CN115353521B - Synthesis method of complex 3' -spiro indolyl structure - Google Patents

Synthesis method of complex 3' -spiro indolyl structure Download PDF

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CN115353521B
CN115353521B CN202211100870.7A CN202211100870A CN115353521B CN 115353521 B CN115353521 B CN 115353521B CN 202211100870 A CN202211100870 A CN 202211100870A CN 115353521 B CN115353521 B CN 115353521B
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indolyl
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CN115353521A (en
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贺小龙
王周玉
钱珊
宋巧
黄清武
文幼午
李和平
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Sichuan North Hongguang Special Chemical Co ltd
Xihua University
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Xihua University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention belongs to the field of organic synthesis, and mainly relates to a synthesis method of a complex 3' -spiro-indolyl derivative. The implementation of two dearomatization reactions based on two molecules of aromatic fragments is an important means for constructing complex natural structures and drug molecules, and has not been studied so far. The invention provides a synthesis method of a complex 3 '-spiro-indolyl structure, which adopts onium salt of 3-position electrodeficient pyridine to react with 2-nitroindole or 2-nitrobenzofuran, further increases electrophilicity of pyridine part to promote intramolecular ring closing step, and realizes double dearomatization reaction to construct the complex 3' -spiro-indolyl structure.

Description

Synthesis method of complex 3' -spiro indolyl structure
Technical Field
The invention belongs to the field of organic synthesis, and mainly relates to a synthesis method of a complex 3' -spirocyclic lixividine derivative.
Background
The dearomatization reaction is an efficient means for synthesizing complex ring system structures, and has important application in the efficient synthesis of various natural products and pharmaceutically active intermediates. The two-time dearomatization reaction based on two molecules of aromatic fragments is an important means for constructing complex natural structures and drug molecules, and has not been studied so far.
Disclosure of Invention
The active methylene pyridinium salt is a precursor structure of pyridine She Lide, and previous researches by the inventor show that pyridine She Lide generated in situ under alkaline conditions can perform dearomatization cyclization reaction with the electric-deficient olefin, and an important intermediate of the indolicidines is constructed efficiently.
The above study achieved the aromatization of one molecule of pyridine She Lide, however, achieving a bimolecular aromatization reaction between two molecules is very challenging, and compared with one molecule dearomatization, the bimolecular dearomatization reaction energy barrier is higher, and the reaction is difficult to achieve.
Further studies by the inventors subsequently showed that an intramolecular double dearomatization reaction can be achieved under photocatalytic conditions ((s.—l. You et al angel. Chem. Int. Ed.2021,60, 7036-7040), however, noble metal photosensitizers are required for this reaction, which is expensive.
Aiming at the situation that only one molecular dearomatization or intramolecular double dearomatization can be realized at present, and two-molecular double dearomatization of pyridine She Lide and nitroaromatic hydrocarbon is not reported in literature or patent for constructing a complex polycyclic structure, the invention provides a synthetic method of a complex 3' -spiro-indolyl-doxycycline structure. The method provides a simple and efficient method for constructing the spiroindolizidine skeleton and provides a new strategy for developing the indolizidine alkaloid medicaments in the future.
The invention adopts the onium salt of 3-position electrodeficient pyridine to react with 2-nitroindole or 2-nitrobenzofuran, further increases the electrophilicity of pyridine part to promote the intermolecular ring closing step, and realizes double dearomatization reaction to construct complex 3' -spiro indolicidine structure.
The technical scheme of the invention is as follows:
reacting a compound shown in a formula I with a compound shown in a formula II in the presence of alkali to obtain a 3' -spiro-indolyl-doxycycline compound;
the reaction formula is as follows:
Figure SMS_1
wherein R is 1 Selected from hydrogen, halogen, alkoxy, alkyl; r is R 2 Halogen, alkoxy, alkyl; x is selected from O or NBoc; GWE is an electron withdrawing group; further, GWE is selected from the group consisting of-CO 2 Me、-CN、-Ac；
n has the values of 0, 1, 2, 3 and 4.
In the technical scheme of the invention, R 1 Selected from hydrogen, fluorine, chlorine, bromine, C1-C6 alkoxy, C1-C6 alkyl, R 2 Selected from fluorine, chlorine, bromine, C1-C6 alkoxy, C1-C6 alkyl; n has the values of 0, 1, 2, 3 and 4.
In the technical scheme of the invention, R 1 Selected from hydrogen, fluorine, chlorine, bromine, C1-C4 alkoxy, C1-C4 alkyl, R 2 Selected from fluorine, chlorine, bromine, C1-C4 alkoxy, C1-C4 alkyl; n has the values of 0, 1 and 2.
In the technical scheme of the invention, R 1 Selected from hydrogen, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, R 2 Selected from methoxy, ethoxy, methyl, ethyl; n has the values of 0, 1 and 2.
Prior to the present invention, the inventors have tried other nitro-substituted aromatic hydrocarbons, such as:
Figure SMS_2
Figure SMS_3
react with pyridine She Lide, however, the reaction does not occur. Indicating that not all nitro-substituted aromatic hydrocarbons can undergo such cyclization reactions; only the 2-nitroindole compounds and the 2-nitrobenzofuran compounds can realize double dearomatization.
In the technical scheme of the invention, the 3' -spiro indolyl-doxycycline compound is selected from one of the following structures:
Figure SMS_4
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Figure SMS_5
in the technical scheme of the invention, the solvent is Dichloromethane (DCM), toluene (Tol), tetrahydrofuran (THF), ethanol, chloroform (CHCl) 3 ) One or more of water; dichloromethane is preferred.
In the technical scheme of the invention, the alkali is one or two of inorganic alkali and organic alkali;
further, the inorganic base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate;
further, the organic base is selected from one or more of Triethylamine (TEA), N-Diisopropylethylamine (DIPEA), trimethylamine (TMA), azamethylaniline (NMA) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
In the technical scheme of the invention, the molar equivalent ratio of the compound shown in the formula I to the compound shown in the formula II to the alkali is as follows: 1.2:1:1-2.5.
In the technical scheme of the invention, the reaction temperature is 20-40 ℃; the reaction time is 10-30h.
In the technical scheme of the invention, the compound shown in the reactant formula 1 is a pyridinium salt prepared from pyridine substituted by a 3-electron withdrawing group and 3-bromooxindole or 2-bromonaphthalenone. The electron withdrawing group is selected from-CO 2 Me、-CN、-Ac。
The invention is shown in
Figure SMS_6
The specific structure of the circular arc of the spiro segment in the molecular structure corresponds to the reactant molecular segment shown in the formula I.
In the present invention, nitrogen on the aromatic ring in the starting reactant 2-nitrobenzofuran may be protected with t-butoxycarbonyl (Boc).
The invention has the beneficial effects that:
a novel efficient double dearomatization 3+2 cycloaddition reaction of cyclic pyridine ylide is discovered. By synthesizing cyclic pyridine ylide salts of two frameworks, the 3+2 cycloaddition reaction with nitrobenzofuran or nitroindole at room temperature is completed. The double-molecule dearomatization reaction of pyridine ylide and nitrobenzofuran or nitroindole is realized for the first time. The reaction condition is mild, the stereoselectivity is high, the product yield is up to 95%, and the method meets the current green chemistry requirement.
Detailed Description
The technical solutions provided in the present invention are described in detail below by way of specific examples, but the scope of the claims is not limited to the descriptions.
Example one
Figure SMS_7
The reaction of pyridine ylide salt 1a and nitrobenzofuran 2a is used as a template reaction, triethylamine is used as alkali, and the equivalent ratio is 1.2:1:2 are dissolved in different solvents and stirred at room temperature for reaction for 12 hours, and silica gel plate chromatography (V (petroleum ether): V (ethyl acetate) =4:1) is carried out to obtain a product 3a.
TABLE 1 influence of different solvents on the reaction
Figure SMS_8
Wherein, tol: toluene; THF: tetrahydrofuran; DCM: dichloromethane; CHCl (CHCl) 3 : chloroform; TEA, triethylamine.
In example 1, each solvent was used as a separate example, i.e., example 1 was decomposed into 6 examples, and examples 2 to 6 were similar to example 1.
Example two
The reaction of the pyridine ylide salt 1a and the nitrobenzofuran 2a is used as a template for reaction, dichloromethane is used as a reaction solvent, different bases are added, the pyridine ylide salt, the nitrobenzofuran and the bases are stirred and reacted for 12 hours at room temperature according to the equivalent ratio of 1.2:1:2, and the silica gel plate chromatography (V (petroleum ether): V (ethyl acetate) =4:1) is carried out, so that the product 3a is obtained.
TABLE 2 influence of different solvents on the reaction
Figure SMS_9
Wherein, DIPEA: n, N-diisopropylethylamine; TMA: trimethylamine; NMA: nitrogen methylaniline.
Example three
The pyridine ylide salt 1a and the nitrobenzofuran 2a are mixed according to an equivalent ratio of 1.2:1 was dissolved in dichloromethane, triethylamine of different equivalent was added, and the reaction was stirred at room temperature for 12 hours, followed by chromatography on silica gel plate (V (petroleum ether): V (ethyl acetate) =4:1) to give compound 3a in different yields, respectively.
TABLE 3 influence of different equivalent weights of base on the reaction
Figure SMS_10
Example four
Different types of pyridine ylide salts 1 or 4, 2-nitrobenzofuran or 2-nitroindole 2 and triethylamine are mixed according to an equivalent ratio of 1.2:1:2 is dissolved in dichloromethane and stirred for 12-20 hours at normal temperature, and silica gel plate chromatography (V (petroleum ether): V (ethyl acetate) =4:1) is carried out to obtain spiro-indolyl cetirizine products 3 or 5 with different yields respectively.
Figure SMS_11
/>
Figure SMS_12
1H),5.16(dd,J＝10.2,1.4Hz,1H),4.83(s,1H),3.63(s,3H),3.01(s,3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.8,166.1,159.5,144.5,138.9,131.9,130.9,125.8,125.6,125.2,124.5,123.2,123.1,123.0,121.1,111.2,109.5,106.5,100.1,73.4,68.9,61.4,51.0,26.0 ppm；ESI-HRMS:calcd.for C 24 H 20 N 3 O 6 +H + 446.1347,found446.1349.
Figure SMS_13
(s,3H),2.99(s,3H),2.45(s,3H)ppm； 13 C NMR(100 MHz,CDCl 3 )δ172.8,166.1,159.5,142.1,139.0,134.4,132.2,130.9,126.0,125.8,125.2,123.2,123.1,123.0,121.2,111.1,109.2,106.4,100.1,73.4,68.8,61.4,51.0,26.0,21.1 ppm；ESI-HRMS:calcd.for C 25 H 21 N 3 O 6 +H + 460.1503,found 460.1490.
Figure SMS_14
ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.6,166.0,159.4,157.2,138.9,137.6,130.9,125.7,125.2,124.1,123.2,123.1,121.1,116.5,112.1,111.1,110.1,106.4,100.3,73.6,68.9,61.5,56.0,51.0,26.0 ppm；ESI-HRMS:calcd.for C 25 H 22 N 3 O 7 +H + 476.1452,found 476.1465.
Figure SMS_15
1H),4.83(s,1H),3.66(s,3H),3.01(s,3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.6,165.9159.4,138.4,131.0,125.4,125.2,124.5,123.3,123.0,120.8,118.6,118.4,113.7,113.5,111.2,110.3,106.6,100.8,73.3,68.9,61.4,51.0,26.1 ppm；ESI-HRMS:calcd.for C 24 H 19 ClN 3 O 6 +H + 480.0957,found 480.0943.
Figure SMS_16
3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.4,165.9,159.4,143.5,138.4,134.9,131.1,128.5,125.3,125.2,125.1,123.4,123.0,120.8,117.0,111.3,110.9,106.7,101.2,73.0,68.9,61.5,51.1,26.1 ppm；ESI-HRMS:calcd.for C 24 H 19 BrN 3 O 6 +H + 524.0452,found 524.0444.
Figure SMS_17
1H),3.65(s,3H),3.01(s,3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.6,165.9,159.4,140.4(d,J C-F ＝2.2 Hz),138.4,131.0,125.4,125.2,124.6(d,J C-F ＝7.7 Hz),123.4,123.0,120.8,118.5(d,J C-F ＝23.4 Hz),113.6(d,J C-F ＝25.3 Hz),111.2,110.4(d,J C-F ＝8.0 Hz),106.6,100.8,73.2,68.9,61.4,51.1,26.1 ppm； 19 F NMR(376 MHz,CDCl 3 ):δ-116.48–-116.44(m)ppm；ESI-HRMS:calcd.for C 24 H 19 FN 3 O 6 +H + 464.1252,found 464.1255.
Figure SMS_18
9.8 Hz,1H),4.82(s,1H),3.66(s,3H),3.02(s,3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.6,165.9,159.5,145.7,138.4,131.1,127.3,126.8,126.0,125.6,125.2,123.4,123.0,121.9,120.8,113.1,111.3,106.7,100.6,73.0,68.9,61.3,51.1,26.1ppm；ESI-HRMS:calcd.for C 24 H 19 BrN 3 O 6 +H + 524.0452,found 524.0436./>
Figure SMS_19
1H),3.02(s,3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.3,159.5,144.5,140.5,132.3,131.0,125.6,124.6,124.3,123.4,123.1,122.2,120.8,119.3,111.2,109.7,108.5,80.3,73.4,68.0,60.9,29.6,26.0 ppm；ESI-HRMS:calcd.for C 23 H 17 N 4 O 4 +H + 413.1244,found 413.1239.
Figure SMS_20
CDCl 3 ):δ191.8,172.6,159.5,144.5,139.3,132.1,131.0,125.5,125.4,124.8,124.4,123.3,123.1,122.7,121.0,111.2,110.3,109.6,107.2,73.6,68.8,61.4,26.0,24.6ppm；ESI-HRMS:calcd.for C 24 H 20 N 3 O 5 +H + 430.1397,found 430.1379.
Figure SMS_21
13 C NMR(100 MHz,CDCl 3 ):δ172.5,166.0,160.0,145.4,138.9,136.9,136.5,131.9,131.9,129.9,125.7,125.5,125.1,124.3,123.5,123.4,120.9,109.5,109.4,106.1,100.1,94.2,73.1,72.8,68.7,68.5,62.0,60.5,51.5,51.0,26.2,26.1 ppm；ESI-HRMS:calcd.for C 24 H 18 ClN 3 O 6 +H + 480.0957,found 480.0958.
Figure SMS_22
CDCl 3 ):δ172.6,166.0,155.5,144.5,138.7,132.1,126.3,125.6,125.3,124.6,122.6,122.4,122.3,117.6(d,J C-F ＝24.6 Hz),111.9(d,J C-F ＝8.6Hz),110.3(d,J C-F ＝25.8 Hz),109.7,106.5,100.3,73.3,68.9,61.1,51.0,26.1 ppm； 19 F NMR(376 MHz,CDCL 3 ):δ-119.71–-119.69(m)ppm；ESI-HRMS:calcd.for C 24 H 19 FN 3 O 6 +H + 464.1252,found 464.1250.
Figure SMS_23
138.7,132.1,131.0,128.4,126.1,125.6,125.4,124.6,123.2,123.0,122.6,112.2,109.7,106.4,100.3,73.3,68.8,60.9,51.0,26.1 ppm；ESI-HRMS:calcd.for C 24 H 19 ClN 3 O 6 +H + 480.0957,found 480.0958.
Figure SMS_24
13 C NMR(100 MHz,CDCl 3 ):δ172.6,166.0,158.6,144.4,138.7,133.8,132.1,126.1,125.9,125.6,125.4,124.6,123.5,122.6,115.4,112.7,109.7,106.4,100.3,73.3,68.8,60.8,51.0,26.0 ppm；ESI-HRMS:calcd.for C 24 H 19 BrN 3 O 6 +H + 524.0452,found 524.0430.
Figure SMS_25
1H),3.63(s,3H),3.03(s,3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.6,166.0,160.0,144.5,138.7,132.0,126.5,126.1,125.6,125.4,124.6,124.2,124.1,122.7,120.4,115.0,109.6,106.4,100.3,73.3,68.8,60.7,51.0,26.1ppm；ESI-HRMS:calcd.for C 24 H 19 BrN 3 O 6 +H + 524.0452,found 524.0446./>
Figure SMS_26
MHz,CDCl 3 ):δ172.6,166.0,156.9,144.5,138.7,134.1,132.0,125.6,125.3,125.1,124.6,124.4,122.7,122.6,121.9,109.6,106.5,103.8,100.3,73.4,68.9,61.9,51.0,26.0 ppm；ESI-HRMS:calcd.for C 24 H 19 BrN 3 O 6 +H + 524.0452,found 524.0443.
Figure SMS_27
MHz,CDCl 3 ):δ172.4,165.9,156.2,144.4,138.5,136.3,132.3,125.6,125.4,125.1,125.0,124.7,124.3,122.4,115.6,109.8,106.4,104.7,100.5,73.3,68.8,61.4,51.1,26.1 ppm；ESI-HRMS:calcd.for C 24 H 18 Br 2 N 3 O 6 +H + 601.9557,found 601.9557.
Figure SMS_28
NMR(100 MHz,CDCl 3 ):δ172.8,166.1,157.6,144.5,138.9,132.9,131.8,131.4,126.0,125.6,125.2,124.5,123.4,123.2,121.0,110.7,109.5,106.6,100.0,73.3,68.9,61.4,51.0,26.0,20.8 ppm；ESI-HRMS:calcd.for C 25 H 21 N 3 O 6 +H + 460.1503,found 460.1497.
Figure SMS_29
3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.7,166.1,156.0,153.6,144.5,138.9,131.9,126.3,125.6,125.2,124.5,123.0,122.0,115.2,111.2,109.6,109.5,106.6,100.1,73.3,68.9,61.5,55.9,51.0,26.1 ppm；ESI-HRMS:calcd.for C 25 H 22 N 3 O 7 +H + 476.1452,found 476.1449.
Figure SMS_30
1H),4.75(s,1H),3.76(s,3H),3.63(s,3H),3.02(s,3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ173.0,166.1,162.2,160.9,144.5,139.0,131.8,126.6,125.5,125.2,124.4,123.3,123.0,112.5,109.9,109.4,106.5,100.0,97.0,73.5,68.8,61.2,55.5,51.0,26.0 ppm；ESI-HRMS:calcd.for C 25 H 22 N 3 O 7 +H + 476.1452,found476.1452.
Figure SMS_31
3.02(s,3H)ppm； 13 C NMR(100MHz,CDCl 3 ):δ172.8,166.1,147.9,144.7,144.5,138.9,131.8,125.9,125.6,125.1,124.4,124.2,123.1,122.2,114.6,113.8,109.4,106.6,100.1,73.3,68.9,62.0,56.1,51.0,26.0 ppm；ESI-HRMS:calcd.for C 25 H 22 N 3 O 7 +H + 476.1452,found 476.1450.
Figure SMS_32
3.63(s,3H),3.02(s,3H),1.47(t,J＝7.0 Hz,3H)ppm； 13 C NMR(100 MHz,CDCl 3 ):δ172.8,166.1,148.2,144.5,144.0,138.9,131.8,125.9,125.6,125.1,124.4,124.1,123.1,122.4,115.6,114.5,109.4,106.7,100.1,73.3,68.9,65.0,62.0,51.0,26.0,14.8ppm；ESI-HRMS:calcd.for C 26 H 24 N 3 O 7 +H + 490.1609,found 490.1612./>
Figure SMS_33
(s,9H)； 13 C NMR(100 MHz,CDCl 3 ):δ172.9,170.8,166.2,158.1,151.4,144.8,138.6,138.4,131.8,130.4,125.3,124.3,123.8,123.4,122.7,122.4,109.9,109.4,73.5,60.4,51.0,28.3,26.2,25.8,21.0,14.2；ESI-HRMS:calcd.for C 29 H 29 N 4 O 7 +H + 545.2031,found 545.2032.
Figure SMS_34
1H),5.08(dd,J＝10.1,1.3 Hz,1H),4.73(s,1H),3.67(s,3H),3.50–3.45(m,2H),2.92–2.85(m,1H),2.63(dt,J＝12.9,3.5 Hz,1H)； 13 C NMR(100 MHz,CDCl 3 ):δ194.2,166.2,158.5,141.8,139.4,134.8,132.7,130.6,128.7,128.2,127.8,125.4,124.8,122.6,120.0,111.1,106.1,100.6,74.8,70.4,59.3,51.0,33.7,27.2；ESI-HRMS:calcd.for C 25 H 21 N 2 O 6 +H + 445.1389,found 445.1394.
Figure SMS_35
Hz,1H),4.69(s,1H),3.92(s,3H),3.66(s,3H),3.48–3.34(m,2H),2.85(td,J＝12.5,5.4 Hz,1H),2.59(dt,J＝12.8,3.4 Hz,1H)； 13 C NMR(100 MHz,CDCl 3 ):δ192.6,166.2,164.7,158.4,144.3,139.6,130.8,130.5,126.2,125.4,125.3,124.7,122.6,120.4,114.3,112.6,111.0,106.0,100.4,74.6,70.5,59.3,55.6,50.9,33.8,27.5；ESI-HRMS:calcd.for C 26 H 23 N 2 O 7 +H + 475.1500,found 475.1497./>
Figure SMS_36
3.53–3.38(m,2H),2.89(ddd,J＝12.9,11.2,6.4Hz,1H),2.61(dt,J＝13.0,3.7Hz,1H)； 13 C NMR(100MHz,CDCl 3 ):δ193.6,166.1,156.9,141.4,139.2,135.1,132.5,130.50,128.7,128.1,128.0,127.8,125.9,125.4,124.9,121.7,111.9,105.9,100.6,74.7,70.2,58.7,51.0,33.2,27.0；ESI-HRMS:calcd.for C 25 H 19 ClN 2 NaO 6 +Na + 501.0824,found 501.0828.
Figure SMS_37
2H),2.92–2.85(m,1H),2.64–2.59(m,1H),1.80(s,3H)； 13 C NMR(100MHz,CDCl 3 )；δ194.0,166.2,156.4,141.8,139.4,134.6,132.9,132.1,130.9,128.6,128.1,127.6,126.2,125.3,124.9,119.7,110.4,106.1,100.5,74.8,70.2,59.2,50.9,33.3,27.2,20.3；ESI-HRMS:calcd.
Figure SMS_38
J＝2.0Hz,1H),5.14–5.11(m,1H),4.73(s,1H),4.10(q,J＝7.0Hz,3H),3.67(s,3H),3.49–3.42(m,2H),2.88(td,J＝12.5,5.5Hz,1H),2.62(dt,J＝12.9,3.5Hz,1H),1.44–1.41(m,3H)； 13 C NMR(100MHz,CDCl 3 ):δ194.3,166.2,147.5,144.0,141.9,139.4,134.7,132.8,128.6,128.2,127.8,125.2,124.9,123.2,121.3,116.8,106.4100.8,74.8,70.3,64.9,60.0,51.0,33.9,27.2,14.7；ESI-HRMS:calcd.for C 27 H 25 N 2 O 7 +H + 489.1656,found 489.1657.
Examples one to four show the yields of the products of the synthesis process of the invention using different components, different solvents and different equivalent weights, which yields are mostly greater than 80% after column purification and greater than 19: the non-corresponding selectivity of 1 shows the correctness, applicability and advancement of the synthetic route.
The foregoing is a further detailed description of the invention in connection with specific embodiments, and it is not intended that the invention be limited to those specific embodiments. It will be apparent to those skilled in the art that several deductions or substitutions may be made without departing from the spirit of the invention, and these shall be considered to be within the scope of the invention.

Claims (5)

1. A synthetic method of a complex 3 '-spiro-indolyl structure is characterized in that a compound shown in a formula I reacts with a compound shown in a formula II in the presence of alkali to obtain a 3' -spiro-indolyl compound;
the reaction formula is as follows:
Figure FDA0004178096010000011
wherein R is 1 Selected from hydrogen, fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl, R 2 Selected from fluorine, chlorine, bromine, methoxy, ethoxy, methyl, ethyl; x is selected from O or NBoc; GWE is an electron withdrawing group; GWE is selected from-CO 2 Me, -CN, -Ac; n has the values of 0, 1 and 2;
the 3' -spiro indolyl-doxycycline compound is selected from one of the following structures:
Figure FDA0004178096010000012
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Figure FDA0004178096010000021
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Figure FDA0004178096010000031
2. the method according to claim 1, wherein the solvent in the reaction is selected from one or more of dichloromethane, toluene, tetrahydrofuran, ethanol, chloroform, and water.
3. The method of claim 1, wherein the base is an inorganic base or an organic base; the inorganic base is selected from sodium bicarbonate, sodium carbonate and potassium carbonate; the organic base is selected from triethylamine, N-diisopropylethylamine, trimethylamine and azomethylaniline.
4. The process according to claim 1, wherein the molar equivalent ratio of the compound of formula I, the compound of formula II and the base is: 1.2:1:1-2.5.
5. The method according to claim 1, wherein the reaction temperature is 20-40 ℃; the reaction time is 10-30h.
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