CN108821974B - Preparation method of alkoxy acrylate - Google Patents

Preparation method of alkoxy acrylate Download PDF

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CN108821974B
CN108821974B CN201810938117.2A CN201810938117A CN108821974B CN 108821974 B CN108821974 B CN 108821974B CN 201810938117 A CN201810938117 A CN 201810938117A CN 108821974 B CN108821974 B CN 108821974B
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alkoxy acrylate
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黄汉民
钱波
李加文
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Lanzhou Institute of Chemical Physics LICP of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Abstract

The invention discloses a preparation method of alkoxy acrylate, which takes diazoformate and substituted acetal or ketal as raw materials, takes Lewis acid as a catalyst, and reacts for 1 to 24 hours at the temperature of between 50 and 120 ℃ to generate an olefination reaction; after the reaction is finished, the solvent is pumped out, and column chromatography separation is carried out to obtain the alkoxy acrylate compound. The reaction raw materials and the catalyst are cheap and easy to obtain, the synthesis process is simple, and the synthesis cost is greatly reduced; the reaction condition is mild, the yield is high, and the industrialization is easy to realize; the reaction raw materials and the catalyst are clean and nontoxic, and the environmental pollution is small.

Description

Preparation method of alkoxy acrylate
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and relates to a preparation method of alkoxy acrylate, in particular to a compound with an alkoxy acrylate structure, which is obtained by taking substituted acetal or ketal and diazo formate as raw materials and carrying out an alkylation reaction under the catalysis of a Lewis acid catalyst.
Background
The alkoxy acrylate compound is a very important fine chemical and has wide application in the pesticide industry. The alkoxy acrylate group is a common pharmacophore and is widely present in various natural products and artificial synthetic drugs with physiological activities. For example, the methoxy acrylate group-containing fungicide sold in 1999 is $ 6 billion, occupies 10% of the worldwide fungicide market, wherein azoxystrobin, as a highly effective, broad-spectrum systemic fungicide, can be used for controlling almost all fungal diseases of over four hundred temperate crops, has no cross-resistance with currently available fungicides, and is now used for over eighty crops in seventy countries; picoxystrobin is a broad-spectrum bactericide with the best using effect at present, has stronger therapeutic activity particularly on wheat leaf hu disease, net blotch and leaf streak disease, and has higher bactericidal activity than picoxystrobin due to the systemic activity and fumigation activity. In addition, the alkoxy acrylate compound has carbon-carbon double bonds and carbon-oxygen single bonds, and can further undergo reactions such as oxidation, reduction, cross coupling and the like to synthesize other compounds. Due to the wide range of uses of alkoxy acrylate compounds, a number of synthetic methods have been developed in recent years.
There are various conventional methods for synthesizing alkoxy acrylate compounds, for example: (1) elimination reaction of acetal; (2) addition reaction of alcohol to alkyne; (3) condensation reaction of acetate and formate; (4) coupling reaction of an alkenyl metal reagent with an organohalide. Although the above methods have high yield, the methods are limited by equivalent amounts of strong base, organic halogen, various additives and substrate adaptability, and the practical application is greatly limited. To overcome the various disadvantages of the above reactions, lewis acid catalyzed methods of synthesizing hydroxyacrylate compounds have been developed, with specific references: m, E.Dudley, M.M. Morshed, C.L. Brennan, M.S. Islam, M.S. Ahmad, M.R. Atuu, B. Branstetter, M.M. Hossain,J. Org. Chem.2004,69,7599-7608。
Figure RE-29614DEST_PATH_IMAGE001
although this method is an improvement over previous methods, some disadvantages remain. For example: firstly, the adaptability of the reaction substrate is limited, the reaction substrate is only suitable for aromatic aldehyde and a small amount of aromatic ketone compounds, and aliphatic aldehyde or ketone compounds do not participate in the reaction; secondly, the alkoxy acrylate compound is synthesized by the method, and hydroxyl needs to be further converted into methoxyl, so that the step economy is low; thirdly, the reaction conditions are harsh, the efficiency is not high, and the industrialization is difficult to realize.
Disclosure of Invention
The invention aims to provide a simple and efficient preparation method of alkoxy acrylate.
Figure 50487DEST_PATH_IMAGE002
A preparation method of alkoxy acrylate is characterized in that diazoformate and substituted acetal or ketal are used as raw materials, Lewis acid is used as a catalyst, and the reaction is carried out for 1 to 24 hours at 50 to 120 ℃ to generate an olefination reaction; after the reaction is finished, the solvent is pumped out, and column chromatography separation is carried out to obtain the alkoxy acrylate compound.
The molar ratio of the diazo formate to the substituted acetal or ketal to the catalyst is 1: 1-2: 0.001-0.05.
The substituted acetal has the structural formula:
Figure 55352DEST_PATH_IMAGE003
(ii) a The structural formula of the substituted ketal is:
Figure 57069DEST_PATH_IMAGE004
or
Figure 477686DEST_PATH_IMAGE005
Wherein: r is selected from C1～C20An aliphatic group of (a); r1、R3And R4Are all selected from C1～C20Fatty radical or C of4～C30An aromatic group of (a); r5Is selected from C1~C6The fatty group of (2).
R is selected from methyl, ethyl or tert-butyl; r1、R3And R4Are all selected from benzyl, methyl, ethyl, tert-butyl, phenyl, substituted phenyl, naphthyl, thienyl or furyl; the R is5Is selected from-CH2-、-CH2CH2-or-CH2CH2CH2-。
The structural formula of the diazo formate is as follows:
Figure 12572DEST_PATH_IMAGE006
wherein: r2Is selected from C1～C20The fatty group of (2).
The R is2Selected from methyl, ethyl or tert-butyl.
The Lewis acid is silver hexafluorophosphate (AgPF)6) Silver hexafluoroantimonate (AgSbF)6) Ytterbium triflate hydrate (Yb (OTf)3·xH2O), hydrated europium triflate (Eu (OTf)3·xH2O) or hydrated bismuth triflate (Bi (OTf)3·xH2O）。
The solvent is tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2, 2-tetrachloroethane, 1, 2-dichloroethane, 1, 2-dibromoethane or 1-bromon-butane.
Compared with the prior art, the invention has the following advantages:
1. the invention is catalyzed by cheap and easily available Lewis acid catalyst, the acetal or ketal and diazoformate react, and the alkoxy acrylate compound can be efficiently prepared by only one step through an alkenyl method.
2. The method can efficiently synthesize the alkoxy acrylate in one step, and expands the range of the synthesis reaction of the alkoxy acrylate.
3. The method has the advantages of mild reaction conditions, simple operation, high yield, wide substrate applicability range and easy industrialization.
4. The reaction process is clean and meets the requirement of green chemistry.
5. The invention has higher conversion efficiency, can realize gram-scale amplification experiments and is easy to realize industrialization.
6. The product of the methoxyl acrylic ester synthesized by the invention can be further synthesized into picoxystrobin and azoxystrobin by a shorter synthetic route and higher yield compared with the existing method.
Detailed Description
EXAMPLE 1 preparation of alkoxy acrylate derivatives 3a and 3a
The synthetic route is as follows:
Figure 188339DEST_PATH_IMAGE007
acetal 1a (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped, and n-tetradecane was added as an internal standard, resulting in a GC yield of 91%. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3a and 3 a'. The product is colorless oil, and the total yield is 81 percent; the molar ratio of 3a to 3 a' is: 3a: 3 a'>20 : 1。
1(400 MHz, CDCl3) 1.29 (t,J= 7.2 Hz, 3H), 3.84 (s, 3H), 4.24 (q,J= 7.2 Hz, 2H), 7.23-7.29 (m, 1H), 7.34-7.35 (m, 4H), 7.54 (s, 1H);13C NMR(100 MHz, CDCl3) 14.4, 60.3, 61.9, 111.9, 127.1, 127.7, 130.2, 132.6,159.4, 167.7; HRMS (ESI) calcd. for C12H14NaO3[M+Na]: 229.0835, found:229.0837。
Example 2 preparation of alkoxy acrylate derivatives 3b and 3b
The synthetic route is as follows:
Figure 113569DEST_PATH_IMAGE008
acetal 1b (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3b and 3 b'. The product was a colorless oil with 89% overall yield, and the molar ratio of 3b to 3 b' was: 3 b: 3 b'>20 : 1。
1(400 MHz, CDCl3) 1.25 (t,J= 6.8 Hz, 3H), 2.19 (s, 3H), 3.82 (s,3H), 4.21 (q,J= 7.2 Hz, 2H), 7.10-7.11 (m, 1H), 7.16-7.26 (m, 3H), 7.55 (s,1H);13C NMR (100 MHz, CDCl3) 14.4, 19.7, 60.2, 61.8, 111.6, 125.4, 127.7,129.8, 130.7, 132.4, 137.2, 159.4, 167.7; HRMS (ESI) calcd. for C13H16NaO3[M+Na]: 243.0992, found: 243.1000。
EXAMPLE 3 preparation of alkoxy acrylate derivatives 3c and 3c
The synthetic route is as follows:
Figure 400194DEST_PATH_IMAGE009
acetal 1c (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgPF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3c and 3 c'. The product was a colorless oil, overall yield 85%, and molar ratio of 3c to 3 c': 3 c: 3 c' = 13: 1.
1(400 MHz, CDCl3) 1.29 (t,J= 7.2 Hz, 3H), 2.34 (s, 3H), 3.81 (s,3H), 4.23 (q,J= 7.2 Hz, 2H), 7.06-7.14 (m, 3H), 7.21-7.25 (m, 1H), 7.52 (s,1H);13C NMR (100 MHz, CDCl3) 14.4, 21.5, 60.3, 61.9, 112.0, 127.3, 127.7,128.0, 130.9, 132.5, 137.2, 159.3, 167.8; HRMS (ESI) calcd. for C13H16NaO3[M+Na]: 243.0992, found: 243.0999。
EXAMPLE 4 preparation of alkoxy acrylate derivatives 3d and 3d
The synthetic route is as follows:
Figure 22543DEST_PATH_IMAGE010
acetal 1d (0.5 mmol), ethyl diazoformate 2a (0.5 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3d and 3 d'. The product was a colorless oil with a total yield of 92%, and the molar ratio of 3d to 3 d' was: 3 d: 3 d' = 18: 1.
1(400 MHz, CDCl3) 1.29 (t,J= 7.2 Hz, 3H), 2.34 (s, 3H), 3.84 (s,3H), 4.24 (q,J= 7.2 Hz, 2H), 7.17 (d,J= 8.0 Hz, 2H), 7.22-7.24 (m, 2H),7.52 (s, 1H);13C NMR (100 MHz, CDCl3) 14.4, 21.3, 60.3, 61.9, 111.8, 128.6,129.6, 130.1, 136.8, 159.2, 167.8; HRMS (ESI) calcd. for C13H16NaO3[M+Na]:243.0992, found: 243.1002。
EXAMPLE 5 preparation of alkoxy acrylate derivatives 3e and 3e
The synthetic route is as follows:
Figure 306894DEST_PATH_IMAGE011
acetal 1e (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent, and separating by column chromatography, wherein the volume ratio of the eluent is ethyl acetate to petroleum ether =1:501:10 to obtain alkoxy acrylate derivatives 3e and 3 e'. The product was a colorless oil with a total yield of 74%, and the molar ratio of 3e to 3 e' was: 3e to 3 e'>20 : 1。
1(400 MHz, CDCl3) 1.29 (t,J= 6.8 Hz, 3H), 2.24-2.25 (m, 6H), 3.82(s, 3H), 4.24 (q,J= 6.8 Hz, 2H), 7.05-7.12 (m, 3H), 7.51 (s, 1H);13C NMR(100 MHz, CDCl3) 14.4, 19.6, 19.9, 60.3, 61.9, 112.0, 127.6, 129.2, 130.0,131.3, 135.6, 135.9, 159.1, 167.9; HRMS (ESI) calcd. for C14H18NaO3[M+Na]:257.1148, found: 257.1147。
EXAMPLE 6 preparation of alkoxy acrylate derivatives 3f and 3f
The synthetic route is as follows:
Figure 781738DEST_PATH_IMAGE012
acetal 1f (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAnd C, reacting in an oil bath for 3 hours, evaporating the solvent, and performing column chromatography separation, wherein the volume ratio of the eluent to the ethyl acetate to the petroleum ether is =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3f and 3 f'. The product was a colorless oil with 83% overall yield, and the molar ratio of 3f to 3 f' was: 3 f: 3 f' = 18: 1.
1(400 MHz, CDCl3) 1.29 (t,J= 7.2 Hz, 3H), 3.79 (s, 3H), 3.83 (s,3H), 4.24 (q,J= 7.2 Hz, 2H), 6.89 (d,J= 8.8 Hz, 2H), 7.29 (d,J= 8.8 Hz,2H), 7.50 (s, 1H);13C NMR (100 MHz, CDCl3) 14.4, 55.2, 60.3, 61.9, 111.4,113.3, 124.9, 131.3, 158.5, 159.0, 167.9; HRMS (ESI) calcd. for C13H16NaO4[M+Na]: 259.0941, found: 259.0953。
EXAMPLE 7 preparation of alkoxy acrylate derivatives 3g and 3g
The synthetic route is as follows:
Figure 872053DEST_PATH_IMAGE013
acetal 1g (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 10, to obtain 3g and 3 g' of the alkoxy acrylate derivative. The product was a colorless oil with a total yield of 48%, and the molar ratio of 3g to 3 g' was: 3 g: 3 g'>20 : 1。
1(400 MHz, CDCl3) 1.26 (t,J= 7.2 Hz, 3H), 3.84 (s, 3H), 4.22 (q,J= 7.2 Hz, 2H), 7.21-7.27 (m, 3H), 7.40-7.42 (m, 1H), 7.56 (s, 1H);13C NMR(100 MHz, CDCl3) 14.3, 60.4, 62.0, 110.2, 126.3, 128.9, 129.3, 132.1,132.3, 134.5, 160.1, 167.0; HRMS (ESI) calcd. for C12H13ClNaO3[M+Na]:263.0445, found: 263.0456。
EXAMPLE 8 preparation of alkoxy acrylate derivatives 3h and 3h
The synthetic route is as follows:
Figure 53636DEST_PATH_IMAGE014
acetal 1h (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3h and 3 h'. The product was a colorless oil with a total yield of 68%, and the molar ratio of 3h to 3 h' was: 3 h: 3 h' = 10: 1.
1(400 MHz, CDCl3) 1.30 (t,J= 7.2 Hz, 3H), 3.86 (s, 3H), 4.24 (q,J= 7.2 Hz, 2H), 7.21-7.29 (m, 3H), 7.35 (s, 1H), 7.55 (s, 1H);13C NMR (100MHz, CDCl3) 14.4, 60.5, 62.1, 110.6, 127.1, 128.4, 128.9, 130.3, 133.5,134.4, 159.9, 167.2; HRMS (ESI) calcd. for C12H13ClNaO3[M+Na]: 263.0445,found: 263.0453。
Example 9 preparation of alkoxy acrylate derivatives 3i and 3i
The synthetic route is as follows:
Figure 305626DEST_PATH_IMAGE015
acetal 1i (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of carbon tetrachloride at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3i and 3 i'. The product was a colorless oil with a total yield of 68%, and the molar ratio of 3i to 3 i' was: 3 i: 3 i' = 13: 1.
1(400 MHz, CDCl3) 1.29 (t,J= 6.8 Hz, 3H), 3.86 (s, 3H), 4.24 (q,J= 7.2 Hz, 2H), 7.26-7.32 (m, 4H), 7.55 (s, 1H);13C NMR (100 MHz, CDCl3)14.4, 60.4, 62.1, 110.8, 127.9, 131.0, 131.6, 132.8, 159.7, 167.3; HRMS (ESI)calcd. for C12H13ClNaO3[M+Na]: 263.0445, found: 263.0452。
EXAMPLE 10 preparation of alkoxy acrylate derivatives 3j and 3j
The synthetic route is as follows:
Figure 769230DEST_PATH_IMAGE016
acetal 1j (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3j and 3 j'. The product was a colorless oil, totalYield 33%, molar ratio of 3j and 3 j': 3 j: 3 j' = 11: 1.
1(400 MHz, CDCl3) 1.27 (t,J= 7.2 Hz, 3H), 3.86 (s, 3H), 4.23 (q,J= 7.2 Hz, 2H), 7.04-7.14 (m, 2H), 7.23-7.31 (m, 2H), 7.59 (s, 1H);13C NMR(100 MHz, CDCl3) 14.3, 60.4, 62.0, 106.2, 115.5 (d,J= 22.0 Hz), 120.6 (d,J= 16.1 Hz), 123.5 (d,J= 3.5 Hz), 129.3 (d,J= 8.2 Hz), 132.3 (d,J= 3.5Hz), 160.4, 161.4 (d,J= 246.1 Hz), 167.0;19F NMR (376 MHz, CDCl3) -112.5;HRMS (ESI) calcd. for C12H13FNaO3[M+Na]: 247.0741, found: 247.0729。
EXAMPLE 11 preparation of alkoxy acrylate derivatives 3k and 3k
The synthetic route is as follows:
Figure 335341DEST_PATH_IMAGE017
acetal 1k (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of methylene chloride at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3k and 3 k'. The product was a colorless oil, overall yield 84%, and molar ratio of 3k to 3 k': 3k to 3 k'>20 : 1。
1(400 MHz, CDCl3) 1.18 (t,J= 7.2 Hz, 3H), 3.76 (s, 3H), 4.18 (q,J= 6.8 Hz, 2H), 7.33-7.34 (m, 1H), 7.41-7.49 (m, 3H), 7.73-7.75 (m, 2H),7.80-7.86 (m, 2H);13C NMR (100 MHz, CDCl3) 14.3, 60.3, 61.9, 110.4, 125.3,125.5, 125.6, 125.8, 128.1, 128.3, 128.4, 130.7, 132.1, 133.6, 160.4, 168.0;HRMS (ESI) calcd. for C16H16NaO3[M+Na]: 279.0992, found: 279.1003。
EXAMPLE 12 preparation of alkoxy acrylate derivatives 3l and 3l
The synthetic route is as follows:
Figure 699326DEST_PATH_IMAGE018
acetal 1l (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain 3l and 3 l' of the alkoxy acrylate derivatives. The product was a colorless oil, with a total yield of 66%, and the molar ratio of 3l to 3 l' was: 3 l: 3 l'>20 : 1。
1(400 MHz, CDCl3) 1.30 (t,J= 7.2 Hz, 3H), 3.85 (s, 3H), 4.27 (q,J= 6.8 Hz, 2H), 7.42-7.46 (m, 3H), 7.62 (s, 1H), 7.79-7.82 (m, 4H);13C NMR(100 MHz, CDCl3) 14.4, 60.4, 62.0, 111.9, 125.7, 125.8, 127.1, 127.6,128.1, 12 8.3, 129.3, 130.2, 132.5, 133.1, 159.7, 167.8; HRMS (ESI) calcd.for C16H16NaO3[M+Na]: 279.0992, found: 279.0993。
EXAMPLE 13 preparation of alkoxy acrylate derivatives 3m and 3m
The synthetic route is as follows:
Figure 122217DEST_PATH_IMAGE019
acetal 1m (0.5 mmol), ethyl diazoformate 2a (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of tetrahydrofuran at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3m and 3 m'. The product was a colorless oil, with an overall yield of 34%, and a molar ratio of 3m to 3 m': 3 m: 3 m' =1: 1.
1(400 MHz, CDCl3) 1.24 (t,J= 7.2 Hz, 3H), 1.36 (t,J= 7.2 Hz,3H), 3.59 (s, 2H), 4.10 (q,J= 3.6 Hz, 2H), 4.15 (q,J= 7.2 Hz, 2H), 7.13-7.28 (m, 5H), 7.46 (s, 1H);13C NMR (100 MHz, CDCl3) 14.3, 15.5, 29.8, 59.9,70.1, 110.3, 125.7, 128.1, 128.6, 141.0, 157.8, 168.3; HRMS (ESI) calcd. forcalcd. C14H18NaO3[M+Na]: 257.1148, found: 257.1145。
EXAMPLE 14 preparation of alkoxy acrylate derivatives 3n and 3n
The synthetic route is as follows:
Figure 509336DEST_PATH_IMAGE020
acetal 1b (0.5 mmol), methyl diazoformate 2b (0.6 mmol) and AgSbF6(0.025 mmol) was added to 0.5mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3n and 3 n'. The product was a colorless oil, overall yield 85%, and molar ratio of 3n to 3 n': 3n to 3 n'>20 : 1。
1(400 MHz, CDCl3) 2.18 (s, 3H), 3.69 (s, 3H), 3.81 (s, 3H), 7.10-7.11 (m, 1H), 7.16-7.23 (m, 3H), 7.56 (s, 1H);13C NMR (100 MHz, CDCl3)19.7, 51.6, 61.8, 111.3, 125.4, 127.8, 129.8, 130.6, 132.3, 137.2, 159.6,168.3。
EXAMPLE 15 preparation of alkoxy acrylate derivatives 3o and 3o
The synthetic route is as follows:
Figure 941455DEST_PATH_IMAGE021
acetal 1n (0.5 mmol), methyl diazoformate 2b (0.6 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and separating by column chromatography, wherein the volume ratio of the eluent is acetic acidPetroleum ether =1:50 to 1:10, yielding alkoxy acrylate derivatives 3o and 3 o'. The product was a colorless oil with an overall yield of 51%, and the molar ratio of 3o to 3 o' was: 3o to 3'>20 : 1。
1(400 MHz, CDCl3) 3.70 (s, 3H), 3.83 (s, 3H), 4.41 (s, 2H), 7.11-7.16 (m, 1H), 7.28-7.34 (m, 2H), 7.45-7.49 (m, 1H), 7.64 (s, 1H);13C NMR (100MHz, CDCl3) 31.9, 51.7, 62.0, 109.8, 128.5, 130.3, 131.5, 132.6, 136.6,160.5, 167.8。
EXAMPLE 16 preparation of alkoxy acrylate derivatives 5a and 5a
The synthetic route is as follows:
Figure 392902DEST_PATH_IMAGE022
ketal 4a (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5a and 5 a'. The product was a colorless oil with an overall yield of 82%, and the molar ratio of 5a to 5 a' was: 5 a: 5 a' = 4: 1.
1(400 MHz, CDCl3) 1.18 (t,J= 7.2 Hz, 3H), 2.49 (s, 3H), 3.61 (s,3H), 4.15 (q,J= 7.2 Hz, 2H), 7.16-7.29 (m, 3H), 7.29-7.33 (m, 2H);13C NMR(100 MHz, CDCl3) 14.2, 15.2, 55.3, 60.1, 112.9, 126.3, 127.6, 130.3, 136.2,165.1, 169.0; HRMS (ESI) calcd. for C13H16O3Na [M+Na]: 243.0992, found:243.0990。
1(400 MHz, CDCl3) 1.22 (t,J= 7.2 Hz, 3H), 1.89 (s, 3H), 3.79 (s,3H), 4.18 (q,J= 6.8 Hz, 2H), 7.20-7.28 (m, 3H), 7.31-7.35 (m, 2H);13C NMR(100 MHz, CDCl3) 14.2, 15.5, 56.1, 60.2, 113.6, 126.9, 128.2, 130.3, 136.9,160.8, 167.4; HRMS (ESI) calcd. for C13H16O3Na [M+Na]: 243.0992, found:243.0990。
EXAMPLE 17 preparation of alkoxy acrylate derivatives 5b and 5b
The synthetic route is as follows:
Figure 252274DEST_PATH_IMAGE023
ketal 4b (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 2.0mL of 1, 2-dichloroethane at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5b and 5 b'. The product was a colorless oil with 90% overall yield, and the molar ratio of 5b to 5 b' was: 5 b: 5 b' = 3: 1.
1(400 MHz, CDCl3) 1.19 (t,J= 6.8 Hz, 3H), 2.34 (s, 3H), 2.47 (s,3H), 3.61 (s, 3H), 4.15 (q,J= 7.2 Hz, 2H), 7.08 (d,J= 8.0 Hz, 2H), 7.13(d,J= 8.0 Hz, 2H);13C NMR (100 MHz, CDCl3) 14.3, 15.3, 21.3, 55.3, 60.1,112.7, 128.5, 130.1, 133.1, 135.9, 164.9, 169.2; HRMS (ESI) calcd. forC14H18O3Na [M+Na]: 257.1148, found: 257.1145。
1(400 MHz, CDCl3) 1.22 (t,J= 7.2 Hz, 3H), 1.88 (s, 3H), 2.34 (s,3H), 3.77 (s, 3H), 4.18 (q,J= 7.2 Hz, 2H), 7.11 (d,J= 8.4 Hz, 2H), 7.14(d,J= 8.4 Hz, 2H);13C NMR (100 MHz, CDCl3) 14.3, 15.4, 21.2, 56.1, 60.2,113.6, 128.9, 130.0, 133.8, 136.5, 160.3, 167.6; HRMS (ESI) calcd. forC14H18O3Na [M+Na]: 257.1148, found: 257.1148。
EXAMPLE 18 preparation of alkoxy acrylate derivatives 5c and 5c
The synthetic route is as follows:
Figure 861110DEST_PATH_IMAGE024
ketal 4c (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5c and 5 c'. The product was a colorless oil, overall yield 77%, molar ratio of 5c and 5 c': 5 c: 5 c' = 2: 1.
1(400 MHz, CDCl3) 1.20 (t,J= 6.8 Hz, 3H), 2.46 (s, 3H), 3.62 (s,3H), 3.81 (s, 3H), 4.16 (q,J= 7.2 Hz, 2H), 6.87 (d,J= 8.8 Hz, 2H),7.12(d,J= 8.4 Hz, 2H);13C NMR (100 MHz, CDCl3) 14.3, 15.3, 55.1, 55.3, 60.1,112.4, 113.1, 128.4, 131.3, 158.0, 164.7, 169.3; HRMS (ESI) calcd. forC14H18O4Na [M+Na]: 273.1097, found: 273.1096。
1(400 MHz, CDCl3) 1.23 (t,J= 6.8 Hz, 3H), 1.88 (s, 3H), 3.78 (s,3H), 3.81 (s, 3H), 4.18 (q,J= 6.8 Hz, 2H), 6.87 (d,J= 8.8 Hz, 2H), 7.14(d,J= 8.8 Hz, 2H);13C NMR (100 MHz, CDCl3) 14.3, 15.4, 55.2, 56.1, 60.2,113.2, 113.6, 129.1, 131.3, 158.5, 160.4, 167.7; HRMS (ESI) calcd. forC14H18O4Na [M+Na]: 273.1097, found: 273.1094。
EXAMPLE 19 preparation of alkoxy acrylate derivatives 5d and 5d
The synthetic route is as follows:
Figure 96919DEST_PATH_IMAGE025
the ketal 4d (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating solvent, separating by column chromatography, and eluting with eluentThe volume ratio of ethyl acetate to petroleum ether =1: 50-1: 5, thereby obtaining alkoxy acrylate derivatives 5d and 5 d'. The product was a colorless oil with an overall yield of 76%, and the molar ratio of 5a to 5 a' was: 5 d: 5 d' = 3: 1.
1(400 MHz, CDCl3) 1.18 (t,J= 6.8 Hz, 3H), 2.49 (s, 3H), 3.62 (s,3H), 4.14 (q,J= 6.8 Hz, 2H), 6.97-7.01 (m, 2H), 7.11-7.15 (m, 2H);13C NMR(100 MHz, CDCl3) 14.2, 15.1, 55.2, 60.1, 111.7, 114.6 (d,J= 21.0 Hz),131.9 (d,J= 7.9 Hz), 132.1 (d,J= 3.5 Hz), 162.6 (d,J= 243.1 Hz), 165.7,168.8;19F NMR (376 MHz, CDCl3) -116.5; HRMS (ESI) calcd. for C13H15FO3Na [M+Na]: 261.0897, found: 261.0891。
1(400 MHz, CDCl3) 1.22 (t,J= 7.2 Hz, 3H), 1.87 (s, 3H), 3.80 (s,3H), 4.17 (q,J= 7.2 Hz, 2H), 6.98-7.04 (m, 2H), 7.14-7.20 (m, 2H);13C NMR(100 MHz, CDCl3) 14.2, 15.6, 56.2, 60.2, 112.3, 115.2 (d,J= 21.2 Hz),132.0 (d,J= 7.9 Hz), 132.9 (d,J= 3.5 Hz), 161.4, 163.1 (d,J= 244.2 Hz),167.1;19F NMR (376 MHz, CDCl3) -115.6; HRMS (ESI) calcd. for C13H15FO3Na [M+Na]: 261.0897, found: 261.0892。
EXAMPLE 20 preparation of alkoxy acrylate derivatives 5e and 5e
The synthetic route is as follows:
Figure 169917DEST_PATH_IMAGE026
the ketal 4e (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5e and 5 e'. The product was a colorless oil, overall yield 77The molar ratio of 5e to 5 e' is: 5 e: 5 e' = 4: 1.
1(400 MHz, CDCl3) 1.18 (t,J= 7.2 Hz, 3H), 2.50 (s, 3H), 3.63 (s,3H), 4.14 (q,J= 7.2 Hz, 2H), 7.11 (d,J= 8.8 Hz, 2H), 7.28 (d,J= 8.4 Hz,2H);13C NMR (100 MHz, CDCl3) 14.2, 15.1, 55.2, 60.1, 111.5, 127.9, 131.8,132.1, 134.7, 165.9, 168.5; HRMS (ESI) calcd. for C13H15ClO3Na [M+Na]:277.0602, found: 277.0595。
1(400 MHz, CDCl3) 1.21 (t,J= 7.2 Hz, 3H), 1.88 (s, 3H), 3.80 (s,3H), 4.17 (q,J= 6.8 Hz, 2H), 7.15 (d,J= 8.4 Hz, 2H), 7.31 (d,J= 8.4 Hz,2H);13C NMR (100 MHz, CDCl3) 14.2, 15.6, 56.2, 60.2, 112.2, 128.4, 131.7,132.9, 135.5, 161.7, 166.9; HRMS (ESI) calcd. for C13H16ClO3[M+H]: 255.0782,found: 255.0790。
EXAMPLE 21 preparation of alkoxy acrylate derivatives 5f and 5f
The synthetic route is as follows:
Figure 137873DEST_PATH_IMAGE027
ketal 4f (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5f and 5 f'. The product was a colorless oil with an overall yield of 68% and a molar ratio of 5f to 5 f' of: 5 f: 5 f' = 3: 1.
1(400 MHz, CDCl3) 1.18 (t,J= 6.8 Hz, 3H), 2.49 (s, 3H), 3.62 (s,3H), 4.14 (q,J= 7.2 Hz, 2H), 7.06 (d,J= 8.4 Hz, 2H), 7.43 (d,J= 8.4 Hz,2H);13C NMR (100 MHz, CDCl3) 14.3, 15.1, 55.2, 60.1, 111.5, 120.3, 130.8,132.2, 135.3, 165.9, 168.4; HRMS (ESI) calcd. for C13H15BrO3Na [M+Na]:321.0097, found: 321.0087。
1(400 MHz, CDCl3) 1.21 (t,J= 7.2 Hz, 3H), 1.88 (s, 3H), 3.80 (s,3H), 4.17 (q,J= 7.2 Hz, 2H), 7.09 (d,J= 8.4 Hz, 2H), 7.46 (d,J= 8.4 Hz,2H);13C NMR (100 MHz, CDCl3) 14.2, 15.7, 56.2, 60.3, 112.1, 121.0, 131.4,132.1, 136.0, 161.7, 166.8; HRMS (ESI) calcd. for C13H15BrO3Na [M+Na]:321.0097, found: 321.0085。
EXAMPLE 22 preparation of alkoxy acrylate derivatives 5g and 5g
The synthetic route is as follows:
Figure 797787DEST_PATH_IMAGE028
4g (0.5 mmol) of ketal, ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, to obtain 5g and 5 g' of the alkoxy acrylate derivative. The product was a colorless oil with a total yield of 40%, and the molar ratio of 5g to 5 g' was: 5 g: 5 g' = 2: 1.
1(400 MHz, CDCl3) 0.99 (t,J= 7.2 Hz, 3H), 2.65 (s, 3H), 3.49 (s,3H), 4.04 (q,J= 7.2 Hz, 2H), 7.26 (d,J= 3.6 Hz, 1H), 7.27-7.47 (m, 3H),7.73-7.78 (m, 2H), 7.82-7.85 (m, 1H);13C NMR (100 MHz, CDCl3) 14.1, 15.2,55.3, 59.9, 110.1, 125.3, 125.4, 125.4, 125.5, 127.1, 127.9, 128.2, 132.7,133.6, 134.4, 167.3, 168.9; HRMS (ESI) calcd. for C17H18O3Na [M+Na]: 293.1148,found: 293.1145。
1(400 MHz, CDCl3) 1.07 (t,J= 7.2 Hz, 3H), 1.72 (s, 3H), 3.89 (s,3H), 4.08 (q,J= 6.8 Hz, 2H), 7.33-7.35 (m, 1H), 7.43-7.49 (m, 3H), 7.79-7.87 (m, 2H), 7.91-7.94 (m, 1H);13C NMR (100 MHz, CDCl3) 14.2, 16.0, 56.3,59.9, 110.0, 125.5, 125.5, 125.7, 126.1, 127.8, 128.3, 128.5, 133.0, 133.8,134.9, 163.6, 166.9; HRMS (ESI) calcd. for C17H18O3Na [M+Na]: 293.1148, found:293.1150。
Example 23 preparation of alkoxy acrylate derivatives 5h and 5h
The synthetic route is as follows:
Figure 509391DEST_PATH_IMAGE029
the ketal 4h (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5h and 5 h'. The product was a colorless oil, overall yield 82%, molar ratio of 5h and 5 h': 5 h: 5 h' = 3: 1.
1(400 MHz, CDCl3) 1.12-1.16 (m, 3H), 2.52 (s, 3H), 3.58 (s, 3H),4.09-4.15 (m, 2H), 7.30-7.32 (m, 1H), 7.41-7.43 (m, 2H), 7.65 (s, 1H), 7.76-7.81 (m, 3H);13C NMR (100 MHz, CDCl3) 14.3, 15.3, 55.4, 60.1, 112.7, 125.5,125.6, 126.9, 127.6, 128.0, 129.0, 129.1, 132.2, 133.3, 133.9, 165.8, 169.0;HRMS (ESI) calcd. for C17H18O3Na [M+Na]: 293.1148, found: 293.1144。
1(400 MHz, CDCl3) 1.21 (t,J= 7.2 Hz, 3H), 1.93 (s, 3H), 3.83 (s,3H), 4.19 (q,J= 7.2 Hz, 2H), 7.33-7.36 (m, 1H), 7.44-7.49 (m, 2H), 7.67 (m,1H), 7.79-7.84 (m, 3H);13C NMR (100 MHz, CDCl3) 14.3, 15.7, 56.2, 60.2,113.4, 125.9, 126.0, 127.6, 127.7, 127.9, 128.6, 129.0, 132.3, 133.3, 134.5,161.4, 167.4; HRMS (ESI) calcd. for C17H18O3Na [M+Na]: 293.1148, found:293.1145。
EXAMPLE 24 preparation of alkoxy acrylate derivatives 5i and 5i
The synthetic route is as follows:
Figure 436896DEST_PATH_IMAGE030
ketal 4i (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5i and 5 i'. The product was a colorless oil, with a total yield of 52%, and the molar ratio of 5i to 5 i' was: 5 i: 5 i' = 2: 1.
1H NMR (400 MHz, CDCl3) 1.26 (t,J= 7.2 Hz, 3H), 3.72 (s, 3H),4.13-4.26 (m, 2H), 4.92 (s, 1H), 5.84 (s, 1H), 7.17-7.25 (m, 3H), 7.26-7.33(m, 7H);13C NMR (100 MHz, CDCl3) 14.2, 52.4, 55.2, 61.2, 102.3, 126.1,127.2, 128.3, 128.4, 129.1, 129.1, 136.6, 136.8, 155.5, 171.1; HRMS (ESI)calcd. for C19H20O3Na [M+Na]: 319.1305, found: 319.1296。
1H NMR (400 MHz, CDCl3) 1.22-1.29 (m, 3H), 3.58 (s, 1.1H), 3.72 (s,1.9H), 4.12-4.29 (m, 2H), 4.66 (s, 0.4H), 4.92 (s, 0.6H), 5.61 (s, 0.4H),5.83 (s, 0.6H), 7.14-7.50 (m, 10H);13C NMR (100 MHz, CDCl3) 14.2, 14.2,52.4, 55.2, 56.0, 58.0, 61.2, 61.4, 102.3, 112.8, 126.1, 126.6, 127.2, 127.8,128.2, 128.3, 128.4, 128.7, 128.7, 129.1, 129.1, 135.3, 135.9, 136.6, 136.8,154.9, 155.5, 171.1, 171.2; HRMS (ESI) calcd. for C19H20O3Na [M+Na]: 319.1305,found: 319.1299。
EXAMPLE 25 preparation of alkoxy acrylate derivatives 5j and 5j
The synthetic route is as follows:
Figure 638070DEST_PATH_IMAGE031
ketal 4j (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.01 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5j and 5 j'. The product was a colorless oil with an overall yield of 68%, and the molar ratio of 5j to 5 j' was: 5 j: 5 j' =1: 1.
+5j’:1H NMR (400 MHz, CDCl3) 0.88 (t,J= 7.2 Hz, 1.7H), 1.32 (t,J= 7.2 Hz, 1.3H), 3.39 (s, 1.8H), 3.52 (s, 1.2H), 3.93 (q,J= 6.8 Hz, 1.1H),4.32 (q,J= 7.2 Hz, 0.8H), 7.02-7.04 (m, 0.8H), 7.04-7.13 (m, 1.2H), 7.21-7.30 (m, 3H), 7.35-7.43 (m, 5H);13C NMR (100 MHz, CDCl3) 13.6, 14.3, 57.8,58.2, 60.4, 60.8, 116.6, 118.9, 126.8, 127.0, 128.0, 128.0, 128.2, 128.3,128.9, 129.1, 129.3, 129.6, 130.1, 130.1, 132.8, 134.6, 135.3, 135.4, 159.0,162.2, 168.6, 169.1; HRMS (ESI) calcd. for C18H18O3Na [M+Na]: 305.1148, found:305.1142。
EXAMPLE 26 preparation of alkoxy acrylate derivatives 5k and 5k
The synthetic route is as follows:
Figure 283815DEST_PATH_IMAGE032
ketal 4k (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5k and 5 k'. The product was a colorless oil with an overall yield of 89%, and the molar ratio of 5k to 5 k' was: 5 k: 5 k' = 3: 1.
:1H NMR (400 MHz, CDCl3) 1.14 (t,J= 6.8 Hz, 3H), 1.19 (t,J= 7.2Hz, 3H), 2.45 (s, 3H), 3.92 (q,J= 6.8 Hz, 2H), 4.15 (q,J= 6.8 Hz, 2H),7.18-7.23 (m, 3H), 7.27-7.31 (m, 2H);13C NMR (100 MHz, CDCl3) 14.3, 15.1,15.9, 60.0, 63.6, 113.5, 126.2, 127.5, 130.3, 136.4, 164.5, 169.2; HRMS (ESI)calcd. for C14H19O3[M+H]: 235.1329, found: 235.1318。
1(400 MHz, CDCl3) 1.25 (t,J= 6.8 Hz, 3H), 1.38 (t,J= 7.2 Hz,3H), 1.88 (s, 3H), 4.06 (q,J= 6.8 Hz, 2H), 4.20 (q,J= 7.2 Hz, 2H), 7.22-7.27 (m, 3H), 7.31-7.37 (m, 2H);13C NMR (100 MHz, CDCl3) 14.3, 15.3, 15.9,60.2, 64.4, 114.5, 126.9, 128.2, 130.2, 136.8, 159.6, 167.7; HRMS (ESI)calcd. for C14H19O3[M+H]: 235.1329, found: 235.1328。
EXAMPLE 27 preparation of alkoxy acrylate derivatives 5l and 5l
The synthetic route is as follows:
Figure 533531DEST_PATH_IMAGE033
4l of ketal (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 1 hour of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain 5l and 5 l' of the alkoxy acrylate derivatives. The product was a colorless oil, with an overall yield of 67%, and a molar ratio of 5l to 5 l': 5 l: 5 l' = 2: 1.
1(400 MHz, CDCl3) 1.27 (t,J= 7.2 Hz, 3H), 1.30 (t,J= 6.8 Hz,3H), 2.35 (s, 3H), 4.03 (q,J= 6.8 Hz, 2H), 4.25 (q,J= 7.2 Hz, 2H), 6.38-6.40 (m, 2H), 7.35 (m, 1H);13C NMR (100 MHz, CDCl3) 14.2, 15.2, 16.0, 60.5,64.0, 104.7, 109.3, 110.5, 140.4, 148.6, 163.6, 168.1; HRMS (ESI) calcd. forC12H16O4Na [M+Na]: 247.0941, found: 247.0938。
1(400 MHz, CDCl3) 1.29 (t,J= 6.8 Hz, 3H), 1.36 (t,J= 7.2 Hz,3H), 2.07 (s, 3H), 4.07 (q,J= 7.2 Hz, 2H), 4.25 (q,J= 7.2 Hz, 2H), 6.17-6.18 (m, 1H), 6.37-6.39 (m, 1H), 7.38-7.39 (m, 1H);13C NMR (100 MHz, CDCl3)14.2, 15.2, 15.8, 60.8, 64.1, 109.0, 124. 3, 125.2, 125.7, 136.5, 158.2,168.8; HRMS (ESI) calcd. for C12H16O4Na [M+Na]: 247.0941, found: 247.0934。
EXAMPLE 28 preparation of alkoxy acrylate derivatives 5m and 5m
The synthetic route is as follows:
Figure 79656DEST_PATH_IMAGE034
ketal 4m (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 1 hour of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5m and 5 m'. The product was a colorless oil, with an overall yield of 73%, and a molar ratio of 5m to 5 m': 5 m: 5 m' = 2: 1.
1(400 MHz, CDCl3) 1.33 (t,J= 7.2 Hz, 3H), 1.39 (t,J= 7.2 Hz,3H), 2.27 (s, 3H), 4.10 (q,J= 6.8 Hz, 2H), 4.31 (q,J= 7.2 Hz, 2H), 6.94-6.98 (m, 2H), 7.19-7.20 (m, 1H);13C NMR (100 MHz, CDCl3) 14.2, 15.2, 15.8,60.8, 64.1, 109.0, 124.3, 125.2, 125.7, 136.5, 158.2, 168.8; HRMS (ESI)calcd. for C12H16O3SNa [M+Na]: 263.0712, found: 263.0714。
1(400 MHz, CDCl3) 1.28 (t,J= 7.2 Hz, 3H), 1.37 (t,J= 6.8 Hz,3H), 2.01 (s, 3H), 4.07 (q,J= 6.8 Hz, 2H), 4.22 (q,J= 6.8 Hz, 2H), 6.84-6.85 (m, 1H), 6.96-6.99 (m, 1H), 7.26-7.28 (m, 1H);13C NMR (100 MHz, CDCl3)14.2, 15.2, 16.1, 60.4, 64.6, 107.0, 125.7, 126.7, 127.7, 138.1, 161.6,167.1; HRMS (ESI) calcd. for C12H16O3SNa [M+Na]: 263.0712, found: 263.0705。
Example 29 preparation of alkoxy acrylate derivatives 5n and 5n
The synthetic route is as follows:
Figure 451732DEST_PATH_IMAGE035
ketal 4n (0.5 mmol), ethyl diazoformate 2c (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5n and 5 n'. The product was a colorless oil with 65% overall yield, and the molar ratio of 5n to 5 n' was: 5 n: 5 n' = 4: 1.
1(400 MHz, CDCl3) 1.41 (s, 9H), 2.33 (s, 3H), 2.39 (s, 3H), 3.58(s, 3H), 7.09 (s, 4H);13C NMR (100 MHz, CDCl3) 15.4, 21.2, 28.2, 55.3,80.0, 114.7, 128.3, 129.9, 133.5, 135.6, 162.4, 168.8; HRMS (ESI) calcd. forC16H22O3Na [M+Na]: 285.1461, found: 285.1451。
1(400 MHz, CDCl3) 1.36 (s, 9H), 1.80 (s, 3H), 2.26 (s, 3H), 3.68(s, 3H), 7.01-7.06 (m, 4H);13C NMR (100 MHz, CDCl3) 15.3, 21.2, 28.2, 56.1,80.1, 115.9, 128.8, 129.8, 134.0, 136.3, 158.3, 167.3; HRMS (ESI) calcd. forC16H22O3Na [M+Na]: 285.1461, found: 285.1449。
EXAMPLE 30 preparation of alkoxy acrylate derivatives 5o and 5o
The synthetic route is as follows:
Figure 522456DEST_PATH_IMAGE036
ketal 4o (0.5 mmol), ethyl diazoformate 2a (1.0 mmol) and AgSbF6(0.005 mmol) was added to 1.0mL of chloroform at 120oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5a and 5 a'. The product was a colorless oil in 47% yield.
1(400 MHz, CDCl3) 1.31 (t,J= 7.2 Hz, 3H), 1.53-1.62 (m, 4H),1.72-1.78 (m, 2H), 2.37-2.40 (m, 2H), 2.42-2.45 (m, 2H), 3.63 (s, 3H), 4.21(q,J= 7.2 Hz, 2H);13C NMR (100 MHz, CDCl3) 14.3, 24.8, 26.8, 27.7, 30.7,31.8, 56.9, 60.0, 115.3, 167.3, 168.8; HRMS (ESI) calcd. for C11H19O3[M+H]:199.1329, found: 199.1324。
Example 31 gram-Scale preparation of alkoxy acrylate derivatives 5b and 5b
The synthetic route is as follows:
Figure 638180DEST_PATH_IMAGE037
the ketal 4b (10 mmol), ethyl diazoformate 2a (20 mmol) and AgSbF6(0.01 mmol) was added to 10 mL of chloroform at 100oAfter 4 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 5b and 5 b'. The product was a colorless oil, 1.4 g, total yield 60%, molar ratio of 5b and 5 b': 5 b: 5 b' = 3: 1.
Example 32 preparation of picoxystrobin 6
The total yield is 65%, and the synthetic route is as follows:
Figure 540276DEST_PATH_IMAGE038
the first step is as follows: preparation of Acetal 1b
2-methylbenzaldehyde (30 mmol) and trimethyl orthoformate (30 mmol) were added to 15 mL of methanol, followed by dropwise addition of 50uL of concentrated sulfuric acid. After stirring at room temperature for 24 hours, the reaction was stopped. 30% sodium hydroxide aqueous solution (3.0 mL) was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on neutral alumina, petroleum ether was used as eluent, to give pure acetal 1b as a colorless liquid in 86% yield.
The second step is that: preparation of the alkoxy acrylates 3n
Acetal 1b (0.5 mmol), methyl diazoformate 2b (0.6 mmol) and AgSbF6(0.025 mmol) was added to 1.0mL of chloroform at 100oAfter 3 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 10, so as to obtain alkoxy acrylate derivatives 3n and 3 n'. The product was a colorless oil, overall yield 85%, and molar ratio of 3n to 3 n': 3n to 3 n'>20 : 1。
The third step: preparation of methoxyacrylate 3o
A mixture of methoxyacrylate 3n (1.0 mmol), azobisisobutyronitrile (AIBN, 0.1 mmol) andNbromo-succinimide (NBS, 1.2 mmol) was added to 2.0mL of carbon tetrachloride. At 80oAfter 3 hours of reaction under C, the reaction was stopped, and the solvent was distilled off under reduced pressure. And (3) performing column chromatography separation and purification on the residue by using silica gel, wherein the volume ratio of the eluent to the ethyl acetate to the petroleum ether is =1: 50-1: 10, so that the pure product of the methoxyacrylate is 3o, and the yield is 91%.
The fourth step: preparation of picoxystrobin 6
The methoxyacrylate compound 3o (1.0 mmol), 6-trifluoromethyl-2-hydroxypyridine (1.3 mmol) and potassium carbonate (2.0mmol) were added to 5.0 mL of DMF at 50oAfter 24 hours of reaction in the oil bath of C, the reaction was stopped and cooled to room temperature. Adding 20 mL of water and 20 mL of ethyl acetate into the reaction solution for extraction, washing the water phase with 20 mL of ethyl acetate for 3 times, combining the organic phases, washing with 20 mL of saturated sodium chloride, and washing the organic phase withDried over anhydrous sodium sulfate. Filtering, evaporating the solvent under reduced pressure, and performing column chromatography separation and purification on the residue by using silica gel, wherein the volume ratio of the eluent to the ethyl acetate to the petroleum ether is =1: 20-1: 10, so that the picoxystrobin 6 is obtained, and the yield is 98%.
1(400 MHz, CDCl3) 3.67 (s, 3H), 3.81 (s, 3H), 5.33 (s, 2H), 6.89(d,J= 8.4 Hz, 1H), 7.18-7.24 (m, 2H), 7.32-7.36 (m, 2H), 7.55-7.59 (m, 2H),7.70 (t,J= 7.6 Hz, 1H);13C NMR (100 MHz, CDCl3) 51.6, 61.9, 66.3, 110.2,113.3 (d,J= 3.3 Hz), 114.7, 122.8 (d,J= 271.9 Hz), 127.9 (d,J= 4.7 Hz),128.9, 131.1, 132.3, 135.7, 139.4, 145.9 (q,J= 34.4 Hz), 160.0, 163.6,168.0;19F NMR (376 MHz, CDCl3) -68.4。
Example 33 preparation of azoxystrobin 8
The total yield is 56%, and the synthetic route is as follows:
Figure 584718DEST_PATH_IMAGE039
the first step is as follows: preparation of Acetal 1o
2-hydroxybenzaldehyde (10 mmol) and trimethyl orthoformate (10 mmol) were added to 15 mL of methanol followed by 0oTetrachlorinated peptide (0.5 mmol) and triethylamine (1.2 mmol) were added dropwise to the mixture at C. After stirring at room temperature for 3 hours, the reaction was stopped. The reaction solution was neutralized by adding a saturated potassium carbonate solution, extracted with 10 mL of a saturated aqueous sodium chloride solution and 10 mL of dichloromethane, and the aqueous phase was washed 3 times with 10 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give pure acetal 1o as a yellow liquid in 86% yield.
1(400 MHz, CDCl3) 8.07 (s, 1H), 7.26 – 7.15 (m, 2H), 6.88 (d,J=7.5 Hz, 1H), 5.55 (s, 1H), 3.38 (s, 6H);13C NMR (100 MHz, CDCl3) 155.69,130.26, 128.39, 119.68, 116.97, 104.52, 52.78。
The second step is that: preparation of methoxyacrylate 3p
Subjecting an acetal to a reaction1o (0.5 mmol), methyl diazoformate 2b (0.6 mmol) and AgSbF6(0.025 mmol) was added to 1.0mL of chloroform at 50oAfter 24 hours of reaction in an oil bath, the reaction was stopped. Evaporating the solvent to dryness, and performing column chromatography separation, wherein the volume ratio of the used eluent to ethyl acetate to petroleum ether =1: 50-1: 5, so as to obtain alkoxy acrylate derivatives 3p and 3 p'. The product was a colorless oil, with an overall yield of 81%, and the molar ratio of 3p to 3 p' was: 3p to 3'>20 : 1。
1(400 MHz, CDCl3) 7.73 (s, 1H), 7.13 – 7.04 (m, 2H), 6.99 – 6.93(m, 2H), 6.69 (s, 1H), 3.77 (s, 3H), 3.68 (s, 3H);13C NMR (100 MHz, CDCl3)167.60, 158.40, 154.60, 131.03, 129.33, 122.50, 122.24, 118.75, 99.98, 63.60,52.34。
The third step: preparation of pyrimidine Compound 7
2-Hydroxybenzonitrile (10 mmol), 4, 6-dichloropyrimidine (20 mmol) and potassium carbonate (11 mmol) were added to 10 mL of DMF at 50oAfter 24 hours of reaction in the oil bath of C, the reaction was stopped and cooled to room temperature. 30 mL of water and 30 mL of ethyl acetate were added to the reaction solution to extract, and the aqueous phase was washed 3 times with 30 mL of ethyl acetate. And (2) combining organic phases, washing the organic phases once with 30 mL of saturated sodium chloride, drying the organic phases with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing column chromatography separation and purification on the residue by using silica gel, wherein the volume ratio of the eluent is ethyl acetate to petroleum ether =1: 20-1: 5, so that the pure pyrimidine compound 7 is obtained, the product is a white solid, and the yield is 87%.
1(400 MHz, CDCl3) 8.55 (d,J= 5.6 Hz, 1H), 7.77 – 7.67 (m, 2H),7.45 – 7.34 (m, 2H), 7.05 (d,J= 5.6 Hz, 1H);13C NMR (100 MHz, CDCl3)169.08, 160.88, 160.31, 153.19, 134.40, 133.72, 126.64, 123.03, 115.00,107.39, 107.10。
The fourth step: preparation of azoxystrobin 8
The methoxyacrylate compound 3p (1.0 mmol), the pyrimidine compound 7 (1.3 mmol) and potassium carbonate (2.0mmol) were added to 5.0 mL of DMF at 50oAfter 24 hours of reaction in the oil bath of C, the reaction was stopped and cooled to room temperature. 20 mL of water and 20mL of ethyl acetate was added to the reaction mixture and extracted, and the aqueous phase was washed 3 times with 20 mL of ethyl acetate. And combining organic phases, washing the organic phases once with 20 mL of saturated sodium chloride, drying the organic phases with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing column chromatography separation and purification on the residue by using silica gel, wherein the volume ratio of the eluent is ethyl acetate to petroleum ether =1: 20-1: 5, so that the pure azoxystrobin 8 is obtained, and the yield is 95%.
1(400 MHz, CDCl3) 8.41 (s, 1H), 7.65-7.74 (m, 2H), 7.50 (s, 1H),7.22- 7.45 (m, 6H), 6.43 (s, 1H), 3.76 (s, 3H), 3.65 (s, 3H);13C NMR (100MHz, CDCl3) 168.84, 168.74, 167.15, 160.07, 158.43, 154.34, 152.02, 133.40,132.93, 131.04, 125.60, 124.12, 122.19, 121.55, 117.73, 115.57, 104.27,101.91, 90.92, 63.60, 52.34。

Claims (5)

1. A preparation method of alkoxy acrylate is characterized in that diazoformate and substituted acetal or ketal are used as raw materials, Lewis acid is used as a catalyst, and the reaction is carried out for 1 to 24 hours at 50 to 120 ℃ to generate an olefination reaction; after the reaction is finished, the solvent is pumped out, and the alkoxy acrylate compound can be obtained by column chromatography separation; the substituted acetal has the structural formula:
Figure DEST_PATH_IMAGE002
(ii) a The structural formula of the substituted ketal is:
Figure DEST_PATH_IMAGE004
or
Figure DEST_PATH_IMAGE006
Wherein: r is selected from C1～C20An aliphatic group of (a); r1And R3Is selected from C4～C30Aryl of (a); r4Is selected from C1～C20An aliphatic group of (a); r5Is selected from C1~C6An aliphatic group of (a); the structural formula of the diazo formate is as follows:
Figure DEST_PATH_IMAGE008
wherein: r2Is selected from C1～C20An aliphatic group of (a); the Lewis acid is one of silver hexafluorophosphate, silver hexafluoroantimonate, ytterbium trifluoromethanesulfonate hydrate, europium trifluoromethanesulfonate hydrate or bismuth trifluoromethanesulfonate hydrate.
2. The method according to claim 1, wherein the molar ratio of the diazoformate, the substituted acetal or ketal, and the catalyst is 1:1 to 2: 0.001 to 0.05.
3. The method of claim 1, wherein R is selected from the group consisting of methyl, ethyl, and tert-butyl; r1And R3Selected from phenyl, substituted phenyl, naphthyl, thienyl, furyl; r4Selected from benzyl, methyl, ethyl; the R is5Is selected from-CH2-、-CH2CH2-or-CH2CH2CH2-。
4. The method of claim 1, wherein R is2Selected from methyl, ethyl or tert-butyl.
5. The method of claim 1, wherein the solvent is tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2, 2-tetrachloroethane, 1, 2-dichloroethane, 1, 2-dibromoethane, or 1-bromon-butane.
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