preparation method of 23-ketone avermectin B2a/B2B derivative Download PDFInfo
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- CN113735924A CN113735924A CN202111020222.6A CN202111020222A CN113735924A CN 113735924 A CN113735924 A CN 113735924A CN 202111020222 A CN202111020222 A CN 202111020222A CN 113735924 A CN113735924 A CN 113735924A
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- oxidant
- ketoavermectin
- derivatives
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- hydroxyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 37
- 230000001590 oxidative effect Effects 0.000 claims abstract description 13
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- -1 alkyl chlorosilane Chemical compound 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 7
- 239000012442 inert solvent Substances 0.000 claims abstract description 7
- 239000005046 Chlorosilane Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 239000003223 protective agent Substances 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 11
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 8
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 8
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 claims description 8
- 230000003244 pro-oxidative effect Effects 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 8
- 239000005660 Abamectin Substances 0.000 abstract description 29
- 229950008167 abamectin Drugs 0.000 abstract description 29
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 abstract description 16
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- CWGATOJEFAKFBK-UHFFFAOYSA-N Ac-(E)-8-Tridecen-1-ol Natural products C1C(O)C(C)C(C(C)CC)OC11OC(CC=C(C)C(OC2OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C2)C(C)C=CC=C2C3(C(C(=O)O4)C=C(C)C(O)C3OC2)O)CC4C1 CWGATOJEFAKFBK-UHFFFAOYSA-N 0.000 description 8
- SHURRSUZDBDBMX-JLSLGBNPSA-N avermectin B2a Natural products CC[C@H](C)[C@H]1O[C@@]2(C[C@@H]3C[C@@H](CC=C(/C)[C@@H](O[C@H]4C[C@H](OC)[C@@H](O[C@H]5C[C@H](OC)[C@@H](O)[C@H](C)O5)[C@H](C)O4)[C@@H](C)C=CC=C6/OC[C@@H]7[C@H](O)C(=C[C@@H](C(=O)O3)[C@]67O)C)O2)C[C@@H](O)[C@@H]1C SHURRSUZDBDBMX-JLSLGBNPSA-N 0.000 description 8
- CWGATOJEFAKFBK-PDVFGPFMSA-N 5-o-demethyl-22,23-dihydro-23-hydroxy-(13r,23s)-avermectin a1a Chemical compound C1[C@H](O)[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 CWGATOJEFAKFBK-PDVFGPFMSA-N 0.000 description 7
- ZPAKHHSWIYDSBJ-YAGODIQJSA-N Avermectin B2b Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)[C@@H](O)C4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C ZPAKHHSWIYDSBJ-YAGODIQJSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- ZPAKHHSWIYDSBJ-UHFFFAOYSA-N avermectin B2b Natural products O1C(C)C(O)C(OC)CC1OC1C(OC)CC(OC2C(=CCC3CC(CC4(OC(C(C)C(O)C4)C(C)C)O3)OC(=O)C3C=C(C)C(O)C4OCC(C34O)=CC=CC2C)C)OC1C ZPAKHHSWIYDSBJ-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000000749 insecticidal effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- PKUPAJQAJXVUEK-UHFFFAOYSA-N 2-phenoxyacetyl chloride Chemical compound ClC(=O)COC1=CC=CC=C1 PKUPAJQAJXVUEK-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- JYGWVCOFTZZSGS-UHFFFAOYSA-N methylsulfonylmethanamine Chemical compound CS(=O)(=O)CN JYGWVCOFTZZSGS-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a preparation method of a 23-keto abamectin B2a/B2B derivative, which comprises the steps of reacting an abamectin B2a/B2B derivative with at least one hydroxyl at the 5-position and the 4' -position with alkyl chlorosilane in an inert solvent at a certain temperature to obtain a protected abamectin B2a/B2B derivative, adding an oxidant to oxidize 23-hydroxyl into carbonyl, and removing a protecting group under an acidic condition to obtain a target product, namely a formula I.
Description
Technical Field
The invention relates to a preparation method of a 23-ketoavermectin B2a/B2B derivative, belonging to the field of organic synthesis reaction.
Background
With the research on the abamectin series compounds, the abamectin B2 series compounds with high content can be separated at present. Researches show that the abamectin B2 series compounds and abamectin B1 series compounds have different insecticidal spectrums and insecticidal effects, so that the abamectin B2 series compounds have high research significance.
For example, the abamectin B2a has good insecticidal activity on underground nematodes, after the abamectin B2a is metabolized into 23-keto abamectin B2a, the 23-keto abamectin B2a is further researched to obtain the 23-keto abamectin B2a/B2B derivative, and the 23-keto abamectin B2a/B2B derivative such as the compound formula I has certain insecticidal activity on pests, so that the compound formula I has great research value.
Wherein:
wherein:
R1is hydrogen or methyl;
R2is hydroxy or other group;
R3is hydroxy or other group;
R2or R3At least one is a hydroxyl group.
The avermectin B1 compounds also relate to protection oxidation and reduction deprotection of hydroxyl, which is to use allyl chloroformate to protect the hydroxyl of avermectin B2a, oxidize light and dimethyl sulfoxide, and reduce and deprotect by using sodium borohydride, but during deprotection reaction, the carbonyl at the 23-position is also reduced to hydroxyl, and a target product shown in formula I cannot be obtained.
In addition, the target product of formula I can be obtained by performing a protection reaction on abamectin B2a and phenoxyacetyl chloride under the action of pyridine and performing an oxidation reaction under the action of dimethyl sulfoxide, oxalyl chloride and triethylamine. However, the reaction carried out in this way gives only a very small amount of the desired product.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of the 23-keto abamectin B2a/B2B derivative, and the yield of the obtained 23-keto abamectin B2a/B2B derivative formula I is more than 80%.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of a 23-ketoavermectin B2a/B2B derivative is disclosed, wherein the 23-ketoavermectin B2a/B2B derivative is a compound shown as a formula I:
wherein:
R1is hydrogen or methyl;
R2is hydroxy or other group;
R3is hydroxy or other group;
R2or R3At least one is hydroxyl;
the preparation method comprises the following steps:
s1, dissolving the compound shown in the formula II in an inert solvent, adding a protective agent and organic alkali at a certain temperature, and protecting the hydroxyl at the 5-position and/or the 4-position;
wherein:
R1is hydrogen or methyl;
R2is hydroxy or other group;
R3is hydroxy or other group;
R2or R3At least one is hydroxyl;
s2, adding organic alkali and a certain amount of oxidant and pro-oxidant into S1, oxidizing the hydroxyl at the 23 position into carbonyl, adding alkali to remove excessive oxidant, washing with water to remove salt generated by the reaction, and layering to obtain an organic phase;
and S3, adding a certain amount of acid into the organic phase, removing the protective agent, washing with water for layering, and evaporating the solvent from the organic phase to obtain the target product shown in the formula I.
The technical scheme of the invention is further improved as follows: the protective agent in the step S1 is alkoxy chlorosilane, the molar ratio of the protective agent to the raw material formula II is 1.0-3.0: 1.0, and the reaction temperature is-20-10 ℃.
The technical scheme of the invention is further improved as follows: the protective agent in the step S1 is trimethylchlorosilane or triethylchlorosilane.
The technical scheme of the invention is further improved as follows: the inert solvent in the step S1 is dichloromethane, dichloroethane, toluene, sec-butyl acetate or isopropyl acetate, and the weight ratio of the inert solvent to the raw material formula II is 2-5: 1.
The technical scheme of the invention is further improved as follows: the organic base in the steps S1 and S2 is triethylamine, tetramethyl ethylene diamine or diisopropylamine, and the molar ratio of the organic base to the protective agent is 1-1.5: 1.
The technical scheme of the invention is further improved as follows: the oxidant in step S2 is dimethyl sulfoxide; the pro-oxidant is solid phosgene or phenyl phosphate diacid chloride, the molar ratio of the oxidant to the pro-oxidant to the raw material formula II is 1.0-5.0: 0.5-4.0: 1.0, and the reaction temperature is as follows: -20 ℃ to 30 ℃.
The technical scheme of the invention is further improved as follows: the pro-oxidant is phenyl phosphate diacid chloride.
The technical scheme of the invention is further improved as follows: the acid in the step S3 is organic strong acid and inorganic strong acid, and the molar ratio of the acid to the raw material formula II is 0.1-2.0: 1.0, the reaction temperature is: 0 to 30 ℃.
The technical scheme of the invention is further improved as follows: the acid is trifluoroacetic acid.
The invention is suitable for preparing compounds containing a plurality of hydroxyl groups with different activities and needing to oxidize the hydroxyl group at the position with lower activity into carbonyl.
Starting from R in formula II2And R3And when the hydroxyl is simultaneously the abamectin B2a/B2B, the reaction equation is as follows:
starting from R in formula II2And R3When only one is hydroxyl, abamectin B2a/B2B is used as a raw material, and a non-hydroxyl substituent is subjected to a series of reactions to prepare the abamectin compound.
Due to the adoption of the technical scheme, the invention has the technical progress that:
1. the use of the protective agent of alkyl chlorosilane well protects the hydroxyl outside the 23-position, so that the hydroxyl at the 23-position can be completely oxidized;
2. the alkyl chlorosilane is easy to strip off under the action of trifluoroacetic acid, is changed into hydroxyl in situ, has no influence on a macrocyclic structure and a carbonyl group at the 23 th site, and can obtain a target product with higher content and yield.
3. In the traditional allyl protection method, a protected 23-carbonyl abamectin B2a/B2B derivative can be obtained after oxidation, but during deprotection, a catalyst and sodium borohydride are used to reduce a 23-carbonyl group back to a hydroxyl group, so that a target product, namely the 23-keto abamectin B2a/B2B derivative cannot be obtained.
Detailed Description
The present invention will be described in further detail with reference to the following examples:
the invention is suitable for preparing compounds containing a plurality of hydroxyl groups with different activities and needing to oxidize the hydroxyl group at the position with lower activity into carbonyl.
R2And R3Meanwhile, the preparation process of the hydroxyl group comprises the following steps:
example 123 Synthesis of ketoavermectin B2a/B2B
10g (0.01mol) of 95% avermectin B2a/B2B, 50g of dichloromethane, cooling to-20 ℃, adding 2.4g (0.022mol) of trimethylchlorosilane, slowly adding 2.6g (0.022mol) of tetramethylethylenediamine, keeping the temperature of-10-0 ℃ for 0.5h after finishing adding, adding 2.4g (0.02mol) of tetramethylethylenediamine, 1.6g (0.02mol) of dimethyl sulfoxide, adding 4.2g (0.02mol) of phenyl phosphate diacid chloride, slowly raising the temperature to 0-10 ℃, keeping the temperature for 2h, adding 1% of sodium hydroxide aqueous solution to adjust the pH value to 7-8, layering, adding 1.2g (0.01mol) of trifluoroacetic acid into the organic phase, stirring for 2h at room temperature, washing with water, separating out the water phase, distilling off the dichloromethane to obtain 9.0g of white-like solid, 23-keto avermectin B2 a/B2B% content, and yield of 90.7%.
Hydrogen nuclear magnetic resonance spectroscopy:
lH NMR(400.13MHz):5.55(m,3H),5.42(t,J＝5.0,1H),5.28(t,J＝5.0,1H),5.00(m,lH),4.87(brd,lH),4.70(m,2H),4.40(br d,J＝6.0,lH),4.20(br q,J＝7.7,lH),4.00(d,J＝6.6,lH),3.90(br s,lH),3.86(m,2H),3.80(dq,J＝8.8,6.8,lH),3.84(ddd,J＝12.5,5.8,4.6,lH),3.70(s,lH),3.68(m,lH),3.55(dd,J＝10.8,2.0,lH),3.40(s,3H),3.35(m,lH),3.30(q,J＝2.2,lH),3.23(dd,J＝9.1,8.7,lH),2.80(s,1H),2.67(s,3H),2.52(m,lH),2.41-2.17(m,3H),2.10-1.90(m,2H),1.80(br s,3H),1.76(m,lH),1.70(d,J＝4.5,2H),1.65-1.50(m,6H),1.44(brs,3H),1.34(d,J＝6.7,3H),1.20(d,J＝6.2,3H),1.19(d,J＝7.0,3H),1.13(d,J＝7.6,3H),0.93-0.88(m,9H),0.80(m,1H).
LC-MS [ M + Na ] liquid mass analysis]+911.48, 23-ketoavermectin B2a [ M + Na [ ]]+Calculated values: 911.48.
the nuclear magnetic resonance and liquid-state results show that the obtained white-like solid is the compound shown in the formula I.
Example 223 Synthesis of ketoavermectin B2a/B2B
10g (0.01mol) of 95 percent abamectin B2a/B2B, 50g of dichloromethane, cooling to-10 ℃, adding 4.5g (0.03mol) of triethylchlorosilane, dropwise adding 3.5g (0.03mol) of tetramethylethylenediamine, keeping the temperature of 0-10 ℃ for 2h after the dropwise adding is finished, then adding 2.4g (0.02mol) of tetramethylethylenediamine, 2.4g (0.03mol) of dimethyl sulfoxide, dropwise adding 4.2g (0.02mol) of phenyl phosphate diacid chloride, keeping the temperature slowly to 20 ℃, keeping the temperature for 1h, adding 1 percent sodium hydroxide aqueous solution to adjust the pH value to 7-8, demixing, adding 0.6g (0.005mol) of trifluoroacetic acid into the organic phase, stirring for 2h at room temperature, washing, separating out the aqueous phase, evaporating the organic phase to remove dichloromethane, obtaining 8.7g of white-like solid, 23-keto abamectin B2a/B2B percent, and the yield is 86.2 percent.
The results of hydrogen nuclear magnetic resonance and mass spectrometry are the same as in example 1.
The results of nuclear magnetic resonance and liquid mass analysis show that the obtained white-like solid is the compound shown in the formula I.
R2Is hydroxy, R3Is acetylThe preparation process of the amino group comprises the following steps:
example 34 Synthesis of "-acetamido-23-ketoavermectin B2a/B2B
10g (0.01mol) of 96.0 percent 4 '-acetamido abamectin B2a/B2B, 50g of dichloroethane, cooling to-20 ℃, adding 1.1g (0.01mol) of trimethylchlorosilane, slowly adding 1.2g (0.01mol) of tetramethylethylenediamine, keeping the temperature for 2h at-10 to 0 ℃, adding 2.4g (0.02mol) of tetramethylethylenediamine, 1.6g (0.02mol) of dimethyl sulfoxide, adding 3.2g (0.015mol) of phenyl phosphate diacid chloride, slowly raising the temperature to 10 ℃, keeping the temperature for 2h, adding 1 percent sodium hydroxide aqueous solution to adjust the pH value to 7-8, demixing, adding 0.6g (0.005mol) of trifluoroacetic acid in the organic phase, stirring for 2h at room temperature, washing with water, separating out the water phase, evaporating dichloromethane to obtain light yellow solid with the content of 8.5g, 4' -acetamido-23-keto abamectin B2a/B2B percent, the yield thereof was found to be 83.3%.
Hydrogen nuclear magnetic resonance spectrum and mass spectrum analysis results:
lH NMR(400.0MHz):5.90(m,lH),5.75(dd,J＝9.8,2.6,lH),5.53(m,3H),5.20(m,lH),4.90(br d,J＝5.0,lH),4.75(m,2H),4.52(br d,J＝4.5,lH),4.33(br q,J＝7.7,lH),4.18(br s,lH),4.08(m,2H),3.99(dq,J＝9.9,6.5,lH),3.85(ddd,J＝12.4,5.0,6.8,lH),3.70(s,lH),3.62(s,3H),3.54(s,3H),3.48(m,lH),3.40(q,J＝3.5,lH),3.33(dd,J＝7.8,7.6,lH),2.97(s,3H),2.64(m,lH),2.50(s,3H),2.41-2.35(m,3H),2.20(s,lH),2.15-2.00(m,2H),1.90(brs,3H),1.88(m,lH),1.82(d,J＝4.4,2H),1.78-1.49(m,5H),1.42(brs,3H),1.30(d,J＝5.8,3H),1.35(d,J＝6.8,3H),1.20(d,J＝7.0,3H),1.16(d,J＝7.6,3H),0.99-0.89(m,9H),0.88(m,1H),.
LC-MS [ M + Na ] liquid mass analysis]+952.50, 4' -acetamido-23-one avermectin B2a [ M + Na]+Calculated values: 952.50.
the results of nuclear magnetic resonance and liquid mass analysis show that the obtained light yellow solid is the compound shown in the formula I.
The 4 ' -acetamido-5-avermectin B2a/B2B is prepared by using avermectin B2a/B2B as a raw material, protecting 5-hydroxy with allyl chloroformate in dichloromethane, oxidizing 4 ' -hydroxy, performing ammoniation and acylation to obtain 4 ' -acetamido-5-protected avermectin B2a/B2B, and removing 5-protection.
R2Is hydroxy, R3The preparation process of methylsulfonylmethylamine comprises the following steps:
example 44 Synthesis of "-Methylsulfonylmethylamino-23-one Avermectin B2a/B2B
10g (0.01mol) of 96.0 percent 4 '-methylsulfonylmethylaminoacetin B2a/B2B is added into 50g sec-butyl acetate, the temperature is reduced to 0 ℃, 1.1g (0.01mol) of trimethylchlorosilane is added, 1.5g (0.015mol) of triethylamine is slowly dripped, after the dripping is finished, the temperature is kept for 2h at the temperature of 10 ℃ to 0 ℃, 2.0g (0.02mol) of triethylamine, 2.0g (0.025mol) of dimethyl sulfoxide is added, 3.2g (0.015mol) of phenyl phosphate diacid chloride is dripped, the temperature is slowly raised to 10 ℃, the temperature is kept for 2h, 1 percent sodium hydroxide aqueous solution is added to adjust the pH value to be 7-8, the mixture is layered, 1.1g (0.01mol) of trifluoroacetic acid is added into the organic phase, the mixture is stirred for 2h at room temperature, the water is washed, the aqueous phase is separated out, the sec-butyl acetate is distilled out from the organic phase, and light yellow solid with the content of 9.0g, 4' -methylsulfonylmethylamido-23-keto-abamectin B2a/B2B is obtained, the yield thereof was found to be 89.2%.
Hydrogen nuclear magnetic resonance spectrum and mass spectrum analysis results:
lH NMR(400.0MHz):5.53(m,3H),5.40(m,lH),4.76(br d,J＝2.0,lH),4.70(m,2H),4.50(br d,J＝4.8,lH),4.42(br q,J＝6.6,lH),4.30(d,J＝6.6,lH),4.00(br s,lH),3.88(m,2H),3.85(s,1H),3.82(dq,J＝11.5,6.2,lH),3.74(ddd,J＝11.5,5.0,3.8,lH),3.68(s,lH),3.42(s,3H),3.40(s,3H),3.38(m,lH),3.32(s,1H),3.30(q,J＝3.2,lH),3.23(dd,J＝10.8,8.4,lH),3.00(s,3H),2.87(br d,J＝5.8,lH),2.67(s,3H),2.52(m,lH),2.31-2.25(m,3H),2.21(dd,J＝10.8,5.0,lH),2.05-1.90(m,2H),1.87(br s,3H),1.78(m,lH),1.72(d,J＝5.7,2H),1.70(d,J＝5.6,2H),1.63-1.46(m,6H),1.49(brs,3H),1.34(d,J＝7.5,3H),1.23(d,J＝8.8,3H),1.16(d,J＝8.4,3H),1.11(d,J＝9.7,3H),0.96-0.91(m,9H),0.89(m,1H).
LC-MS [ M + Na ] liquid mass analysis]+1002.49, 4' -methylsulfonylmethylamino-23-one avermectin B2a [ M + Na]+Calculated values: 1002.49.
the results of nuclear magnetic resonance and liquid mass analysis show that the obtained light yellow solid is the compound shown in the formula I.
The 4 ' -methylsulfonylmethylamine abamectin B2a/B2B is prepared by using abamectin B2a/B2B as a raw material, protecting 5-hydroxy with allyl chloroformate in dichloromethane, oxidizing 4 ' -hydroxy, performing methylamination and sulfonylation to obtain 4 ' -methylsulfonylmethylamine-5-protected abamectin B2a/B2B, and removing 5-protection.
Claims (9)
1. A preparation method of a 23-ketone avermectin B2a/B2B derivative is characterized by comprising the following steps: the 23-ketone avermectin B2a/B2B derivative is a compound shown as a formula I:
wherein:
R1is hydrogen or methyl;
R2is hydroxy or other group;
R3is hydroxy or other group;
R2or R3At least one is hydroxyl;
the preparation method comprises the following steps:
s1, dissolving the compound shown in the formula II in an inert solvent, adding a protective agent and organic alkali at a certain temperature, and protecting the hydroxyl at the 5-position and/or the 4-position;
wherein:
R1is hydrogen or methyl;
R2is hydroxy or other group;
R3is hydroxy or other group;
R2or R3At least one is hydroxyl;
s2, adding organic alkali and a certain amount of oxidant and pro-oxidant into S1, oxidizing the hydroxyl at the 23 position into carbonyl, adding alkali to remove excessive oxidant, washing with water to remove salt generated by the reaction, and layering to obtain an organic phase;
and S3, adding a certain amount of acid into the organic phase, removing the protective agent, washing with water for layering, and evaporating the solvent from the organic phase to obtain the target product shown in the formula I.
2. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the protective agent in the step S1 is alkoxy chlorosilane, the molar ratio of the protective agent to the raw material formula II is 1.0-3.0: 1.0, and the reaction temperature is-20-10 ℃.
3. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 2, wherein: the protective agent in the step S1 is trimethylchlorosilane or triethylchlorosilane.
4. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the inert solvent in the step S1 is dichloromethane, dichloroethane, toluene, sec-butyl acetate or isopropyl acetate, and the weight ratio of the inert solvent to the raw material formula II is 2-5: 1.
5. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the organic base in the steps S1 and S2 is triethylamine, tetramethyl ethylene diamine or diisopropylamine, and the molar ratio of the organic base to the protective agent is 1-1.5: 1.
6. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the oxidant in step S2 is dimethyl sulfoxide; the pro-oxidant is solid phosgene or phenyl phosphate diacid chloride, the molar ratio of the oxidant to the pro-oxidant to the raw material formula II is 1.0-5.0: 0.5-4.0: 1.0, and the reaction temperature is as follows: -20 ℃ to 30 ℃.
7. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 6, wherein: the pro-oxidant is phenyl phosphate diacid chloride.
8. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 1, wherein: the acid in the step S3 is organic strong acid and inorganic strong acid, and the molar ratio of the acid to the raw material formula II is 0.1-2.0: 1.0, the reaction temperature is: 0 to 30 ℃.
9. The process for preparing 23-ketoavermectin B2a/B2B derivatives as claimed in claim 8, wherein: the acid is trifluoroacetic acid.
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