CN111909175B - Chiral tetrahydrofuro-oxazine fused benzimidazole-4, 7-diketone derivative and preparation method and application thereof - Google Patents

Chiral tetrahydrofuro-oxazine fused benzimidazole-4, 7-diketone derivative and preparation method and application thereof Download PDF

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CN111909175B
CN111909175B CN202010946758.XA CN202010946758A CN111909175B CN 111909175 B CN111909175 B CN 111909175B CN 202010946758 A CN202010946758 A CN 202010946758A CN 111909175 B CN111909175 B CN 111909175B
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刘丰五
王海霞
霍翔宇
季书杰
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Abstract

The invention discloses a chiral tetrahydrofuran oxazine fused benzimidazole-4, 7-diketone derivative and a preparation method thereofMethod and application, belonging to the field of sugar chemistry and pharmaceutical chemistry. It has a structure shown in the following general formula:

Description

Chiral tetrahydrofuro-oxazine fused benzimidazole-4, 7-diketone derivative and preparation method and application thereof
Technical Field
The invention belongs to the fields of sugar chemistry and pharmaceutical chemistry, and particularly relates to benzimidazole-4, 7-diketone derivatives and a preparation method thereof.
Background
The benzimidazole compound is a nitrogen-containing heterocyclic compound, has special structure, reactivity and physiological activity, and is an important parent nucleus of a plurality of active compounds. On the basis of benzimidazole, benzimidazole-4, 7-diketone compounds can be obtained through further structural modification. The benzimidazole-4, 7-diketone compounds have wide biological activity, the substituent on the quinone ring plays an important role in the biological activity, and the substitution position of most benzimidazole-4, 7-diketone compounds with biological activity is at 2,5 or 6 position.
Figure BDA0002675554760000011
The synthesis of novel benzimidazole-4, 7-diketone derivatives is an effective way for discovering novel medicaments. The preparation method of the benzimidazole-4, 7-diketone comprises the steps of firstly obtaining benzimidazole through condensation reaction of aldehyde or ketone and o-phenylenediamine, and then selectively oxidizing 4,7 sites of the benzimidazole through different methods to obtain the benzimidazole-4, 7-diketone.
Sugars play an important role in drug synthesis as chiral compounds. Ketose is used as a chiral initiator to obtain a target compound with a chiral center, so that the target compound can be endowed with better biological activity. The invention synthesizes chiral benzimidazole-4, 7-diketone derivatives by using 1,4:3, 6-diglycidyl-D-fructose as an initiator. At present, no relevant literature report on the synthesis of benzimidazole-4, 7-diketone analogues from sugars is found.
Disclosure of Invention
The invention aims to provide a series of chiral tetrahydrofuran oxazine fused benzimidazole-4, 7-diketone derivatives; the other purpose is to provide a preparation method and application thereof.
In order to achieve the purpose, the tetrahydrofuran oxazine fused benzimidazole derivative is obtained by condensation, oxidation and rearrangement of 1,4:3, 6-diglycidyl-D-fructose and 3, 6-dimethoxy o-phenylenediamine and other further structural modification, and then a series of chiral tetrahydrofuran oxazine fused benzimidazole-4, 7-diketone derivatives are obtained through oxidation reaction and substitution reaction of amine compounds in sequence.
The tetrahydrofuran oxazine fused benzimidazole-4, 7-diketone derivative is represented by a general formula I.
Figure BDA0002675554760000021
In the general formula I, R represents hydrogen or amino, and when R represents amino, the R is respectively aliphatic amino and aromatic amino. Preferably: r is a cyclic aliphatic amine group; an azacyclo aliphatic amine group; anilino or substituted anilino.
The R substitution position is 8 or 9.
In the general formula I, when R is an aliphatic amine group, the R can be a chain aliphatic amine group, a cyclic aliphatic amine group, a nitrogen heterocyclic aliphatic amine group or a benzyl amine group. R is preferably a chain C1-6 aliphatic amine group, a C3-6 cyclic aliphatic amine group or a C2-6 nitrogen heterocyclic aliphatic amine group;
wherein, when the aliphatic amine group is a chain aliphatic amine group, the general formula one can be represented by a general formula two:
Figure BDA0002675554760000031
in the formula R1Is H, R2Is C1-C6 alkyl; or R1And R2Are identical or different C1-C6 alkyl groups. Such as: methylamino, dimethylamino, ethylamino, diethylamino, dipropylamino, n-butylamino, etc.
Wherein when the aliphatic amine group is cyclic aliphatic amine group, R in the general formula II1Is H, R2Is a cycloalkyl group of C3-C6, i.e., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Wherein, when the aliphatic amine group is nitrogen heterocyclic aliphatic amine group, the general formula is three and four. In the general formula III: n-0, 1,2,3, i.e. aziridin-1-yl, azetidin-1-yl, pyrrolyl or piperidinyl, etc.
In the formula IV: x ═ O, NH, NCH3. Such as: morphininyl, piperazinyl or 4-methylpiperazinyl.
When R in the general formula I is aromatic amino, the compound shown in the general formula I can be represented by a general formula V, and the aromatic amino is preferably anilino or substituted anilino.
In the general formula five: r3Electron donating groups such as hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, and trifluoromethoxy groups; or an electron-withdrawing group such as fluorine, chlorine, bromine, iodine, trifluoromethyl and the like. R3May be mono-or di-substituted. R3When mono-substituted, the amino group can be in ortho-position, meta-position or para-position of the benzene ring amino group; r3When disubstituted, there may be two identical or different substituent groups, which may be ortho, meta or para to each other.
R3Preferably: a methyl, methoxy, isopropyl, chloro, bromo, or iodo group; mono-or di-substituted at the ortho, meta or para positions; r3When disubstituted, the substituents are two of the same substituent groups.
The compound shown in the general formula contains three chiral carbon atoms, and the configuration is respectively as follows: 3R,3aR,11 aS.
The preparation of QIF, a compound of the general formula:
Figure BDA0002675554760000041
the detailed steps are as follows:
(1) slowly adding 1, 4-dimethoxy benzene into concentrated nitric acid, reacting in ice bath, then transferring to room temperature for reaction, heating for reaction, cooling to room temperature after the raw materials are completely converted, pouring the reaction liquid into ice water, and filtering to obtain a yellow solid compound 1(3, 6-dimethoxy o-dinitrobenzene).
(2) Dissolving the compound 1 in absolute ethyl alcohol, adding palladium carbon, and introducing hydrogen to reduce the nitro on the benzene ring. After the reaction, the mixture was filtered and concentrated to obtain a black solid compound 2(3, 6-dimethoxyo-phenylenediamine).
(3) The compound 2 and 1,4:3, 6-diglycidyl-D-fructose obtained as above were dissolved in ethanol, heated for condensation, and after completion of the reaction, ethanol was distilled off under reduced pressure. And adding dichloromethane into the residue to dissolve the residue, adding an oxidant A, heating and refluxing, finishing the reaction, and performing column chromatography separation to obtain a white solid 3.
(4) Dissolving the compound 3 in a mixed solvent of acetonitrile and water, adding an oxidant B, finishing the reaction, and performing column chromatography separation to obtain a yellow solid 4.
(5) Dissolving the compound 4 in an organic solvent, adding an amine compound for substitution reaction, and after the reaction is finished, performing column chromatography separation to obtain two position isomers with different substitution positions, namely the target compound tetrahydrofuran benzoxazine fused benzimidazole-4, 7-diketone derivative (QIF).
The organic solvent used in the step (5) is one of methanol, ethanol and acetonitrile, or a mixed solvent of one of the methanol, the ethanol and the acetonitrile and water.
The oxidant A used in the reaction is hydrogen peroxide, DDQ (2, 3-dichloro-5, 6-dicyan p-benzoquinone), tert-butyl peroxy-alcohol, peroxybenzoic acid or manganese dioxide.
The oxidizing agents B used in the above reaction are DDQ (2, 3-dichloro-5, 6-dicyan-p-benzoquinone), manganese dioxide, PIDA (diacetoxyiodobenzene), PIFA ([ bis (trifluoroacetoxy) iodo ] benzene), ceric ammonium nitrate, or TEMPO (2,2,6, 6-tetramethylpiperidine oxide), respectively.
The invention has the advantages that:
1. the invention fuses the chirality of the sugar and the benzimidazole-4, 7-diketone to obtain the novel chiral tetrahydrofuran oxazine fused benzimidazole 4, 7-diketone derivative with better biological activity.
2. The raw materials adopted by the invention are cheap and easy to obtain, and the synthesis method is simple and easy to operate, and provides a new method for synthesizing the benzimidazole 4, 7-diketone.
3. The preliminary in vitro activity evaluation shows that the compounds have better antitumor activity, and a new way is opened for the discovery of novel antitumor drugs.
Detailed Description
To better illustrate the invention, the following examples are given:
example 1: synthesis of Compound 3
Under the condition of ice bath, 1, 4-dimethoxybenzene (10g, 0.072mol) is added into 60mL of concentrated nitric acid in batches, mechanical stirring is carried out, after 1h, the ice bath is removed, the reaction is carried out for 1h at room temperature, the temperature is increased to 80 ℃ again, and the reaction is continued for 2 h. And (3) cooling, pouring the reaction mixture into ice water, filtering, and airing a filter cake to obtain the yellow solid compound 1.
Dissolving yellow solid 1(12g, 0.053mol) in 60mL of absolute ethanol, adding 0.72g of palladium carbon, replacing 3 times with hydrogen, continuously introducing hydrogen, reacting at room temperature for 2h, filtering, and concentrating under reduced pressure to obtain black solid compound 2.
Dissolving black solid 2(8g, 0.048mol) and 1,4:3, 6-diglycidyl-D-fructose (8.3g, 0.058mol) in 100mL ethanol, heating to 65 ℃ for reaction for 3h under the protection of nitrogen, and removing the solvent by evaporation under reduced pressure after the reaction is finished. 100mL of dried dichloromethane and activated manganese dioxide (24g) were added, heated to reflux for 1h, cooled, concentrated, and chromatographed on silica gel (DCM: MeOH ═ 20:1) to give 3 as a white solid.1H NMR(400MHz,DMSO-d6)δ6.70(d,J＝8.6Hz,1H),6.64(d,J＝8.6Hz,1H),6.11(d,J＝2.5Hz,1H),5.39(d,J＝7.0Hz,1H),5.07(d,J＝15.5Hz,1H),4.82(d,J＝15.5Hz,1H),4.62–4.48(m,1H),4.28(dd,J＝3.9,2.7Hz,1H),3.98(t,J＝7.4Hz,1H),3.85(d,J＝12.9Hz,6H),3.72(dd,J＝9.7,7.3Hz,1H)。
Example 2: synthesis of Compound 4
Compound 3(5g, 0.017mol) was added to a mixed solvent of 20mL of water and 20mL of acetonitrile, and the mixture was cooledStirring at room temperature, adding bis (trifluoroacetoxy) iodobenzene (11g, 0.026mol), reacting for 2h, concentrating under reduced pressure, and separating by silica gel column chromatography (EA: MeOH ═ 20:1) to give yellow solid 4.1H NMR(400MHz,DMSO-d6)δ6.74(s,2H),6.01(s,1H),5.47(d,J＝6.7Hz,1H),5.13(d,J＝16.0Hz,1H),4.81(d,J＝16.0Hz,1H),4.57(m,1H),4.28(s,1H),4.01(t,J＝7.3Hz,1H),3.73(t,J＝8.4Hz,1H).
Example 3: compounds QIF-1a and QIF-1b (formula I, R is arylamino, the amino substitution is at the 8-and 9-positions, respectively; formula V, R3Hydrogen) synthesis
(in the QIF numbering, a represents a 8-position substitution and b represents a 9-position substitution, the same applies hereinafter.)
Compound 4(500mg, 1.91mmol) was dissolved in 35mL of methanol, aniline (174 μ L, 1.91mmol) was added, stirred at room temperature for 15min, concentrated under reduced pressure, and separated by column chromatography (DCM: MeOH ═ 30:1) to give the purple solid compounds QIF-1a and QIF-1b in that order.
QIF-1a：1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),7.43(t,J＝7.6Hz,2H),7.37(d,J＝7.8Hz,2H),7.21(t,J＝7.1Hz,1H),6.04(s,1H),5.67(s,1H),5.45(d,J＝6.7Hz,1H),5.09(d,J＝15.7Hz,1H),4.79(d,J＝15.7Hz,1H),4.62–4.48(m,1H),4.26(s,1H),3.98(t,J＝7.3Hz,1H),3.71(dd,J＝8.9,8.1Hz,1H).
QIF-1b：1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),7.43(t,J＝7.5Hz,2H),7.36(d,J＝7.8Hz,2H),7.21(t,J＝7.2Hz,1H),6.05(s,1H),5.68(s,1H),5.48(d,J＝6.7Hz,1H),5.13(d,J＝16.1Hz,1H),4.81(d,J＝16.1Hz,1H),4.63–4.52(m,1H),4.31(s,1H),4.02(t,J＝7.2Hz,1H),3.75(dd,J＝8.7,8.3Hz,1H).
Example 4: the compounds QIF-2a and QIF-2b (formula I, R is arylamino; formula V, R is3Is 4-methyl)
Two purple solid compounds QIF-2a and QIF-2b were obtained, respectively, as described in example 3, using p-toluidine instead of aniline.
QIF-2a：1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.21(d,J＝8.3Hz,2H),7.13(d,J＝8.4Hz,2H),6.18(d,J＝2.6Hz,1H),5.94(s,1H),5.22(d,J＝15.8Hz,1H),4.79(d,J＝15.8Hz,1H),4.71–4.58(m,1H),4.29(m,2H),3.90(dd,J＝9.3,8.2Hz,1H),2.55(d,J＝11.0Hz,1H),2.36(s,3H).
QIF-2b：1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),7.24(s,4H),6.04(d,J＝2.6Hz,1H),5.61(s,1H),5.49(d,J＝6.8Hz,1H),5.12(d,J＝16.1Hz,1H),4.80(d,J＝16.1Hz,1H),4.62–4.52(m,1H),4.34–4.27(m,1H),4.02(t,J＝7.3Hz,1H),3.75(dd,J＝9.5,7.4Hz,1H),2.31(s,3H).
Example 5: the compounds QIF-3a and QIF-3b (formula I, R is arylamino; formula V, R is3Is 3, 4-dimethyl)
The procedure described in example 3 was followed, using 3, 4-dimethylaniline instead of aniline, to give two purple solid compounds QIF-3a and QIF-3b, respectively.
QIF-3a：1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.18(d,J＝8.1Hz,1H),7.14(d,J＝1.7Hz,1H),7.07(dd,J＝8.0,2.0Hz,1H),6.03(d,J＝2.4Hz,1H),5.59(s,1H),5.46(d,J＝6.9Hz,1H),5.09(d,J＝15.7Hz,1H),4.79(d,J＝15.8Hz,1H),4.59–4.49(m,1H),4.25(dd,J＝3.8,2.7Hz,1H),3.98(t,J＝7.3Hz,1H),,3.72(dd,J＝9.7,7.2Hz,1H),2.23(s,3H),2.22(s,3H).
QIF-3b：1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),7.19(d,J＝8.1Hz,1H),7.12(d,J＝1.7Hz,1H),7.07(dd,J＝8.0,2.0Hz,1H),6.04(d,J＝2.6Hz,1H),5.61(s,1H),5.50(d,J＝6.9Hz,1H),5.12(d,J＝16.1Hz,1H),4.81(d,J＝16.1Hz,1H),4.61–4.54(m,1H),4.30(dd,J＝4.0,2.9Hz,1H),4.02(t,J＝7.3Hz,1H),3.75(dd,J＝9.7,7.4Hz,1H),2.23(s,3H),2.22(s,3H).
Example 6: the compounds QIF-4a and QIF-4b (formula I, R is arylamino; formula V, R is3Is 4-isopropyl) synthesis
Two purple solid compounds QIF-4a and QIF-4b were obtained, respectively, as described in example 3, using 4-isopropylaniline instead of aniline.
QIF-4a：1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),7.34–7.23(m,4H),6.04(s,1H),5.61(s,1H),5.44(d,J＝6.7Hz,1H),5.09(d,J＝15.7Hz,1H),4.79(d,J＝15.7Hz,1H),4.59–4.48(m,1H),4.25(s,1H),3.98(t,J＝7.3Hz,1H),3.72(dd,J＝8.7,7.9Hz,1H),2.93–2.86(m,1H),1.21(d,J＝6.9Hz,6H).
QIF-4b:1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.34–7.23(m,4H),6.05(s,1H),5.63(s,1H),5.49(d,J＝6.9Hz,1H),5.13(d,J＝16.0Hz,1H),4.81(d,J＝16.1Hz,1H),4.63–4.53(m,1H),4.31(dd,J＝4.0,3.0Hz,1H),4.02(t,J＝7.3Hz,1H),3.75(dd,J＝9.7,7.4Hz,1H),2.94–2.87(m,1H),1.21(d,J＝6.9Hz,6H).
Example 7: the compounds QIF-5a and QIF-5b (formula I, R is arylamino; formula V, R is3Is 4-methoxy group)
Two purple solid compounds QIF-5a and QIF-5b were obtained, respectively, as described in example 3, using p-anisidine instead of aniline.
QIF-5a：1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.32–7.24(m,2H),7.03–6.96(m,2H),6.04(d,J＝2.5Hz,1H),5.49(s,1H),5.44(d,J＝6.8Hz,1H),5.08(d,J＝15.7Hz,1H),4.79(d,J＝15.7Hz,1H),4.59–4.49(m,1H),4.25(dd,J＝3.9,2.7Hz,1H),3.98(t,J＝7.3Hz,1H),3.78(s,3H),3.72(dd,J＝9.7,7.2Hz,1H).
QIF-5b：1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),7.27(d,J＝8.6Hz,2H),7.00(d,J＝8.7Hz,2H),6.04(s,1H),5.50(d,J＝5.0Hz,1H),5.49(s,1H),5.12(d,J＝16.1Hz,1H),4.80(d,J＝16.1Hz,1H),4.63–4.52(m,1H),4.30(s,1H),4.02(t,J＝7.2Hz,1H),3.82–3.70(m,4H).
Example 8: the compounds QIF-6a and QIF-6b (formula I, R is arylamino; formula V, R is3Is 3-methoxy group)
The procedure described in example 3 was followed, using 3-methoxyaniline instead of aniline, to give two purple solid compounds QIF-6a and QIF-6b, respectively.
QIF-6a：1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.33(t,J＝8.3Hz,1H),6.96(d,J＝5.9Hz,1H),6.95(s,1H),6.79(d,J＝8.4Hz,1H),6.04(s,1H),5.72(s,1H),5.46(d,J＝6.8Hz,1H),5.10(d,J＝15.7Hz,1H),4.79(d,J＝15.8Hz,1H),4.65–4.45(m,1H),4.27(s,1H),3.99(t,J＝7.3Hz,1H),3.76(s,3H),3.72(t,J＝8.7Hz,1H).
QIF-6b：1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),7.34(t,J＝8.0Hz,1H),6.95(d,J＝8.5Hz,1H),6.94(s,1H),6.79(d,J＝8.0Hz,1H),6.04(s,1H),5.73(s,1H),5.49(d,J＝6.8Hz,1H),5.13(d,J＝16.1Hz,1H),4.81(d,J＝16.1Hz,1H),4.65–4.51(m,1H),4.31(s,1H),4.02(t,J＝7.3Hz,1H),3.76(s,3H),3.75(dd,J＝9.0Hz,6.7Hz,1H).
Example 9: the compounds QIF-7a and QIF-7b (formula I, R is arylamino; formula V, R is3Is 4-ethoxy) synthesis
Two purple solid compounds QIF-7a and QIF-7b were obtained, respectively, as described in example 3, using 4-ethoxyaniline in place of aniline.
QIF-7a：1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.26(d,J＝8.6Hz,2H),6.98(d,J＝8.7Hz,2H),6.03(s,1H),5.49(s,1H),5.44(d,J＝6.8Hz,1H),5.08(d,J＝15.7Hz,1H),4.78(d,J＝15.7Hz,1H),4.59–4.49(m,1H),4.25(s,1H),4.04(q,J＝6.9Hz,2H,H-21),3.98(t,J＝7.3Hz,1H),3.71(dd,J＝8.3Hz,8.6Hz,1H),1.33(t,J＝6.9Hz,3H).
QIF-7b:1H NMR(400MHz,DMSO-d6)δ8.91(s,1H,),7.25(d,J＝8.7Hz,2H),6.98(d,J＝8.8Hz,2H),6.03(s,1H),5.49(s,1H,),5.48(d,J＝7.6Hz,1H),5.12(d,J＝16.1Hz,1H),4.80(d,J＝16.1Hz,1H),4.62–4.54(m,1H),4.31(s,1H),4.05(q,J＝6.9Hz,2H),4.01(t,J＝7.0Hz,1H),3.75(dd,J＝8.0Hz,9.0Hz,1H),1.33(t,J＝6.9Hz,3H).
Example 10: the compounds QIF-8a and QIF-8b (formula I, R is arylamino; formula V, R is3Is 2-fluoro)
Compound 4(500mg, 1.91mmol) was dissolved in a mixed solvent of 15mL of water and 15mL of ethanol, 2-fluoroaniline (855 μ L, 8.77mmol) was added, reacted at room temperature for 2h, concentrated under reduced pressure, and separated by column chromatography (DCM: MeOH ═ 30:1) to give two purple solids, QIF-8a and QIF-8b, in that order.
QIF-8a：1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.43(t,J＝7.7Hz,1H),7.40–7.33(m,2H),7.29(dd,J＝9.3,6.4Hz,1H),6.02(s,1H),5.44(d,J＝6.7Hz,1H),5.10(d,J＝15.5Hz,2H),4.79(d,J＝15.8Hz,1H),4.60–4.48(m,1H),4.26(s,1H),3.98(t,J＝7.3Hz,1H),3.71(dd,J＝9.2,7.6Hz,1H).
QIF-8b：1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),7.43(t,J＝7.8Hz,1H),7.40–7.34(m,2H),7.30(dd,J＝6.8,3.8Hz,1H),6.05(s,1H),5.48(d,J＝6.8Hz,1H),5.13(d,J＝16.0Hz,2H),4.81(d,J＝16.1Hz,1H),4.63–4.52(m,1H),4.31(s,1H),4.03(t,J＝7.2Hz,1H),3.75(t,J＝8.4Hz,1H).
Example 11: the compounds QIF-9a and QIF-9b (formula I, R is arylamino; formula V, R is3Is 3-chloro) synthesis
The same procedure as in example 10, 3-chloroaniline was used instead of 2-fluoroaniline to give two purple solids QIF-9a and QIF-9 b.
QIF-9a：1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.44(d,J＝8.7Hz,2H),7.36(d,J＝8.1Hz,1H),7.25(d,J＝7.9Hz,1H),6.03(s,1H),5.73(s,1H),5.45(d,J＝6.7Hz,1H),5.10(d,J＝15.8Hz,1H),4.79(d,J＝15.8Hz,1H),4.65–4.45(m,1H),4.26(s,1H),3.99(dd,J＝7.2,7.3Hz,1H),3.72(dd,J＝9.0,8.0Hz,1H).
QIF-9b:1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.45(d,J＝8.5Hz,2H),7.36(d,J＝7.8Hz,1H),7.25(d,J＝7.6Hz,1H),6.05(s,1H),5.75(s,1H),5.48(d,J＝6.5Hz,1H),5.13(d,J＝16.0Hz,1H),4.81(d,J＝16.2Hz,1H),4.63–4.50(m,1H),4.31(s,1H),4.02(dd,J＝7.2,6.8Hz,1H),3.74(dd,J＝8.4,8.0Hz,1H).
Example 12: the compounds QIF-10a and QIF-10b (formula I, R is arylamino; formula V, R is3Is 4-bromo) synthesis
The same procedure as in example 10, 4-bromoaniline instead of 2-fluoroaniline gave two purple solids QIF-10a and QIF-10 b.
QIF-10a：1H NMR(400MHz,DMSO-d6)δ9.22(s,1H,H-14),7.60(d,J＝8.5Hz,2H,H-17,19),7.35(d,J＝8.5Hz,2H,H-16,20),6.03(s,1H,H-3),5.71(s,1H,H-9),5.45(d,J＝6.8Hz,1H,H-13),5.09(d,J＝15.8Hz,1H,H-1a),4.79(d,J＝15.8Hz,1H,H-1b),4.63–4.47(m,1H,H-5),4.25(s,1H,H-4),3.98(t,J＝7.2Hz,1H,H-6a),3.71(dd,J＝8.8Hz,8.0Hz,1H,H-6b).
QIF-10b:1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.60(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),6.04(s,1H),5.72(s,1H),5.49(d,J＝6.8Hz,1H),5.13(d,J＝16.1Hz,1H),4.81(d,J＝16.1Hz,1H),4.63–4.52(m,1H),4.31(s,1H),4.02(t,J＝7.2Hz,1H),3.75(t,J＝8.4Hz,1H).
Example 13: the compounds QIF-11a and QIF-11b (formula I, R is arylamino; formula V, R is3Is 4-iodo)
The same procedure as in example 10, 4-iodoaniline instead of 2-fluoroaniline gave QIF-11a and QIF-11b as violet solids in that order.
QIF-11a：1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),7.75(d,J＝8.1Hz,2H),7.20(d,J＝8.1Hz,2H),6.03(s,1H),5.71(s,1H),5.45(d,J＝6.7Hz,1H),5.09(d,J＝15.8Hz,1H),4.78(d,J＝15.8Hz,1H),4.61–4.45(m,1H),4.25(s,1H),3.98(t,J＝7.3Hz,1H),3.71(t,J＝8.4Hz,1H).
QIF-11b:1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.75(d,J＝8.2Hz,2H),7.20(d,J＝8.2Hz,2H),6.04(s,1H),5.73(s,1H),5.49(d,J＝6.7Hz,1H),5.13(d,J＝16.1Hz,1H),4.81(d,J＝16.1Hz,1H),4.64–4.50(m,1H),4.31(s,1H),4.02(t,J＝7.2Hz,1H),3.74(t,J＝8.4Hz,1H).
Example 14: the compounds QIF-12a and QIF-12b (formula I, R is arylamino; formula V, R is3Is 4-trifluoromethyl)
The same procedure as in example 10, 4-trifluoromethylaniline instead of 2-fluoroaniline gave QIF-12a and QIF-12b as violet solids in that order.
QIF-12a：1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),7.76(d,J＝8.6Hz,2H),7.61(d,J＝8.5Hz,2H),6.04(d,J＝2.5Hz,1H),5.91(s,1H),5.46(d,J＝6.8Hz,1H),5.10(d,J＝15.8Hz,1H),4.80(d,J＝15.8Hz,1H),4.61–4.50(m,1H),4.27(dd,J＝3.9,2.8Hz,1H),3.99(t,J＝7.3Hz,1H),3.72(dd,J＝9.7,7.3Hz,1H).
QIF-12b:1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.77(d,J＝8.6Hz,2H),7.60(d,J＝8.5Hz,2H),6.06(d,J＝2.7Hz,1H),5.93(s,1H),5.49(d,J＝6.8Hz,1H),5.14(d,J＝16.1Hz,1H),4.82(d,J＝16.1Hz,1H),4.66–4.52(m,1H),4.35–4.28(m,1H),4.02(t,J＝7.3Hz,1H),3.75(dd,J＝9.6,7.4Hz,1H).
Example 15: a compound QIF-13a (general formula I, R is fatty amino group; general formula II, R1Is n-propyl, R2Is n-propyl) synthesis
The procedure described in example 3 was followed, using dipropylamine in place of aniline, to give the purple solid compounds QIF-13a and QIF-13 b.
QIF-13a：1H NMR(400MHz,DMSO-d6)δ6.02(d,J＝2.4Hz,1H),5.42(d,J＝6.7Hz,1H),5.33(s,1H),5.04(d,J＝15.7Hz,1H),4.74(d,J＝15.7Hz,1H),4.57-4.49(m,1H),4.23(dd,J＝3.6,2.7Hz,1H),3.97(t,J＝7.2Hz,1H),3.69(dd,J＝9.6,7.2Hz,1H),3.42(dd,J＝8.9,6.2Hz,4H),1.61(m,4H),0.89(t,J＝7.3Hz,6H).
QIF-13b：1H NMR(400MHz,DMSO-d6)δ6.02(d,J＝2.5Hz,1H),5.45(d,J＝6.8Hz,1H),5.34(s,1H),5.08(d,J＝16.0Hz,1H)4.77(d,J＝16.0Hz,1H),4.58-4.51(m,1H),4.24(dd,J＝3.8,2.8Hz,1H),4.01(t,J＝7.3Hz,1H),3.72(dd,J＝9.7,7.3Hz,1H),3.40(m,4H),1.69(m,4H),0.89(t,J＝7.3Hz,6H).
Example 16: the compounds QIF-14a and QIF-14b (formula I, R is fatty amino group; formula II, R1Is hydrogen, R2Is cyclohexyl) synthesis
The purple solid compounds QIF-14a and QIF-14b were obtained in the same manner as in example 3, except that cyclohexylamine was used instead of aniline.
QIF-14a：1H NMR(400MHz,DMSO-d6)δ7.12(d,J＝8.4Hz,1H),6.05(d,J＝2.4Hz,1H),5.43(d,J＝6.9Hz,1H),5.27(s,1H),5.05(d,J＝15.7Hz,1H),4.76(d,J＝15.7Hz,1H),4.60–4.48(m,1H),4.24(dd,J＝3.8,2.7Hz,1H),3.98(t,J＝7.3Hz,1H),3.71(dd,J＝9.7,7.3Hz,1H),3.27(m,1H),1.77(m,4H),1.59(d,J＝12.5Hz,1H),1.44–1.26(m,4H),1.19–1.05(m,1H).
QIF-14b:1H NMR(400MHz,DMSO-d6)δ6.89(d,J＝8.4Hz,1H),5.98(s,1H),5.48(d,J＝6.6Hz,1H),5.27(s,1H),5.09(d,J＝16.1Hz,1H),4.78(d,J＝16.1Hz,1H),4.60–4.49(m,1H),4.27(s,1H),3.99(t,J＝7.3Hz,1H),3.71(dd,J＝8.8,8.1Hz,1H),3.28(s,1H),1.90–1.66(m,4H),1.60(d,J＝12.7Hz,1H),1.41–1.29(m,4H),1.19–1.10(m,1H).
Example 17: synthesis of Compounds QIF-15a and QIF-15b (formula I, R is benzyl)
The procedure described in example 3 was followed, using benzylamine instead of aniline, to give the purple solid compounds QIF-15a and QIF-15b, in that order.
QIF-15a：1H NMR(400MHz,DMSO-d6)δ8.23(t,J＝6.5Hz,1H),7.41–7.30(m,4H),7.29–7.22(m,1H),6.00(d,J＝2.3Hz,1H),5.43(d,J＝6.9Hz,1H),5.09(s,1H),5.05(d,J＝15.7Hz,1H),4.75(d,J＝15.7Hz,1H),4.57–4.47(m,1H),4.41(d,J＝6.5Hz,2H),4.20(dd,J＝3.6,2.9Hz,1H),3.95(t,J＝7.3Hz,1H),3.68(dd,J＝9.6,7.3Hz,1H).
QIF-15b:1H NMR(400MHz,DMSO-d6)δ8.01(t,J＝6.4Hz,1H),7.39–7.30(m,4H),7.29-7.22(m,1H),6.00(d,J＝2.6Hz,1H),5.47(d,J＝6.9Hz,1H),5.09(d,J＝16.0Hz,2H),4.77(d,J＝16.1Hz,1H),4.60-4.52(m,1H),4.41(d,J＝6.6Hz,2H),4.26(dd,J＝3.4,3.3Hz,1H),4.01(t,J＝7.3Hz,1H),3.73(dd,J＝9.6,7.4Hz,1H).
Example 18: the compounds QIF-16a and QIF-16b (formula I, R is fatty amine group; formula II, R1Is hydrogen, R2Is cyclopentyl alkyl group)
The purple solid compounds QIF-16a and QIF-16b were obtained in the same manner as in example 3, except that the aniline was replaced by cyclopentylamine.
QIF-16a：1H NMR(400MHz,DMSO-d6)δ7.23(d,J＝7.2Hz,1H),6.05(d,J＝2.4Hz,1H),5.43(d,J＝6.8Hz,1H),5.22(s,1H),5.04(d,J＝15.7Hz,1H),4.75(d,J＝15.7Hz,1H),4.59–4.48(m,1H),4.24(dd,J＝3.7,2.8Hz,1H),3.97(t,J＝7.3Hz,1H),3.73(m,2H),2.00–1.86(m,2H),1.73–1.59(m,4H),1.58–1.47(m,2H).
QIF-16b:1H NMR(400MHz,DMSO-d6)δ6.98(d,J＝7.2Hz,1H),5.97(d,J＝2.6Hz,1H),5.46(d,J＝6.8Hz,1H),5.23(s,1H),5.09(d,J＝16.1Hz,1H),4.78(d,J＝16.1Hz,1H),4.59–4.50(m,1H),4.30–4.24(m,1H),3.98(t,J＝7.3Hz,1H),3.81–3.66(m,2H),2.00–1.87(m,2H),1.73–1.50(m,6H).
Example 19: synthesis of compounds QIF-17a and QIF-17b (general formula I, R is nitrogen heterocyclic aliphatic amine group; general formula III, n is 1)
The procedure described in example 3 was followed, using azetidine instead of aniline, to give the purple solid compounds QIF-17a and QIF-17b, in that order.
QIF-17a：1H NMR(400MHz,DMSO-d6)δ6.05(d,J＝2.4Hz,1H),5.41(d,J＝6.9Hz,1H),5.04(d,J＝15.7Hz,1H),4.92(s,1H),4.74(d,J＝15.7Hz,1H),4.60–4.45(m,3H),4.22(dd,J＝3.8,2.7Hz,1H),4.10–3.92(m,3H),3.69(dd,J＝9.7,7.2Hz,1H),2.45–2.34(m,2H).
QIF-17b:1H NMR(400MHz,DMSO-d6)δ5.95(s,1H),5.45(d,J＝6.8Hz,1H),5.08(d,J＝16.2Hz,1H),4.94(s,1H),4.77(d,J＝16.2Hz,1H),4.59–4.31(m,3H),4.24(s,1H),4.16–3.91(m,3H),3.78–3.66(m,1H),2.45–2.32(m,2H).
Example 20: synthesis of Compounds QIF-18a and QIF-18b (formula one, R is azacycloalkyl; formula three, n is 2)
The purple solid compounds QIF-18a and QIF-18b were obtained in succession, using tetrahydropyrrole instead of aniline, as described in example 3.
QIF-18a：1H NMR(400MHz,DMSO-d6)δ6.05(d,J＝2.4Hz,1H),5.42(d,J＝6.9Hz,1H),5.20(s,1H),5.05(d,J＝15.7Hz,1H),4.75(d,J＝15.7Hz,1H),4.58–4.48(m,1H),4.23(dd,J＝3.8,2.7Hz,1H),3.97(t,J＝15.7Hz),4.03–3.57(m,4H),3.70(dd,J＝7.2,9.7Hz,1H),1.90(s,4H).
QIF-18b:1H NMR(400MHz,DMSO-d6)δ6.00(s,1H),5.47(d,J＝6.7Hz,1H),5.21(s,1H),5.09(d,J＝16.1Hz,1H),4.78(d,J＝16.0Hz,1H),4.61–4.48(m,1H),4.26(s,1H),3.86(m,6H),1.89(s,4H).
Example 21: synthesis of Compound QIF-19a (general formula I, R is azacycloalkyl; general formula IV, X is oxygen atom)
The procedure described in example 3 was followed, using morpholine instead of aniline, to give the compound QIF-19a as a violet solid.
QIF-19a：1H NMR(400MHz,CDCl3)δ6.11(d,J＝2.6Hz,1H),5.59(s,1H),5.20(d,J＝15.8Hz,1H),4.77(d,J＝15.8Hz,1H),4.65(s,1H),4.31(dd,J＝4.1,2.9Hz,1H),4.27(t,J＝7.7Hz,1H),3.89(dd,J＝9.4,8.2Hz,1H),3.85(t,J＝4.8Hz,4H),3.51(m,4H),2.72(d,J＝9.6Hz,1H).
Example 22: synthesis of Compound QIF-20a (general formula I, R is azacycloalkyl; general formula IV, X is imino)
Piperazine was used in place of aniline in the procedure described in example 3 to give the purple solid compound QIF-20 a.
QIF-20a：1H NMR(400MHz,DMSO-d6)δ5.91(s,1H),5.48(s,1H),4.97(d,J＝15.7Hz,1H),4.66(d,J＝15.7Hz,1H),4.44(m,1H),4.15(s,1H),3.88(t,J＝7.3Hz,1H),3.60(dd,J＝9.2,8.0Hz,1H),3.32(s,2H),2.75(s,4H),2.41(s,4H).
Example 23: compound in vitro anti-gastric cancer cell MGC-803 activity
The MTT method is adopted, the action time is 72 hours, and the antitumor activity of the compound is evaluated, so that the compound has a better effect of inhibiting MGC-803 cell proliferation. Half inhibitory concentration IC of partial compound50(. mu.M) as follows:
Figure BDA0002675554760000201
example 24: activity of compound against human breast cancer cell MCF-7 in vitro
The anti-tumor activity of the compound is evaluated by adopting an MTT method with the action time of 72h, and the compound has better effect of inhibiting the proliferation of MCF-7 cells. Half inhibitory concentration IC of partial compound50(. mu.M) as follows:
Figure BDA0002675554760000202

Claims (5)

1. a chiral tetrahydrofuro-oxazine fused benzimidazole-4, 7-dione derivative having the formula:
Figure FDA0003439784360000011
in the formula: r3Is hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy or trifluoromethoxy; fluorine, chlorine, bromine, iodine or trifluoromethyl; r3Is mono-or di-substituted.
2. The chiral tetrahydrofurane oxazine fused benzimidazole-4, 7-dione derivative of claim 1, wherein R is3A methyl, methoxy, isopropyl, chloro, bromo or iodo group; r3Is mono-or di-substituted; r3When disubstituted, the substituents are two identical substituent groups, ortho, meta or para.
3. A chiral tetrahydrofurane oxazine fused benzimidazole-4, 7-dione derivative according to claim 2, selected from the group consisting of:
Figure FDA0003439784360000012
Figure FDA0003439784360000021
4. a process for the preparation of a chiral tetrahydrofurane oxazine fused benzimidazole-4, 7-dione derivative according to claim 1, by:
Figure FDA0003439784360000022
(1) slowly adding 1, 4-dimethoxybenzene into concentrated nitric acid, reacting in ice bath, then transferring to room temperature for reaction, heating for reaction, cooling to room temperature when the raw materials are completely converted, pouring the reaction solution into ice water, and filtering to obtain a compound 1;
(2) dissolving the compound 1 in absolute ethyl alcohol, adding palladium carbon, introducing hydrogen, and filtering after the reaction is finished to obtain a compound 2;
(3) dissolving the compound 2 and 1,4:3, 6-diglycidyl-D-fructose in ethanol, heating for condensation, and removing ethanol by reduced pressure distillation after the reaction is finished; dissolving the residue in dichloromethane, adding oxidant A, heating and refluxing, reacting, and performing column chromatography separation to obtain compound 3;
(4) dissolving the compound 3 in a mixed solvent of acetonitrile and water, adding an oxidant B, finishing the reaction, and performing column chromatography separation to obtain a compound 4;
(5) dissolving the compound 4 in an organic solvent, adding an amine compound for substitution reaction, and after the reaction is finished, performing column chromatography separation to obtain a target compound;
the organic solvent used in the step (5) is one of methanol, ethanol and acetonitrile, or a mixed solvent of one of the methanol, the ethanol and the acetonitrile and water;
the oxidant A is hydrogen peroxide, DDQ (2, 3-dichloro-5, 6-dicyan p-benzoquinone), tert-butyl peroxy-alcohol, peroxybenzoic acid or manganese dioxide;
the oxidant B is DDQ (2, 3-dichloro-5, 6-dicyan p-benzoquinone), manganese dioxide, PIDA (diacetoxyiodobenzene), PIFA ([ bis (trifluoroacetoxy) iodo ] benzene), ammonium ceric nitrate or TEMPO (2,2,6, 6-tetramethylpiperidine oxide).
5. Use of a chiral tetrahydrofurane-oxazine-fused benzimidazole-4, 7-dione derivative according to any one of claims 1 to 3, as active ingredient in the preparation of a medicament against human breast cancer, a medicament against human gastric cancer or as a precursor for the preparation thereof.
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