CN113149890B - Method for synthesizing 3-spiro-2-indolone compounds - Google Patents
Method for synthesizing 3-spiro-2-indolone compounds Download PDFInfo
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/96—Spiro-condensed ring systems
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Abstract
The invention relates to a synthesis method of 3-spiro-2-indolone compounds, which mainly comprises the following steps: taking a compound shown in a formula II and a compound shown in a formula III as initial raw materials, and obtaining a target substance through one-step reaction:
in the formula, R 1 Is hydrogen, C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy, halogen or carbomethoxy; r 2 Is C 1 ～C 6 Alkyl or phenyl; r is 3 Is C 1 ～C 6 An alkyl group; r is 4 Is C 6 ～C 17 Monocyclic or polycyclic radicals of, substituted C 6 ～C 17 Monocyclic or polycyclic radicals of, or by C 1 ～C 16 Alkyl-substituted benzopyranyl; wherein, said substituted C 6 ～C 17 The substituent of the monocyclic group or polycyclic group is selected from one or more of the following groups: c 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy, halogen or oxo.
Description
Technical Field
The invention relates to a synthetic method of a 2-indolone derivative, in particular to a synthetic method of a 3-spiro-2-indolone compound.
Background
3-spiro-2-indolinones are the core backbone of many Natural Products and drug candidates (Bhaskar, G., et al., synthesis of Novel Spirooxindole Derivatives by One Pot Multi-component Reaction and Their Antimicrobial Activity, eur. J. Med. Chem.,2012, 51, 79-91 Miller, K.A.; et al., asymmetry Total Synthesis of (+) -and (-) -Versicoamide B and biosynetic intermediates, nat. Chem.,2009, 63-68 Aho, J.E.; et al., nonaonomeric spirorales in Natural Products: structures, resources, synthesis, chemistry, 105.v., 4406-4406). For example, citrinin B isolated from Penicillium citrinum N059 in the small forest pharmaceutical exhibits moderate cytotoxicity to murine leukemia L1210 cells (Ke K.; et al., an Enantioselective Total Synthesis and Stereochemical review of (+) -citrinin B, J.am.Chem.Soc.,2013, 135, 10890-10893). Ubroglenatan (MK-1602) has completed a phase 2 clinical trial for treating migraine (Zheng Y.J.; et al, the use of Spirocyclic Scaffolds in Drug Discovery, bioorg. Med. Chem. Lett.2014, 24, 3673-3682). Therefore, the synthesis of 3-spiro-2-indolone compounds is of great interest.
Hitherto, methods for synthesizing 3-spiro-2-indolone compounds include: 1+4 cycloaddition reaction, 2+3 cycloaddition reaction and 3+2 cycloaddition reaction, wherein most cycloaddition reactions need to introduce a high-activity group at the 3-position of indole ring in advance to generate cyclization reaction.
First, a method of introducing oxindole having a specific functional group at position 3-of indole ring as a C1 synthon (such as diazooxazole (diazo)), and obtaining spiro [ cyclopentane-3, 3' -oxindole ] by [1+4] cycloaddition has been reported (Ma B.; et al., effective Synthesis of Spirooxindole hydrates by a Rhodium (III) -catalysis C-H Activation/carbon insert/Loosen reaction/Lossen reaction Sequence, angew.chem.int.Ed.,2019, 58, 35-13339Z heng P.F.; 3. Et al., (3) Annulation/reaction of C, N-cymene intermediates 3-chlorine carbonyl of C, N-carbonyl metals of 20135, and chlorine of 2-carbonyl of 2, franzolz of 2, lenzolz of 2, 12, and 52, and 12, and 2-carbonyl of Spiro 2, and 3-carbonyl of the aforementioned genes;
secondly, synthesis of 3-spiro-2-indolone by [2+3] cycloaddition reaction, wherein indole derivatives including N-benzyl protected methylindolone and alkylidene oxindole act as C2-synthon (P.Tehri and R.K.Peddinti, DBU-catalysis [3+2] -cycloadddition and Michael Addition Reactions of 3-benzylidene Succinimides with 3-ylidine oxides and chalcons, org.biomol.chem.,2019, 17, 3964 Zhang J.X.; et al, organic selective Construction of Spirocyclic oxides via Tandem Michael/Michael reaction by multifunctionality query phosphor Salt, J.org.chem.,2016, 81, 10558-10568);
finally, indolone derivatives as C3 synthons (such as N-2, 2-trifluoroethyl substituted imines and N-trifluoroethyl substituted Isatin imines) are reacted with electron-deficient alkenes or alkynes by [3+2] cycloaddition to give 3-spiro-2-indolone compounds (Mei M.S.; et al, enantioselective [3+2] Annulation of Isatis-Derived MBH-Carbonates and 3-Nitroindoles Enabled by b a Bifundamental DMAP-Thiourea Chem, comm. Commun.,2020, 56, 10718-10721 Single K.; et al, lewis Acid catalyst isolated of Spirocyclic intermediates, chemical Donor-acceptors cyclic intermediates, chemical reactions 20155, spiro chemical intermediates, F.709, spiro chemical intermediates, F.7055.
In the above prior art, it is generally required to have a highly reactive group at the C3 position of the 2-indolinone parent ring to accelerate cyclization and ensure regioselectivity. The introduction of these highly reactive groups requires cumbersome steps and harsh reaction conditions incompatible with other functional groups.
In view of the above, there is a need in the art for a new synthesis method (synthesis strategy) for 3-spiro-2-indolone compounds, which overcomes the drawbacks of the prior art (which is also a technical problem to be solved by the present invention).
Disclosure of Invention
The invention aims to provide a novel synthesis method of 3-spiro-2-indolone compounds, which overcomes the defects in the prior art.
The 3-spiro-2-indolone compound disclosed by the invention is a compound shown as a formula I:
the main steps for synthesizing the compound shown in the formula I are as follows: a compound shown in a formula II and a compound shown in a formula III are used as starting materials, and a target compound (a compound shown in a formula I) is obtained through one-step reaction.
In the formula, R 1 Is hydrogen (H), C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy, halogen (F, cl, br or I, the same applies below) or carbomethoxy group (A)
The same as below); r 2 Is C 1 ～C 6 Alkyl or phenyl; r 3 Is C 1 ～C 6 An alkyl group; r is 4 Is C 6 ～C 17 Monocyclic or polycyclic groups of (A), substituted C 6 ～C 17 Monocyclic or polycyclic radicals of, or by C 1 ～C 16 Alkyl-substituted benzopyranyl;
wherein, said substituted C 6 ～C 17 The substituent of the monocyclic group or polycyclic group in (b) is selected from one or more (including two) of the following groups:
C 1 ～C 6 alkyl radical, C 1 ～C 6 Alkoxy, halogen (F, cl, br or I) or oxo
Wherein the curve is marked by a substitution site (the same below).
The compounds of the formula II and the compounds of the formula III are known and are synthesized in the literature (Tang S.et al, palladium-catalyst C-H catalysis of N-arylprotopmides with Aryliodonium Salts: selective Synthesis of 3- (1-arylmethyl) oxindoles, J.org.chem.,2008, 73, 6-5480).
The invention discloses a novel synthesis method of a 3-spiro-2-indolone compound, which has the advantages of easily obtained raw materials, concise synthesis steps, mild reaction conditions and the like, and lays a solid foundation for the commercial application of the 3-spiro-2-indolone compound.
Detailed Description
Herein, ph represents phenyl and Me represents methyl.
In a preferred embodiment of the present invention, R 1 Is H, C 1 ～C 3 Alkyl radical, C 1 ～C 3 Alkoxy, halogen or carbomethoxy;
more preferred R 1 Is H, methyl, methoxy, F, cl or Br.
In another preferred embodiment of the present invention, R 2 Is C 1 ～C 3 Alkyl or phenyl;
more preferred R 2 Is methyl or phenyl.
In another preferred embodiment of the present invention, the recommended compound represented by formula II is one of the following compounds:
in another preferred embodiment of the present invention, R 3 Is C 1 ～C 3 An alkyl group;
more preferred R 3 Is methyl or n-propyl.
In still another preferred embodiment of the present invention, R 4 Is phenyl or substituted phenyl, and the substituent of the substituted phenyl is selected from one or more than two (including two) of the following groups:
C 1 ～C 4 alkyl radical, C 1 ～C 3 Alkoxy, halogen, monovalent phenyl
Divalent phenyl radical
Further preferred R 4 Is phenyl or substituted phenyl, and the substituent of the substituted phenyl is selected from one or more than two (including two) of the following groups:
methyl, methoxy, tert-butyl, F, cl, br,
recommended R 4 Is phenyl, p-methylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, m-chlorophenyl, biphenyl
Naphthyl radical
In summary, in another preferred embodiment of the present invention, the main steps for synthesizing the compound of formula I are: in the presence of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer ([ Cp ] RhCl) 2 ] 2 ) The target compound (the compound shown in the formula I) is obtained by reacting the compound shown in the formula II with the compound shown in the formula III in a polar organic solvent at 100-120 ℃ for at least 48 hours in the presence of manganese acetate, sodium acetate and sodium pivalate, and then sequentially carrying out cooling, filtering, purifying and the like.
The present invention will be described in detail with reference to specific examples. The following examples will aid those skilled in the art in further understanding the present invention, but are not intended to limit the invention in any manner. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Example 1
Preparation of 1', 3-dimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-dien-2 ' -one (compound of formula Ia):
under an air atmosphere, the compound represented by the formula IIa (0.20 mmol), the compound represented by the formula IIIa (0.30 mmol) and [ Cp & RhCl ] were added 2 ] 2 (0.01 mmol), sodium pivalate (0.3 mmol), sodium acetate (0.8 mmol) and manganese acetate (0.12 mmol) were dissolved in 3mL of acetonitrile, heated to 110 ℃ in a sealed tube, and maintained in this state for 48 hours. After the reaction system was cooled to room temperature, insoluble materials were removed by filtration through celite, and the organic phase was concentrated under reduced pressure and purified directly by flash silica gel column chromatography (eluent ethyl acetate/petroleum ether =1:10 to 20 (v/v)) to give a yellow solid (compound represented by formula Ia), mp:143-146 ℃ and a yield of 77 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.21(ddd,J＝7.8,5.3,3.6Hz,1H),7.15-7.03(m,7H),7.03-6.98(m,2H),6.97-6.92(m,2H),6.82(dd,J＝6.6,3.1Hz,2H),6.79-6.74(m,1H),3.13(s,3H),2.06(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.2,145.6,144.5,142.8,140.6,136.1,134.3,133.7,128.4,127.8,127.6,127.0,125.1,123.2,123.0,108.4,71.0,26.7,14.0..
HRMS(EI-TOF)m/z:[M] + C 26 H 21 Theoretical NO value (Calcd for) 363.1623; experimental values (Found) 363.1625.
Example 2
Preparation of 1',3,5' -trimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula Ib):
the procedure and reagents used are the same as in example 1 except that a compound of formula IIb is substituted for the compound of formula IIa in example 1, to give a compound of formula Ib (yellow solid), mp:159-161 ℃ and the yield is 82 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.15-7.09(m,5H),7.09-7.05(m,2H),7.02(dt,J＝7.4,1.6Hz,3H),6.85-6.79(m,2H),6.77(d,J＝1.9Hz,1H),6.67(d,J＝7.9Hz,1H),3.12(s,3H),2.20(s,3H),2.07(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.2,145.7,143.0,142.2,140.4,136.0,134.3,133.7,132.5,128.7,128.5,128.4,127.8,127.5,127.0,126.9,125.1,123.8,108.1,71.0,26.7,21.0,14.1.
HRMS(EI-TOF)m/z:[M] + C 27 H 23 NO Calcd for 377.1780；Found 377.1778
Example 3
Preparation of 5 '-methoxy-1', 3-dimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula Ic):
the procedure and reagents used are the same as in example 1 except that a compound of formula IIc is substituted for the compound of formula IIa in example 1 to give a compound of formula Ic (pink solid), mp:179-180 deg.c and yield 90%.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.18-7.09(m,6H),7.07(s,1H),7.05-7.01(m,2H),6.89-6.83(m,2H),6.77(dd,J＝8.5,2.5Hz,1H),6.72(d,J＝8.4Hz,1H),6.57(d,J＝2.5Hz,1H),3.69(s,3H),3.15(s,3H),2.09(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ173.9,156.2,145.7,142.9,140.6,138.2,136.1,134.3,133.7,129.0,128.5,127.9,127.1,127.0,125.2,113.2,109.9,108.8,71.4,55.6,26.8,14.1.
HRMS(EI-TOF)m/z:[M] + Calcd for C 27 H 23 NO 2 393.1729；Found 393.1733。
Example 4
Preparation of 5 '-fluoro-1', 3-dimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula Id):
the same procedures and reagents as in example 1 were used except that the compound of formula IIa in example 1 was replaced with a compound of formula IId to give a compound of formula Id (yellow solid), mp:173-176 ℃ and the yield is 71 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.17-7.08(m,6H),7.05(s,1H),7.03-6.98(m,2H),6.93-6.82(m,3H),6.70(ddd,J＝9.1,5.7,3.3Hz,2H),3.14(s,3H),2.05(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ173.9,159.3(d,J＝241.3Hz),,145.3,142.5,141.0,140.5,140.5,136.3,134.0,133.4,129.5(d,J＝8.5Hz),,128.5,128.4,127.9,127.2,127.2,125.1,114.7(d,J＝23.6Hz),111.2(d,J＝24.8Hz),108.9(d,J＝8.1Hz),71.1,71.1,26.8,14.0；
19 F NMR(376MHz,CDCl 3 ,ppm):δ-119.7.
HRMS(EI-TOF)m/z:[M] + Calcd for C 26 H 20 FNO 381.1529；Found 381.1531.
Example 5
Preparation of 5 '-chloro-1', 3-dimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula Ie):
the same procedures and reagents as in example 1 were used except that the compound of formula IIa in example 1 was replaced with a compound of formula IIe to give a compound of formula Ie (yellow solid), mp:194-195 ℃ with a yield of 74%.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.20-7.10(m,7H),7.06(s,1H),7.02-6.98(m,2H),6.94(d,J＝2.1Hz,1H),6.87-6.81(m,2H),6.70(d,J＝8.4Hz,1H),3.14(s,3H),2.06(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ173.8,145.2,143.1,142.4,141.1,136.4,133.9,133.4,129.5,128.6,128.5,128.4,128.3,128.0,127.3,127.2,125.1,123.5,109.3,70.8,26.8,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 26 H 20 ClNO 397.1233；Found 397.1233.
Example 6
Preparation of 5 '-bromo-1', 3-dimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula If):
the procedure and reagents used are the same as in example 1 except that a compound of formula IIf is substituted for the compound of formula IIa in example 1, to give a compound of formula If (yellow solid), mp:204-206 ℃ and the yield is 71 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.34(dd,J＝8.4,2.0Hz,1H),7.14(pd,J＝5.8,5.2,2.8Hz,6H),7.09-7.05(m,2H),7.02-6.97(m,2H),6.87-6.80(m,2H),6.67(d,J＝8.4Hz,1H),3.14(s,3H),2.06(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ173.7,145.2,143.6,142.5,141.1,136.5,136.4,133.9,133.4,131.3,129.9,128.6,128.5,128.0,127.3,126.2,125.1,115.6,109.8,70.8,26.8,14.1,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 26 H 20 BrNO 441.0728；Found 441.0729.
Example 7
Preparation of methyl 5 '-carboxylate-1', 3-dimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula Ig):
the procedure and reagents used are the same as in example 1, except that a compound of formula IIg is substituted for the compound of formula IIa in example 1, to give a compound of formula Ig (yellow solid), mp:170-172 ℃ and the yield is 57 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ8.00(dd,J＝8.2,1.8Hz,1H),7.62(d,J＝1.6Hz,1H),7.16-7.07(m,7H),7.01-6.95(m,2H),6.86-6.78(m,3H),3.83(s,3H),3.20(s,3H),2.07(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.6,166.7,148.6,145.2,142.4,141.2,136.6,134.0,133.4,131.2,128.6,128.5,128.0,127.9,127.3,127.2,125.1,125.0,124.5,108.0,70.6,52.0,26.9,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 28 H 23 NO 3 421.1678；Found 421.1681.
Example 8
Preparation of 1',3,7' trimethyl 2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula Ih):
the same procedures and reagents used in example 1 were identical except that the compound of formula IIh was substituted for the compound of formula IIa in example 1, to give a compound of formula Ih (yellow solid), mp: the yield is 75 percent at the temperature of between 164 and 167 ℃.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.13(ddd,J＝7.4,4.0,1.8Hz,5H),7.10-7.05(m,1H),7.04-7.01(m,3H),6.96-6.91(m,1H),6.84-6.79(m,3H),6.76(dd,J＝7.4,1.6Hz,1H),3.40(s,3H),2.49(s,3H),2.05(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.9,145.9,143.3,142.4,140.3,136.0,134.4,133.8,132.1,132.1,128.6,128.5,128.5,127.8,127.8,127.0,125.2,122.8,122.8,121.1,121.1,119.9,70.8,30.0,19.0,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 27 H 23 NO 377.1780；Found 377.1782.
Example 9
Preparation of 7 '-methoxy-1', 3-dimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula Ii):
the procedure and reagents used are the same as in example 1 except that a compound of formula IIi is substituted for the compound of formula IIa in example 1 to give a compound of formula Ii (yellow solid), mp:188-189 deg.C, yield 87%.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.17-7.10(m,5H),7.10-7.02(m,4H),6.88-6.82(m,3H),6.75(dd,J＝8.4,1.2Hz,1H),6.56(dd,J＝7.4,1.2Hz,1H),3.77(s,3H),3.43(s,3H),2.05(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.3,145.7,145.3,143.0,140.4,136.0,134.4,133.8,132.4,129.0,128.5,127.8,127.0,126.9,125.2,123.4,115.9,112.1,71.2,55.8,30.0,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 27 H 23 NO 2 393.1729；Found 393.1732.
Example 10
Preparation of 7 '-chloro-1', 3-dimethyl-2, 5-diphenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound represented by formula Ij):
the procedure and reagents used are the same as in example 1 except that a compound of formula IIj is substituted for the compound of formula IIa in example 1 to give a compound of formula Ij (yellow solid), mp: the yield was 73% at 156-157 ℃.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.20-7.08(m,7H),7.06-6.99(m,3H),6.82(td,J＝5.4,2.6Hz,4H),3.51(s,3H),2.05(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.4,145.6,142.9,140.8,140.3,136.3,133.9,133.4,130.7,130.3,128.6,128.5,128.0,127.3,125.2,123.7,121.7,115.5,70.7,30.1,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 26 H 20 ClNO 397.1233；Found 397.1230.
Example 11
Preparation of 1',3, 5-trimethyl-2-phenylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-dien-2 ' -one (compound of formula Ik):
the same procedures and reagents used in example 1 were identical except that the compound of formula IIk was used in place of the compound of formula IIa in example 1, to give the compound of formula Ik (yellow oil) in a yield of 32%.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.27-7.21(m,1H),7.15-7.04(m,3H),6.99(td,J＝7.5,1.0Hz,1H),6.89(ddd,J＝7.4,6.5,1.5Hz,3H),6.82(dd,J＝7.9,0.9Hz,1H),6.25(d,J＝1.6Hz,1H),3.22(s,3H),2.09(s,3H),1.59(d,J＝1.6Hz,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.7,145.3,144.9,141.9,139.2,135.4,134.8,128.2,128.0,127.9,127.7,126.4,123.0,122.9,108.3,72.5,26.7,14.5,12.5.
HRMS(EI-TOF)m/z:[M] + Calcd for C 21 H 19 NO 301.1467；Found 301.1469.
Example 12
Preparation of 1', 3-dimethyl-5-phenyl-2- (p-tolyl) spiro [ cyclopentane-1, 3' -indoline ] -2, 4-dien-2 ' -one (compound represented by formula Il):
the same procedures and reagents as in example 1 were used except that the compound of formula IIIa in example 1 was replaced with the compound of formula IIIb to give a compound of formula Il (yellow solid), mp:185-186 ℃ and the yield is 79 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.25-7.20(m,1H),7.14-7.05(m,4H),7.01-6.98(m,2H),6.96-6.90(m,4H),6.80(d,J＝7.8Hz,1H),6.74-6.69(m,2H),3.17(s,3H),2.22(s,3H),2.07(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.4,145.4,144.6,143.0,140.3,136.6,136.2,133.8,131.3,128.6,128.5,128.3,127.8,127.0,125.2,123.2,123.0,108.4,71.0,26.7,21.1,14.1.
HRMS(EI-TOF)m/z:[M] + Calcd for C 27 H 23 NO 377.1780；Found 377.182.
Example 13
Preparation of 2- (4- (tert-butyl) phenyl) -1', 3-dimethyl-5-phenylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-dien-2 ' -one (compound of formula Im):
the same procedures and reagents as in example 1 were used except that the compound of formula IIIa in example 1 was replaced with a compound of formula IIIc to give a compound of formula Im (yellow solid), mp:194-195 ℃ with a yield of 83%.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.25(ddd,J＝7.8,5.0,3.8Hz,1H),7.15-7.06(m,5H),7.04-6.93(m,5H),6.82(d,J＝7.8Hz,1H),6.77-6.70(m,2H),3.15(s,3H),2.11(s,3H),1.22(s,9H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.4,149.6,145.5,144.8,142.7,140.4,136.4,133.8,131.3,128.5,128.4,127.9,127.8,127.0,125.2,124.8,123.2,123.1,108.5,70.9,34.3,31.2,26.8,14.3.
HRMS(EI-TOF)m/z:[M] + Calcd for C 30 H 29 NO 419.2249；Found 419.2248.
Example 14
Preparation of 2- (4-methoxyphenyl) -1', 3-dimethyl-5-phenylspiro [ cyclopentane-1, 3' -indolin ] -2, 4-dien-2 ' -one (compound of formula In):
the same procedures and reagents used In example 1 were identical except that the compound of formula IIIa of example 1 was replaced with a compound of formula IIId to give a compound of formula In (yellow solid), mp:151-152 ℃ and the yield is 79%.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.26-7.20(m,1H),7.14-7.04(m,4H),7.02-6.97(m,2H),6.96-6.91(m,2H),6.80(d,J＝8.0Hz,1H),6.77-6.71(m,2H),6.68-6.63(m,2H),3.69(s,3H),3.16(s,3H),2.05(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.4,158.5,145.2,144.6,142.7,140.0,136.2,133.8,129.6,128.5,128.3,127.8,127.0,126.7,125.1,123.2,123.0,113.3,108.4,71.0,55.0,26.7,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 27 H 23 NO 2 393.1729；Found 393.1730.
Example 15
Preparation of 2- (4-fluorophenyl) -1', 3-dimethyl-5-phenylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-dien-2 ' -one (compound of formula Io):
the same procedures and reagents as in example 1 were used except that the compound of formula IIIa in example 1 was replaced with a compound of formula IIIe to give a compound of formula Io (yellow solid), mp:153-154 ℃ and 75% yield.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.24(ddd,J＝7.8,6.6,2.4Hz,1H),7.16-7.04(m,4H),7.03-6.93(m,4H),6.85-6.75(m,5H),3.15(s,3H),2.03(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.1,161.9(d,J＝246.4Hz),145.7,144.5,141.8,140.9,135.9,133.6,130.3,130.2,128.5,128.5,127.4,127.2,125.2,123.2,123.1,114.8(d,J＝21.2Hz),108.5,71.1,26.7,13.9；
19 F NMR(376MHz,CDCl 3 ):δ-114.79.
HRMS(EI-TOF)m/z:[M] + Calcd for C 26 H 20 FNO 381.1529；Found 381.1528.
Example 16
Preparation of 2- (4-chlorophenyl) -1', 3-dimethyl-5-phenylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-dien-2 ' -one (compound of formula Ip):
the procedure and reagents used are the same as in example 1, except that a compound of formula IIIf is substituted for that of formula IIIa in example 1, to give a compound of formula Ip (yellow solid), mp:165-166 ℃ and the yield is 75 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.24(ddd,J＝7.8,6.8,2.0Hz,1H),7.15-7.07(m,5H),7.04(s,1H),7.02-6.91(m,4H),6.81(d,J＝7.8Hz,1H),6.78-6.71(m,2H),3.16(s,3H),2.05(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.1,146.1,144.6,141.6,141.4,136.0,133.6,133.0,132.9,129.9,128.7,128.6,128.2,127.4,127.3,125.3,123.3,108.7,71.1,26.9,14.1.
HRMS(EI-TOF)m/z:[M] + Calcd for C 26 H 20 ClNO 397.1233；Found 397.1232.
Example 17
Preparation of 2- (4-bromophenyl) -1', 3-dimethyl-5-phenylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-dien-2 ' -one (compound of formula Iq):
the same procedures and reagents as in example 1 were used except that the compound of formula IIIa of example 1 was replaced with a compound of formula IIIg to give a compound of formula Iq (yellow solid), mp:154-155 ℃ and the yield is 75 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.29-7.21(m,3H),7.16-7.06(m,3H),7.04(s,1H),7.02-6.91(m,4H),6.82(d,J＝8.0Hz,1H),6.71-6.65(m,2H),3.17(s,3H),2.05(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.0,146.0,144.5,141.4,141.3,135.9,133.5,133.3,131.1,130.1,128.6,128.5,127.3,125.2,123.2,121.2,108.6,70.9,26.8,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 26 H 20 BrNO 441.0728；Found 441.0723.
Example 18
Preparation of 1', 3-dimethyl-5-phenyl-2- (m-chlorophenyl) spiro [ cyclopentane-1, 3' -indolin ] -2, 4-dien-2 ' -one (compound of formula Ir):
the same procedures and reagents used in example 1 were identical except that the compound of formula IIIa of example 1 was replaced by a compound of formula IIIh to give a compound of formula Ir (yellow solid), mp:153-154 ℃ and a yield of 68%.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.28-7.23(m,1H),7.16-7.04(m,6H),7.03-6.98(m,2H),6.94(ddd,J＝13.0,7.3,1.3Hz,2H),6.85-6.78(m,2H),6.72(dt,J＝7.3,1.5Hz,1H),3.19(s,3H),2.08(s,3H).；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.0,146.2,144.5,141.7,141.1,136.1,135.9,133.6,133.5,129.1,128.7,128.5,128.4,127.3,127.1,126.7,125.2,123.2,108.6,70.9,26.8,14.1.
HRMS(EI-TOF)m/z:[M] + Calcd for C 26 H 20 ClNO 397.1233；Found 397.1234.
Example 19
Preparation of 2- ([ 1,1 '-biphenyl ] -4-yl) -1', 3-dimethyl-5-phenylspiro [ cyclopentane-1, 3 '-indoline ] -2, 4-dien-2' -one (compound of formula Is):
the same procedures and reagents used in example 1 were identical except that the compound of formula IIIa in example 1 was replaced with a compound of formula IIIi to give a compound of formula Is (yellow solid), mp:105-106 ℃ and the yield is 76 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.51-7.45(m,2H),7.39-7.31(m,4H),7.29-7.18(m,2H),7.14-7.05(m,4H),7.04-6.99(m,2H),6.98-6.93(m,2H),6.93-6.87(m,2H),6.79(d,J＝7.8Hz,1H),3.15(s,3H),2.11(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.2,145.8,144.6,142.4,140.9,140.4,139.4,136.2,133.6,133.4,128.7,128.6,128.5,127.6,127.1,126.7,126.5,125.1,123.2,123.1,108.5,70.9,26.7,14.2.
HRMS(EI-TOF)m/z:[M] + Calcd for C 32 H 25 NO 439.1936；Found 439.1938.
Example 20
Preparation of 1', 3-dimethyl-2- (naphthalen-2-yl) -5-phenylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-dien-2 ' -one (compound of formula It):
the same procedures and reagents as in example 1 were used except that the compound of formula IIIa of example 1 was replaced with a compound of formula IIIj to give a compound of formula It (yellow solid), mp:125-127 ℃ and the yield is 80 percent.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.67(dt,J＝6.8,3.6Hz,1H),7.62-7.55(m,2H),7.35(dt,J＝6.2,3.4Hz,2H),7.28(s,1H),7.21-6.89(m,11H),6.71(d,J＝7.8Hz,1H),3.09(s,3H),2.09(s,3H)；
13 C NMR(100MHz,CDCl 3 ,ppm):δ174.2,145.8,144.5,142.7,141.1,136.1,133.6,132.9,132.2,131.9,128.5,128.4,127.9,127.6,127.4,127.3,127.1,126.7,125.7,125.1,123.2,123.0,108.5,71.1,26.7,14.1.
HRMS(EI-TOF)m/z:[M] + Calcd for C 30 H 23 NO 413.1780；Found 413.1820.
Example 21
Preparation of 1 '-methyl-2- ((8R, 9S,13S, 14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthryl-3-yl) -5-phenyl-3-propylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-diene (compound represented by formula Iu):
the same procedures and reagents as in example 1 were used except that the compound of formula IIIa in example 1 was replaced with a compound of formula IIIk to give the compound of formula Iu as a yellow oil in 80% yield.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.32-7.20(m,1H),7.16-6.90(m,8H),6.81(d,J＝7.8Hz,1H),6.62-6.54(m,1H),6.50(d,J＝9.9Hz,1H),3.17(d,J＝1.8Hz,2H),2.54-2.36(m,2H),2.35-2.27(m,1H),2.21-1.97(m,3H),1.93(tt,J＝9.2,2.5Hz,2H),1.54-1.43(m,2H),1.43-1.21(m,1H),0.96(t,J＝7.3Hz,2H),0.89(s,3H).
13 C NMR(100MHz,CDCl 3 ):δ174.4,174.3,145.6,144.9,144.7,143.1,138.4,135.6,134.6,133.9,131.7,129.1,128.5,128.3,127.9,127.0,125.8,125.1,124.6,123.2,123.0,108.4,71.0,50.5,47.9,44.2,37.9,35.8,31.5,29.8,29.2,26.7,26.4,25.4,22.4,21.5,13.9,13.8.
HRMS(EI-TOF)m/z:[M] + Calcd for C 40 H 41 NO 2 567.3137；Found 567.3127.
Example 22
Preparation of 2- ((S) -2, 8-dimethyl-2- ((4S, 8S) -4,8, 12-trimethyltridecyl) chromen-7-yl) -1 '-methyl-5-phenyl-3-propylspiro [ cyclopentane-1, 3' -indoline ] -2, 4-diene (compound of formula IV):
the same procedures and reagents as in example 1 were used except that the compound of formula IIIa in example 1 was replaced with a compound of formula IIIl to give the compound of formula Iv (yellow oil) in 37% yield.
1 H NMR(400MHz,CDCl 3 ,ppm):δ7.26-7.22(m,1H),7.14-7.04(m,4H),7.03-6.99(m,2H),6.99-6.91(m,2H),6.80(dd,J＝7.8,0.9Hz,1H),6.31(d,J＝2.7Hz,2H),3.16(s,3H),2.60-2.47(m,2H),2.43-2.35(m,2H),1.95(s,3H),1.67(dddd,J＝27.5,13.5,8.1,6.3Hz,6H),1.55-1.47(m,3H),1.38-1.22(m,11H),1.20(d,J＝2.1Hz,3H),1.17-1.10(m,3H),1.08-1.02(m,3H),0.96(t,J＝7.4Hz,3H),0.88-0.84(m,11H).
13 C NMR(100MHz,CDCl 3 ):δ174.6,151.2,144.9,144.8,143.9,143.8,134.9,134.0,128.6,128.5,128.2,127.2,126.8,125.1,124.7,123.2,122.9,119.6,108.2,76.0,71.1,40.3,39.4,37.4,37.3,32.8,32.7,31.2,29.8,28.0,26.7,24.8,24.4,24.1,22.7,22.6,22.4,22.2,20.9,19.7,19.6,16.0,14.0.
HRMS(EI-TOF)m/z:[M] + Calcd for C 49 H 65 NO 2 699.5015；Found 699.5013。
Claims (6)
1. A method for synthesizing a compound shown as a formula I mainly comprises the following steps: under the condition of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, manganese acetate, sodium acetate and sodium pivalate, the compound shown in the formula II and the compound shown in the formula III react for at least 48 hours in a polar organic solvent at 100-120 ℃, and then the target compound is obtained through cooling, filtering and purifying steps in sequence;
in the formula, R 1 Is hydrogen, C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy, halogen or carbomethoxy; r 2 Is C 1 ～C 6 Alkyl or phenyl; r 3 Is C 1 ～C 6 An alkyl group; r 4 Is C 6 ～C 17 Monocyclic or polycyclic radicals of, substituted C 6 ～C 17 Monocyclic or polycyclic radicals of, or by C 1 ～C 16 Alkyl-substituted benzopyranyl;
wherein, said substituted C 6 ～C 17 The substituent of the monocyclic group or polycyclic group is selected from one or more of the following groups:
C 1 ～C 6 alkyl radical, C 1 ～C 6 Alkoxy, halogen or oxo.
2. The method of claim 1, wherein R is 1 Is hydrogen, C 1 ～C 3 Alkyl radical, C 1 ～C 3 Alkoxy, halogen or carbomethoxy.
3. The method of claim 1, wherein R is 2 Is C 1 ～C 3 Alkyl or phenyl.
4. A process according to claim 2 or 3, wherein the compound of the formula II used is one of the following compounds:
5. the method of claim 1, wherein R is 3 Is C 1 ～C 3 An alkyl group.
6. The method of claim 1, wherein R is 4 Is phenyl, p-methylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, m-chlorophenyl,
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