CN108084200B - Halogenated dihydropyranopyrrolone compound and preparation method and application thereof - Google Patents

Halogenated dihydropyranopyrrolone compound and preparation method and application thereof Download PDF

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CN108084200B
CN108084200B CN201711296699.0A CN201711296699A CN108084200B CN 108084200 B CN108084200 B CN 108084200B CN 201711296699 A CN201711296699 A CN 201711296699A CN 108084200 B CN108084200 B CN 108084200B
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李俊龙
沈旭东
李强
周亮
朱红萍
戴青松
李青竹
张翔
曾荣
冷海军
刘悦
杨开川
张鹰
刘宇
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Chengdu University
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    • 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
    • C07D491/02—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 two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention provides a halogenated dihydropyranopyrrolopyrrole ketone compound shown as a formula (I) or a crystal form thereof, wherein X is fluorine, chlorine, bromine or iodine; l is1Is absent or vinyl; the ring A is a naphthalene ring, a benzene ring and a thiophene ring; r1Is benzyl, C1‑C8Alkyl or (CH)2)n-O-Bn; n is an integer of 1-5; r2Is benzyl, allyl, p-methoxybenzyl; r3、R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1‑C3Alkyl, nitro, methoxy. The invention also provides a preparation method of the compound or the crystal form thereof. The compound of the invention has the advantages of simple preparation method, mild reaction, high yield, certain antitumor activity and wide market application prospect.

Description

Halogenated dihydropyranopyrrolone compound and preparation method and application thereof
Technical Field
The invention relates to a halogenated dihydropyranopyrrolopyrrole ketone compound, a preparation method and application thereof.
Background
The polysubstituted pyran compounds, especially the polysubstituted compounds based on pyrano ring skeleton, are widely existed in natural products or pharmaceutical intermediates with physiological activity, and the modification of substituents, derivatization of structural analogues and further re-evaluation of biological activity of the compounds become research hotspots.
Huynh et al (t.h.v.huynh, i.shim, h.bohr, b.abrahamsen, b.nielsen, a.a.jensen, l.bunch, j.med.chem.2012,55, 5403-.
Figure BDA0001500439950000011
CN105541853A discloses polysubstituent type γ -pyranopyrrolidone compounds as shown below, which have good antibacterial activity.
Figure BDA0001500439950000012
At present, no report has been made on the halogenated dihydropyranopyrrolopyrrolone compounds of the present invention.
Disclosure of Invention
In order to solve the technical problems, the invention provides a halogenated dihydropyranopyrrolopyrrole ketone compound and a preparation method and application thereof.
The invention firstly provides a halogenated dihydropyranopyrrolopyrrole ketone compound shown as a formula (I) or a crystal form thereof:
Figure BDA0001500439950000021
wherein X is fluorine, chlorine, bromine or iodine;
L1is absent or vinyl;
the ring A is a naphthalene ring, a benzene ring and a thiophene ring;
R1is benzyl, C1-C8Alkyl or (CH)2)n-O-Bn; n is an integer of 1-5;
R2is benzyl, allyl, p-methoxybenzyl;
R3、R4each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxy.
Further, the above compound is one of the following compounds:
Figure BDA0001500439950000022
Figure BDA0001500439950000031
the invention also provides a preparation method of the compound or the crystal form thereof, which comprises the following steps:
Figure BDA0001500439950000032
(1) taking a compound shown as a formula (1-1) and ethyl acrylate shown as a formula (1-2), reacting in ethanol at 25 +/-2 ℃ for 16 +/-2 h, adding diethyl oxalate and sodium ethoxide shown as a formula (1-4), and reacting at 90 +/-2 ℃ to obtain a compound shown as a formula (1-5);
(2) taking the compound shown in the formula (1-5) and the compound shown in the formula (1-6), reacting at 90 +/-3 ℃ to obtain the compound shown in the formula (1),
(3) taking a compound shown in a formula (1) and a compound shown in a formula (2) to react at 25 +/-3 ℃ by taking chlorobenzene as a solvent and squaramide as a catalyst to obtain the compound shown in the formula (I).
Further, X is fluorine, chlorine, bromine, iodine; l is1Is absent or vinyl; the ring A is a naphthalene ring, a benzene ring and a thiophene ring; r1Is benzyl, C1-C8Alkyl or (CH)2)n-O-Bn; n is an integer of 1-5; r2Is benzyl, allyl, p-methoxybenzyl; r3、R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxy.
Further, in the step (1), the molar ratio of the compound represented by the formula (1-1), ethyl acrylate, diethyl oxalate and sodium ethoxide is 1: 1: 1: 1.5.
further, in the step (2), the molar ratio of the compound represented by the formula (1-5) to the compound represented by the formula (1-6) is 1: 1.
Further, in the step (3), the molar ratio of the compound represented by the formula (1) to the compound represented by the formula (2) and the squaramide is 10:30: 1.
Further, in the step (3), the squaramide structure is as follows:
Figure BDA0001500439950000041
the invention also provides application of the compound or the crystal form thereof in preparing antitumor drugs.
Further, the tumor is breast cancer or melanoma.
The experimental results show that: the preparation method of the invention has the advantages of simple preparation method, mild reaction, high yield, antitumor activity and wide market application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
C1-C3The alkyl group of (A) means a methyl group, an ethyl group or a propyl group.
In the structural formula of the compound, Et represents ethyl, Me represents methyl, and Bn represents benzyl; PMB represents p-methoxybenzyl.
EXAMPLE 1 preparation of Compounds of the invention
Raw materials
Quinidine squaramide catalyst: has the structure of
Figure BDA0001500439950000051
From Daiiol drug chiral technology (Shanghai) Co., Ltd
General synthetic route:
Figure BDA0001500439950000052
wherein X is fluorine, chlorine, bromine or iodine; l is1Is absent or vinyl; the ring A is a naphthalene ring, a benzene ring and a thiophene ring; r1Is benzyl, C1-C8Alkyl or (CH)2)n-O-Bn; n is an integer of 1-5; r2Is benzyl, allyl, p-methoxybenzylA group; r3、R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxy.
The following compounds were prepared:
Figure BDA0001500439950000061
Figure BDA0001500439950000071
Figure BDA0001500439950000081
1. preparation of Compound 4a
Figure BDA0001500439950000082
① A150 mL round bottom flask is taken, 30mmol of benzylamine, 10mL of absolute ethyl alcohol and equivalent ethyl acrylate are respectively measured, stirring is carried out for 16h at room temperature, 1.0 time equivalent of diethyl oxalate of benzylamine and 1.5 time equivalent of sodium ethoxide are weighed and added into the reaction liquid in the first step, 10mL of absolute ethyl alcohol is supplemented, the system is moved to an oil bath kettle at 90 ℃ for reflux reaction for 1h, and after-treatment, the absolute ethyl alcohol in the reaction liquid is dried in a vacuum manner, 70mL of deionized water is added after cooling to room temperature, concentrated hydrochloric acid is added to adjust the pH value of the system to 1, at this moment, the system releases heat and is moved to an ice bath for cooling, at this moment, a yellowish white solid is separated out, supernatant is poured, and drying is carried out, so that the compound shown in formula 1-5 is obtained.
② adding 36mmol of the compound shown in formula 1-5, 36mmol of benzaldehyde and 112.5ml of 20% HCl solution into 55ml of absolute ethyl alcohol, reacting at 90 ℃ for 4h, cooling to 25 +/-2 ℃, filtering to obtain a residue, adding ethyl acetate, standing at 90 ℃ until the solution is clear, cooling to 25 +/-2 ℃, and precipitating to obtain the compound shown in formula (1).
③ taking α -chloropropylaldehyde (0.3mmol) and a compound (0.1mmol) shown in formula (1) as raw materials, sequentially adding the raw materials into a reaction test tube, adding 1ml of chlorobenzene as a solvent and a quinidine squaramide catalyst (0.01mmol), reacting at room temperature for 16h, monitoring the reaction by using thin layer chromatography, concentrating the solvent after the reaction is completed, purifying the obtained crude product by using column chromatography, and separating by using petroleum ether, dichloromethane and ethyl acetate, wherein the ethyl acetate is 4: 4: 1 to obtain a compound 4a, a white solid, the yield is 95%, the dr value is 90: 10, and the ee value is 99%.
1H NMR(400MHz,CDCl3)δ(ppm):7.69(s,1H),7.46–7.05(m,15H),5.30(d,J＝2.8Hz,1H),4.71(d,J＝14.8Hz,1H),4.43(d,J＝14.8Hz,1H),4.24(s,1H),3.64(d,J＝18.4Hz,1H),3.41(d,J＝18.4Hz,1H),3.32(d,J＝13.6Hz,1H),2.69(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.8,142.5,136.5,134.7,134.4,131.4,128.8,128.3,128.1,128.0,127.8,127.1,122.1,96.1,70.1,48.1,46.8,46.5,43.2.
HRMS(ESI):m/z calculated for C27H24ClNO3+Na+:468.1337,found:468.1340.
2. Preparation of Compound 4b
The preparation method can obtain the compound 4b by only replacing benzaldehyde in the step ② with p-tolualdehyde, wherein the yield of the compound 4b is 95%, the dr value is 87: 13, and the ee value is 99%.
1H NMR(400MHz,CDCl3)δ(ppm):7.70(s,1H),7.38–7.07(m,14H),5.36(s,1H),4.77(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),4.27(s,1H),3.71(d,J＝18.4Hz,1H),3.47(d,J＝18.4Hz,1H),3.37(d,J＝13.6Hz,1H),2.77(d,J＝13.6Hz,1H),2.36(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):166.8,142.4,137.9,136.5,134.5,131.6,131.4,128.8,128.3,128.0,127.8,127.0,122.3,96.1,70.2,48.1,46.8,46.1,43.1,21.1.
HRMS(ESI):m/z calculated for C28H26ClNO3+Na+:482.1493,found:482.1499.
3. Preparation of Compound 4c
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with p-fluorobenzaldehyde to obtain a compound 4c which is a white solid and has the yield of 99 percent, the dr value of 88: 12 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.77(s,1H),7.44–7.17(m,12H),7.14–6.95(m,2H),5.36(s,1H),4.77(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),4.30(s,1H),3.66(d,J＝18.4Hz,1H),3.48(d,J＝18.4,1H),3.37(d,J＝13.6Hz,1H),2.72(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.6,136.4,134.2,131.4,128.9,128.3,128.1,127.9,127.1,121.7,96.1,70.0,48.0,46.8,45.8,43.1.
HRMS(ESI):m/z calculated for C27H23ClFNO3+H+:464.1423,found:464.1428.
4. Preparation of Compound 4d
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with p-chlorobenzaldehyde to obtain a compound 4d which is a white solid with the yield of 98 percent, the dr value of 87: 13 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.80(s,1H),7.43–7.12(m,14H),5.36(s,1H),4.76(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),4.28(s,1H),3.65(d,J＝18.4Hz,1H),3.46(d,J＝18.4Hz,1H),3.37(d,J＝13.6Hz,1H),2.72(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.7,136.4,134.2,134.1,133.2,131.4,128.9,128.4,128.3,128.1,127.9,127.2,121.4,96.0,69.9,47.9,46.8,46.0,43.1.
HRMS(ESI):m/z calculated for C27H23Cl2NO3+Na+:502.0947,found:502.0955.
5. Preparation of Compound 4e
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with p-bromobenzaldehyde to obtain a compound 4e which is a white solid with the yield of 96 percent, the dr value of 90: 10 and the ee value of 97 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.90(s,1H),7.48(d,J＝8.4Hz,2H),7.37–7.12(m,12H),5.36(d,J＝3.2Hz,1H),4.76(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),4.27(s,1H),3.65(d,J＝18.8Hz,1H),3.46(d,J＝18.8Hz,1H),3.37(d,J＝13.6Hz,1H),2.72(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.7,136.3,134.1,133.8,131.4,128.9,128.3,128.1,127.9,127.2,122.4,121.3,96.0,69.8,47.9,46.9,46.1,43.1.
HRMS(ESI):m/z calculated for C27H23BrClNO3+Na+:546.0442,found:546.0447.
6. Preparation of Compound 4f
The preparation method can obtain the compound 4f as a white solid with the yield of 99 percent, the dr value of 91: 9 and the ee value of 99 percent by only replacing the benzaldehyde in the step ② with p-nitrobenzaldehyde.
1H NMR(400MHz,CDCl3)δ(ppm):7.91(s,1H),7.48–7.14(m,14H),5.37(d,J＝4.0Hz,1H),4.81(s,1H),4.49(d,J＝14.8Hz,1H),4.28(s,1H),3.68(d,J＝18.4Hz,1H),3.48(d,J＝18.4Hz,1H),3.38(d,J＝13.6Hz,1H),2.74(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.7,136.9,136.4,134.1,131.4,129.4,128.9,128.4,128.3,128.1,127.9,127.2,121.1,96.1,69.7,47.9,46.8,46.3,43.2.
HRMS(ESI):m/z calculated for C27H23ClN2O5+Na+:513.1188,found:513.1193.
7. Preparation of Compound 4g
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with o-chlorobenzaldehyde to obtain the compound 4g, white solid with the yield of 99 percent, the dr value of 96: 4 and the ee value of 95 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.88(s,1H),7.57–7.50(m,1H),7.47–7.38(m,1H),7.37–7.14(m,12H),5.42(d,J＝2.4Hz,1H),5.15(s,1H),4.78(d,J＝14.8Hz,1H),4.49(d,J＝14.8Hz,1H),3.70(d,J＝14.0Hz,1H),3.58(d,J＝18.8Hz,1H),3.46(d,J＝18.8Hz,1H),2.69(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.8,142.8,136.4,136.3,134.5,131.5,129.8,129.4,128.9,128.3,128.0,127.9,127.0,126.3,121.8,96.3,71.6,48.0,46.8,42.8,41.6.
HRMS(ESI):m/z calculated for C27H23Cl2NO3+Na+:502.0947,found:502.0952.
8. Preparation of Compound 4h
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with m-tolualdehyde, and the compound 4h is a white solid with the yield of 90 percent, the dr value of 91: 9 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.77(s,1H),7.39–7.12(m,14H),5.37(s,1H),4.79(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),4.27(s,1H),3.70(d,J＝18.8Hz,1H),3.47(d,J＝18.8Hz,1H),3.39(d,J＝13.6Hz,1H),2.78(d,J＝13.6Hz,1H),2.34(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):166.9,142.4,137.7,136.5,134.7,134.5,131.4,128.8,128.3,128.0,127.9,127.8,127.0,122.2,96.1,70.1,48.1,46.8,46.5,43.2,21.5.
HRMS(ESI):m/z calculated for C28H26ClNO3+Na+:482.1493,found:482.1501.
9. Preparation of Compound 4i
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with m-methoxybenzaldehyde to obtain the compound 4i, which is a white solid with the yield of 76%, the dr value of 85: 15 and the ee value of 99%.
1H NMR(400MHz,CDCl3)δ(ppm):7.85(s,1H),7.40–7.09(m,11H),7.08–6.74(m,3H),5.27(s,1H),4.74(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),4.28(s,1H),3.84–3.68(m,4H),3.48(d,J＝18.8Hz,1H),3.35(d,J＝14.0Hz,1H),2.80(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):165.7,158.2,141.4,135.5,135.1,133.4,130.3,128.0,127.8,127.2,127.0,126.8,126.0,121.0,95.1,68.9,54.2,47.0,45.7,42.2,28.7.
HRMS(ESI):m/z calculated for C28H26ClNO4+Na+:498.1443,found:498.1450.
10. Preparation of Compound 4j
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with m-chlorobenzaldehyde to obtain the compound 4j as a white solid, wherein the yield is 99%, the dr value is 88: 12, and the ee value is 98%.
1H NMR(400MHz,CDCl3)δ(ppm):7.89(s,1H),7.51–7.05(m,14H),5.36(s,1H),4.82(s,1H),4.49(d,J＝14.8Hz,1H),4.28(s,1H),3.68(d,J＝18.8Hz,1H),3.48(d,J＝18.8Hz,1H),3.38(d,J＝13.6Hz,1H),2.74(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.7,136.9,136.3,134.1,131.4,129.4,128.9,128.4,128.3,128.1,127.9,127.2,121.1,96.1,69.7,47.9,46.8,46.3,43.2.
HRMS(ESI):m/z calculated for C27H23Cl2NO3+Na+:502.0947,found:502.0955.
11. Preparation of Compound 4k
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with m-bromobenzaldehyde to obtain the compound 4k which is a white solid with the yield of 98 percent, the dr value of 87: 13 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.70(s,1H),7.58–7.39(m,2H),7.39–7.14(m,12H),5.35(s,1H),4.81(s,1H),4.49(d,J＝14.8Hz,1H),4.26(s,1H),3.67(d,J＝18.8Hz,1H),3.48(d,J＝18.8Hz,1H),3.37(d,J＝13.6Hz,1H),2.74(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.6,142.7,137.1,136.4,134.0,131.3,129.6,128.9,128.3,128.1,127.9,127.2,121.1,96.0,69.7,47.9,46.8,46.3,43.2.
HRMS(ESI):m/z calculated for C27H23BrClNO3+Na+:546.0442,found:546.0446.
12. Preparation of Compound 4l
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with 2, 4-dichlorobenzaldehyde, and the compound 4l is obtained as a white solid with the yield of 99 percent, the dr value of 96: 4 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.94(s,1H),7.53–7.42(m,2H),7.39–7.14(m,12H),5.40(s,1H),5.08(s,1H),4.76(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),3.66(d,J＝14.0Hz,1H),3.53(d,J＝18.4Hz,1H),3.46(d,J＝18.4Hz,1H),2.65(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.6,143.0,136.9,136.3,134.7,134.2,134.1,131.5,129.6,129.0,128.9,128.3,128.0,127.9,127.1,126.8,121.1,96.3,71.4,47.8,46.9,42.8,41.2.
HRMS(ESI):m/z calculated for C27H22Cl3NO3+Na+:536.0557,found:536.0567.
13. Preparation of Compound 4m
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with 2-naphthaldehyde to obtain a compound 4m which is a white solid with the yield of 90 percent, the dr value of 90: 10 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.97–7.79(m,3H),7.79–7.55(m,2H),7.54–7.46(m,2H),7.38–7.13(m,10H),5.42(s,1H),4.80(d,J＝12.4Hz,1H),4.56–4.32(m,2H),3.72(d,J＝14.8Hz,1H),3.55–3.42(m,2H),2.84(d,J＝11.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.8,142.6,136.5,134.4,133.1,131.4,128.9,128.4,128.1,127.9,127.7,127.2,126.4,96.3,68.3,48.2,46.9,43.3,41.4.
HRMS(ESI):m/z calculated for C31H26ClNO3+Na+:518.1493,found:518.1498.
14. Preparation of Compound 4n
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with thiophenecarboxaldehyde, and the compound 4n is a white solid with the yield of 98 percent, the dr value of 85:andthe e15e value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.92(s,1H),7.37–7.16(m,11H),7.10–6.97(m,2H),5.38(d,J＝2.4Hz,1H),4.81(d,J＝14.8Hz,1H),4.70(s,1H),4.45(d,J＝14.8Hz,1H),3.70(d,J＝18.8Hz,1H),3.52(d,J＝18.8Hz,1H),3.34(d,J＝14.0Hz,1H),2.88(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,141.8,136.4,136.3,134.4,131.3,129.7,128.8,128.3,128.1,127.8,127.1,126.5,126.4,121.8,96.0,69.9,48.2,46.8,43.1,42.6.
HRMS(ESI):m/z calculated for C25H22ClNO3S+Na+:474.0901,found:474.0907.
15. Preparation of Compound 4o
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with 1-naphthaldehyde to obtain a compound 4o which is a white solid with the yield of 92 percent, the dr value of 93: 7 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):8.27(s,1H),8.07(s,1H),7.91–7.82(m,2H),7.69(d,J＝6.0Hz,1H),7.56–7.42(m,3H),7.33–7.12(m,10H),5.53(s,1H),5.48(s,1H),4.82(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),3.73(d,J＝18.4Hz,1H),3.60(d,J＝13.6Hz,1H),3.43(d,J＝18.4Hz,1H),2.49(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.9,143.0,136.4,134.5,133.8,133.5,131.4,130.4,129.2,128.8,128.3,128.0,127.8,127.0,126.6,125.7,124.8,123.3,123.1,96.4,71.9,48.2,46.8,43.6,39.4.
HRMS(ESI):m/z calculated for C31H26ClNO3+Na+:518.1493,found:518.1495.
16. Preparation of Compound 4p
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with cinnamaldehyde to obtain the compound 4p which is a white solid with the yield of 99 percent, the dr value of 88: 12 and the ee value of 98 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.53(s,1H),7.46–7.17(m,15H),6.65(d,J＝15.6Hz,1H),6.34(dd,J＝15.6,9.2Hz,1H),5.34(s,1H),4.71(d,J＝14.8Hz,1H),4.56(d,J＝14.8Hz,1H),3.77(d,J＝9.2Hz,1H),3.66(s,2H),3.32(d,J＝14.0Hz,1H),3.12(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.8,141.0,136.6,136.5,136.2,134.6,131.4,128.9,128.7,128.4,128.2,128.1,127.8,127.1,126.6,123.7,121.5,95.7,70.2,48.3,46.8,44.6,43.3.
HRMS(ESI):m/z calculated for C29H26ClNO3+Na+:494.1493,found:494.1496.
17. Preparation of Compound 4q
The preparation method can obtain the compound 4q as a white solid with the yield of 98 percent, the dr value of 86: 14 and the ee value of 99 percent by only replacing the benzaldehyde in the step ② with the cinnamaldehyde.
1H NMR(400MHz,CDCl3)δ(ppm):8.19(d,J＝8.5Hz,2H),7.73(s,1H),7.51(d,J＝8.6Hz,2H),7.43–7.17(m,11H),6.70(d,J＝16.0Hz,1H),6.51(dd,J＝16.0,9.2Hz,1H),5.37(s,1H),4.70(d,J＝14.8Hz,1H),4.57(d,J＝14.8Hz,1H),3.84(d,J＝9.2Hz,1H),3.66(s,2H),3.34(d,J＝14.0Hz,1H),3.10(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,147.3,142.4,141.3,136.4,134.3,131.4,129.2,129.0,128.9,128.3,128.1,127.9,127.3,127.2,124.1,120.5,95.8,69.9,48.2,46.8,44.7,43.5.
HRMS(ESI):m/z calculated for C29H25ClN2O5+Na+:539.1344,found:539.1353.
18. Preparation of Compound 4r
The preparation method of the compound 4a only needs to replace benzylamine in the step ① with p-methoxybenzylamine and replace benzaldehyde in the step ② with phenylpropylaldehyde, and the compound 4r is obtained, namely a white solid, the yield is 95%, the dr value is 88: 12, and the ee value is 99%.
1H NMR(600MHz,CDCl3)δ(ppm):7.86(s,1H),7.52–7.28(m,7H),7.26–7.14(m,5H),6.90–6.81(m,2H),5.36(d,J＝2.2Hz,1H),4.73(d,J＝14.8Hz,1H),4.44(d,J＝14.8Hz,1H),4.32(d,J＝13.6Hz,1H),3.79(s,3H),3.68(d,J＝18.6Hz,1H),3.45(d,J＝18.6Hz,1H),3.39(d,J＝13.8Hz,1H),2.75(d,J＝13.8Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.8,159.3,142.6,134.8,134.5,131.5,129.8,128.6,128.2,128.1,127.1,122.0,114.2,96.1,70.1,55.4,48.0,46.6,46.3,43.2.
HRMS(ESI):m/z calculated for C28H26ClNO4+Na+:498.1443,found:498.1448.
19. Preparation of Compound 4s
The preparation method can obtain the compound 4a by only replacing the benzylamine in the step ① with allylamine, wherein the compound 4s is white solid, the yield is 92%, the dr value is 90: 10, and the ee value is 99%.
1H NMR(600MHz,CDCl3)δ(ppm):7.81(s,1H),7.54–7.32(m,5H),7.32–7.27(m,1H),7.26–7.14(m,4H),5.83–5.70(m,1H),5.33(s,1H),5.21–5.12(m,2H),4.34(s,1H),4.14(dd,J＝15.3,6.0Hz,1H),4.00(dd,J＝15.3,6.6Hz,1H),3.76(d,J＝18.6Hz,1H),3.57(d,J＝18.6Hz,1H),3.39(d,J＝13.8Hz,1H),2.76(d,J＝13.8Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.7,142.6,134.8,134.4,132.9,131.4,128.2,128.1,127.1,122.2,118.8,96.1,70.1,48.1,46.6,45.6,43.2.
HRMS(ESI):m/z calculated for C23H22ClNO3+Na+:418.1180,found:418.1183.
20. Preparation of Compound 4t
The preparation method of the compound 4a only needs to replace α -chloropropylaldehyde in the step ③ with 2-chlorohexanal to obtain the compound 4t which is a white solid with the yield of 93 percent, the dr value of 95: 5 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.76(s,1H),7.37–7.16(m,10H),5.88(s,1H),4.73(d,J＝14.8Hz,1H),4.48(d,J＝14.8Hz,1H),4.17(s,1H),3.69(d,J＝18.4Hz,1H),3.45(d,J＝18.4,1H),2.13–2.01(m,1H),1.63–1.42(m,3H),1.38–1.27(m,1H),1.22–1.09(m,1H),0.87(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.0,142.1,136.5,135.0,128.9,128.3,128.1,128.0,127.9,122.4,96.8,71.2,48.2,46.8,46.6,38.1,25.4,23.0,14.1.
HRMS(ESI):m/z calculated for C24H26ClNO3+Na+:434.1493,found:434.1501.
21. Preparation of Compound 4u
The preparation method of the compound 4a only needs to replace α -chloropropylaldehyde in the step ③ with 2-chloroheptanal to obtain the compound 4u which is a white solid with the yield of 93 percent, the dr value of 95: 5 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.78(s,1H),7.39–7.16(m,10H),5.87(s,1H),4.72(d,J＝14.8Hz,1H),4.48(d,J＝14.8Hz,1H),4.17(s,1H),3.69(d,J＝18.8Hz,1H),3.45(d,J＝18.8Hz,1H),2.14–1.99(m,1H),1.62–1.45(m,3H),1.38–1.19(m,3H),1.19–1.04(m,1H),0.85(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.0,142.0,136.5,134.9,128.9,128.3,128.0,127.9,122.4,96.8,71.2,48.2,46.8,46.6,38.3,32.1,23.0,22.7,14.2.
HRMS(ESI):m/z calculated for C25H28ClNO3+Na+:448.1650,found:448.1658.
22. Preparation of Compound 4v
The preparation method of the compound 4a only needs to replace α -chloropropylaldehyde in the step ③ with chlorobenzyloxybutyraldehyde to obtain the compound 4v which is a white solid with the yield of 96 percent, the dr value of 95: 5 and the ee value of 99 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.79–7.45(br,1H),7.36–7.22(m,13H),7.18(d,J＝6.4Hz,2H),5.99(s,1H),4.70(d,J＝14.8Hz,1H),4.51–4.41(m,3H),4.20(s,1H),3.86(dd,J＝16.4,8.0Hz,1H),3.74–3.59(m,2H),3.45(d,J＝18.8Hz,1H),2.58–2.45(m,1H),1.94–1.81(m,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.0,138.1,136.5,134.6,128.8,128.4,128.2,128.1,127.9,127.8,127.5,121.8,96.9,73.3,70.0,66.3,48.1,46.7,46.3,37.3.
HRMS(ESI):m/z calculated for C29H28ClNO4+Na+:512.1599,found:512.1606.
23. Preparation of Compound 4w
The preparation method of the compound 4a only needs to replace α -chloropropylaldehyde in the step ③ with α -bromophenylaldehyde to obtain the compound 4w which is a white solid and has the yield of 93 percent, the dr value of 94: 6 and the ee value of 98 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.55–7.16(m,16H),5.49(s,1H),4.80(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),4.31(s,1H),3.76(d,J＝18.8Hz,1H),3.56–3.41(m,2H),2.88(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.4,136.5,134.8,131.5,128.8,128.3,128.2,128.0,127.9,127.8,127.1,122.4,96.4,68.4,48.0,46.9,46.8,43.8.
HRMS(ESI):m/z calculated for C27H24BrNO3+Na+:512.0832,found:512.0836.
24. Preparation of Compound 4x
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with p-methyl phenylpropyl aldehyde and replace α -chloro phenylpropyl aldehyde in the step ③ with α -bromo phenylpropyl aldehyde, so that the compound 4x is obtained, and the white solid is obtained, wherein the yield is 89%, the dr value is 96: 4, and the ee value is 99%.
1H NMR(600MHz,CDCl3)δ(ppm):7.38–7.27(m,7H),7.26–7.11(m,8H),5.48(d,J＝3.6Hz,1H),4.80(d,J＝15.0Hz,1H),4.49(d,J＝15.0Hz,1H),4.28(s,1H),3.76(d,J＝18.6Hz,1H),3.51–3.41(m,2H),2.88(d,J＝14.1Hz,1H),2.37(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):166.8,142.4,138.0,136.6,134.9,131.5,128.9,128.8,128.4,128.0,127.9,127.1,122.8,96.4,68.7,48.1,46.9,46.5,43.9,21.3.
HRMS(ESI):m/z calculated for C28H26BrNO3+Na+:526.0988,found:526.0988.
25. Preparation of Compound 4y
The preparation method can obtain the compound 4y in white solid with the yield of 90 percent, the dr value of 95: 5 and the ee value of 98 percent by only replacing benzaldehyde in the step ② with p-bromophenylaldehyde and replacing α -chlorophenylaldehyde in the step ③ with α -bromophenylaldehyde to obtain the compound 4 a.
1H NMR(600MHz,CDCl3)δ(ppm):7.67(s,1H),7.48(d,J＝6.2Hz,2H),7.38–7.27(m,6H),7.26–7.17(m,6H),5.48(s,1H),4.78(d,J＝15.0Hz,1H),4.51(d,J＝15.0Hz,1H),4.27(s,1H),3.70(d,J＝18.6Hz,1H),3.51–3.40(m,2H),2.82(d,J＝14.1Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.7,142.6,136.4,134.6,131.5,131.3,129.0,128.4,128.1,128.0,127.3,122.6,121.7,96.4,68.1,48.0,46.9,46.4,43.8.
HRMS(ESI):m/z calculated for C27H23Br2NO3+Na+:589.9937,found:589.9938.
26. Preparation of Compound 4z
The preparation method of the compound 4a only needs to replace benzaldehyde in the step ② with 2, 4-dichlorobenzaldehyde and α -chloropropylaldehyde in the step ③ with α -bromophenylaldehyde to obtain the compound 4z which is a white solid and has the yield of 99 percent, the dr value of 96: 4 and the ee value of 98 percent.
1H NMR(600MHz,CDCl3)δ(ppm):7.71(s,1H),7.57(d,J＝7.8Hz,1H),7.45(s,1H),7.39–7.25(m,7H),7.24–7.15(m,4H),5.52(s,1H),5.07(s,1H),4.80(d,J＝15.0Hz,1H),4.48(d,J＝15.0Hz,1H),3.75(d,J＝14.1Hz,1H),3.57(d,J＝18.6Hz,1H),3.46(d,J＝18.6Hz,1H),2.73(d,J＝14.1Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.7,142.9,137.0,136.3,134.8,134.7,131.6,129.6,129.0,128.4,128.0,127.2,126.7,121.6,96.6,70.0,47.9,46.9,43.5,41.5.
HRMS(ESI):m/z calculated for C27H22BrCl2NO3+Na+:580.0052,found:580.0055.
27. Preparation of Compound 6a
The preparation method of the compound 4a only needs to replace α -chloropropylaldehyde in the step ③ with 3-phenylpropylaldehyde to obtain the compound 6a which is a white solid with the yield of 80 percent, the dr value of 90: 10 and the ee value of 97 percent.
1H NMR(600MHz,CDCl3):δ(ppm):7.35–7.31(m,2H),7.30–7.23(m,4H),7.21–7.16(m,6H),7.13(t,J＝7.5Hz,1H),7.05(d,J＝7.2Hz,2H),6.48(s,1H),5.44(s,1H),4.73(d,J＝15.0Hz,1H),4.39(d,J＝15.0Hz,1H),3.64(d,J＝10.8Hz,1H),3.48(d,J＝18.4Hz,1H),3.34(d,J＝18.4Hz,1H),2.73(dd,J＝13.6,11.4Hz,1H),2.56(dd,J＝13.6,3.6Hz,1H),2.29–2.22(m,1H).
13C NMR(150MHz,CDCl3):δ(ppm):166.9,142.6,140.5,139.6,136.8,129.1,128.8,128.5,128.2,127.7,127.5,126.2,124.1,94.2,48.0,46.8,46.7,40.8,34.7.
HRMS(ESI):m/z calculated for C27H25NO3+Na+:434.1727,found:434.1737.
28. Preparation of Compound 6b
The preparation method of the compound 4a only needs to change α -chloropropylaldehyde in the step ③ into benzyloxybutyraldehyde to obtain a compound 6b which is a white solid and has the yield of 82 percent, the dr value of 88: 12 and the ee value of 98 percent.
1H NMR(600MHz,CDCl3):δ(ppm):7.33–7.26(m,7H),7.24–7.21(m,4H),7.18–7.10(m,4H),6.37(s,1H),5.85(s,1H),4.70(d,J＝15.0Hz,1H),4.40(d,J＝15.0Hz,1H),4.32(d,J＝0.9Hz,2H),3.58(d,J＝10.8Hz,1H),3.49–3.42(m,2H),3.37–3.30(m,2H),2.30–2.21(m,1H),1.91–1.80(m,1H),1.66–1.57(m,1H).
13C NMR(150MHz,CDCl3):δ(ppm):166.9,142.4,140.5,138.4,136.9,128.9,128.8,128.4,128.3,128.2,127.7,127.6,127.4,124.2,95.1,72.7,68.1,48.1,46.6,41.7,41.0,28.9.
HRMS(ESI):m/z calculated for C29H29NO4+Na+:478.1989,found:478.1993.
The advantageous effects of the present invention will be specifically described below by way of test examples.
Test example 1 antitumor study
1. Experimental tumor cell strain
The human breast cancer MB468 cell line, the human breast cancer SKBR3 cell line, the human breast cancer MB231 cell line and the mouse melanoma A375 cell line are all provided by the national focus laboratory of biological treatment of Sichuan university, and the tumor cells are all frozen and stored in the national focus laboratory of biological treatment of Sichuan university.
2. Experimental methods
2.1 preparation and treatment of cells
4 kinds of tumor cells are cultured in RPMI-1640 culture solution containing 10% inactivated newborn calf serum at 37 deg.C and 5% CO2Growing in incubator until 80% cell fusion, digesting with 0.1% pancreatin solution to obtain single cell suspension, adjusting cell concentration to 5 × 104/mL, uniformly inoculating into 96-well microplate, each group having 3 multiple wells and 100 μ l/well, placing at 37 deg.C saturation humidity and 5% CO2After culturing in an incubator for 24h, adding culture solution with the same amount into a normal control group; a concentration gradient of test drug (100, 50, 25, 12.5, 6.25. mu.g/mL) was added, 3 replicates per concentration and experiments were performed in 2 replicates. After the drug and the cells act for 24 hours, 10 mu L of MTT solution (5mg/mL) is added into each hole, after the culture is continued for 4 hours, 100 mu L of DMSO is added into each hole, the mixture is shaken and uniformly mixed to ensure that the crystal is fully dissolved, the absorbance value (A value) is measured at the 490nm wavelength of an enzyme-labeling instrument, and the average value of each concentration group is taken.
2.2 measurement of tumor cell proliferation inhibition Rate
The cell proliferation inhibition rate was calculated according to the following formula: the cell growth inhibition ratio (%) × 100% (1-test group a value/control group a value). All experimental data were statistically analyzed using SPSS 13.0. Experimental results adopt Probit to obtain IC50The value is obtained.
3. Results of the experiment
TABLE 1 inhibition of growth of test cells by compounds of the invention
Figure BDA0001500439950000181
Figure BDA0001500439950000191
Experimental results show that the compound has an anti-tumor effect, wherein the anti-tumor effect of the compound 25 is the best.
In conclusion, the invention prepares a series of halogenated dihydropyranopyrrolopyrrole ketone compounds, and the preparation method is simple and convenient, has mild reaction and high yield, has antitumor activity and wide market application prospect.

Claims (10)

1. A halogenated dihydropyranopyrrolopyrrole compound of formula (I):
Figure FDA0002384487580000011
wherein X is fluorine, chlorine, bromine or iodine;
L1is absent or vinyl;
the ring A is a naphthalene ring, a benzene ring and a thiophene ring;
R1is benzyl, C1-C8Alkyl or (CH)2)n-O-Bn; n is an integer of 1-5;
R2is benzyl, allyl, p-methoxybenzyl;
R3、R4each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxy.
2. The compound according to claim 1, which is one of the following compounds:
Figure FDA0002384487580000012
Figure FDA0002384487580000021
3. a process for the preparation of a compound according to claim 1 or 2, characterized in that: the method comprises the following steps:
Figure FDA0002384487580000022
(1) taking a compound shown as a formula (1-1) and ethyl acrylate shown as a formula (1-2), reacting in ethanol at room temperature for 16 +/-2 h, adding diethyl oxalate and sodium ethoxide shown as a formula (1-4), and reacting at 90 ℃ to obtain a compound shown as a formula (1-5);
(2) taking the compound shown in the formula (1-5) and the compound shown in the formula (1-6), reacting at 90 +/-3 ℃ to obtain the compound shown in the formula (1),
(3) taking a compound shown in a formula (1) and a compound shown in a formula (2), taking chlorobenzene as a solvent and squaramide as a catalyst, and reacting at room temperature to obtain the compound shown in the formula (I).
4. The production method according to claim 3, characterized in that: x is fluorine, chlorine, bromine or iodine; l is1Is absent or vinyl; the ring A is a naphthalene ring, a benzene ring and a thiophene ring; r1Is benzyl, C1-C8Alkyl or (CH)2)n-O-Bn; n is an integer of 1-5; r2Is benzyl, allyl, p-methoxybenzyl; r3、R4Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxy.
5. The production method according to claim 3 or 4, characterized in that: in the step (1), the molar ratio of the compound shown in the formula (1-1), ethyl acrylate, diethyl oxalate and sodium ethoxide is 1: 1: 1: 1.5.
6. the production method according to claim 3 or 4, characterized in that: in the step (2), the molar ratio of the compound represented by the formula (1-5) to the compound represented by the formula (1-6) is 1: 1.
7. The production method according to claim 3 or 4, characterized in that: in the step (3), the molar ratio of the compound represented by the formula (1) to the compound represented by the formula (2) and the squaramide is 10:30: 1.
8. The production method according to claim 3 or 4, characterized in that: in the step (3), the squaramide structure is as follows:
Figure FDA0002384487580000031
9. use of a compound according to claim 1 or 2 for the preparation of an antitumor medicament.
10. Use according to claim 9, characterized in that: the tumor is breast cancer and melanoma.
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