CN108084200A - A kind of halogenated dihydropyran and pyrroles's ketone compound and its preparation method and application - Google Patents
A kind of halogenated dihydropyran and pyrroles's ketone compound and its preparation method and application Download PDFInfo
- Publication number
- CN108084200A CN108084200A CN201711296699.0A CN201711296699A CN108084200A CN 108084200 A CN108084200 A CN 108084200A CN 201711296699 A CN201711296699 A CN 201711296699A CN 108084200 A CN108084200 A CN 108084200A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- values
- cdcl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CN(CC(CC1)=C2O[C@@](*)C1=*I)C2=O Chemical compound CN(CC(CC1)=C2O[C@@](*)C1=*I)C2=O 0.000 description 5
- ZVNKNYQXQZEVIQ-OJPGYLCKSA-N C/[O]=C1\N(Cc2ccccc2)CC([C@H]([C@@H]2Cc3ccccc3)C(C=C3)=CCC3[N+]([O-])=O)=C1OC2O Chemical compound C/[O]=C1\N(Cc2ccccc2)CC([C@H]([C@@H]2Cc3ccccc3)C(C=C3)=CCC3[N+]([O-])=O)=C1OC2O ZVNKNYQXQZEVIQ-OJPGYLCKSA-N 0.000 description 1
- IBWWUXXEHHBSNE-TYNCELHUSA-N C[B]([C@@H]1[C@H](O)OC(C(N(C2)O)=O)=C2[C@H]1c1ccccc1)=C Chemical compound C[B]([C@@H]1[C@H](O)OC(C(N(C2)O)=O)=C2[C@H]1c1ccccc1)=C IBWWUXXEHHBSNE-TYNCELHUSA-N 0.000 description 1
- RNQPSEKGHMGMFU-PAUUQQFRSA-N C[C@@H]([C@H]1Cc2ccccc2)OC(C(N(Cc2ccccc2)C2)=O)=C2[C@H]1C(C1)C=CC=C1Br Chemical compound C[C@@H]([C@H]1Cc2ccccc2)OC(C(N(Cc2ccccc2)C2)=O)=C2[C@H]1C(C1)C=CC=C1Br RNQPSEKGHMGMFU-PAUUQQFRSA-N 0.000 description 1
- FRNFJTJLUCVRRU-QDPGVEIFSA-N C[C@@]([C@@H]1Cc2ccccc2)(C(CN(Cc2ccccc2)C2=O)=C2OC1=O)c(cc1)ccc1Cl Chemical compound C[C@@]([C@@H]1Cc2ccccc2)(C(CN(Cc2ccccc2)C2=O)=C2OC1=O)c(cc1)ccc1Cl FRNFJTJLUCVRRU-QDPGVEIFSA-N 0.000 description 1
- JIGGZTMSBSHDBG-NQFGZBMSSA-N C[C@H]([C@H](Cc1ccccc1)[C@H](O)OC1=C2CN(Cc3ccccc3)C1=O)[C@@H]2c1ccc(C)cc1 Chemical compound C[C@H]([C@H](Cc1ccccc1)[C@H](O)OC1=C2CN(Cc3ccccc3)C1=O)[C@@H]2c1ccc(C)cc1 JIGGZTMSBSHDBG-NQFGZBMSSA-N 0.000 description 1
- FZOCBTRZDASDEA-YRLRHBCXSA-N Cc1cc([C@@H]([C@@H]2Cc3ccccc3)C(CN(Cc3ccccc3)C3=O)=C3O[C@H]2O)ccc1 Chemical compound Cc1cc([C@@H]([C@@H]2Cc3ccccc3)C(CN(Cc3ccccc3)C3=O)=C3O[C@H]2O)ccc1 FZOCBTRZDASDEA-YRLRHBCXSA-N 0.000 description 1
- GIQLOLIIVYXNMD-VXDLEIAFSA-N O[C@@H]([C@H]1Cc2ccccc2)OC(C(N(Cc2ccccc2)C2)=O)=C2[C@H]1/C=C/c1ccccc1 Chemical compound O[C@@H]([C@H]1Cc2ccccc2)OC(C(N(Cc2ccccc2)C2)=O)=C2[C@H]1/C=C/c1ccccc1 GIQLOLIIVYXNMD-VXDLEIAFSA-N 0.000 description 1
- MXQNSJPHKDMXAO-RCSBWOJUSA-N O[C@@H]([C@H]1Cc2ccccc2)OC(C(N(Cc2ccccc2)C2)=O)=C2[C@H]1c1ccccc1Cl Chemical compound O[C@@H]([C@H]1Cc2ccccc2)OC(C(N(Cc2ccccc2)C2)=O)=C2[C@H]1c1ccccc1Cl MXQNSJPHKDMXAO-RCSBWOJUSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—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
- C07D491/04—Ortho-condensed systems
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides halogenated dihydropyran of the one kind as shown in formula (I) and pyrroles's ketone compound or its crystal form, wherein, X is fluorine, chlorine, bromine, iodine；L1For nothing or vinyl；Ring A is naphthalene nucleus, phenyl ring, thiphene ring；R1For benzyl, C1‑C8Alkyl or (CH2)n‑O‑Bn；N is 1~5 integer；R2For benzyl, pi-allyl, to methoxybenzyl；R3、R4Separately selected from hydrogen, fluorine, chlorine, bromine, iodine, C1‑C3Alkyl, nitro, methoxyl group.The present invention also provides the preparation methods of above-claimed cpd or its crystal form.The compound of the present invention preparation method is easy, reaction is mild, high income, and with certain antitumor activity, has a vast market application prospect.
Description
Technical field
The present invention relates to a kind of halogenated dihydropyran and pyrroles's ketone compounds and its preparation method and application.
Background technology
Polysubstituted pyran compounds, the polysubstitution compound for being based especially on pyrans and ring skeleton are widely present in and have
In the natural products or medicine intermediate of physiological activity, the derivatization of substituent group modification, analogue to such compound
And further biological activity revalues and becomes research hotspot.
Huynh etc. (T.H.V.Huynh, I.Shim, H.Bohr, B.Abrahamsen, B.Nielsen, A.A.Jensen,
L.Bunch, J.Med.Chem.2012,55,5403-5412.) report the more of a series of pyrans as follows and ring skeleton
Purposes of the substituted compound as EAAT1- selective depressants.
CN105541853A discloses γ-pyrans pyrrolizine ketone compound of multi-substituent type as follows, this
Class compound has good antibacterial activity.
It yet there are no the halogenated dihydropyran and pyrroles's ketone compound of structure shown in the report present invention.
The content of the invention
In order to solve the above technical problem, the present invention provides a kind of halogenated dihydropyran and pyrroles's ketone compound and its systems
Preparation Method and purposes.
Present invention firstly provides halogenated dihydropyran of the one kind as shown in formula (I) and pyrroles's ketone compound or its crystal forms：
Wherein, X is fluorine, chlorine, bromine, iodine；
L1For nothing or vinyl；
Ring A is naphthalene nucleus, phenyl ring, thiphene ring；
R1For benzyl, C1-C8Alkyl or (CH2)n-O-Bn；N is 1~5 integer；
R2For benzyl, pi-allyl, to methoxybenzyl；
R3、R4Separately selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxyl group.
Further, above-claimed cpd is one of following compound：
The present invention also provides the preparation methods of above-claimed cpd or its crystal form, comprise the following steps：
(1) compound shown in modus ponens (1-1) and ethyl acrylate shown in formula (1-2), in 25 ± 2 DEG C, react in ethanol
After 16 ± 2h, diethy-aceto oxalate, sodium ethoxide shown in formula (1-4) are added in, to get chemical combination shown in formula (1-5) after 90 ± 2 DEG C of reactions
Object；
(2) compound shown in modus ponens (1-5) and compound shown in formula (1-6), react at 90 ± 3 DEG C up to shown in formula (1)
Compound,
(3) compound shown in modus ponens (1) and compound shown in formula (2), using chlorobenzene as solvent, squaric amide is catalyst,
Reaction is to get compound shown in formula (I) at 25 ± 3 DEG C.
Further, X is fluorine, chlorine, bromine, iodine；L1For nothing or vinyl；Ring A is naphthalene nucleus, phenyl ring, thiphene ring；R1For benzyl,
C1-C8Alkyl or (CH2)n-O-Bn；N is 1~5 integer；R2For benzyl, pi-allyl, to methoxybenzyl；R3、R4Independently
Ground is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxyl group.
Further, in step (1), compound shown in formula (1-1), ethyl acrylate, diethy-aceto oxalate and sodium ethoxide
Molar ratio is 1：1：1：1.5.
Further, in step (2), the molar ratio of compound shown in formula (1-5) and compound shown in formula (1-6) is 1:1.
Further, in step (3), compound shown in formula (1) and compound and the molar ratio of squaric amide shown in formula (2)
For 10:30:1.
Further, in step (3), the squaric amide structure is as follows：
The present invention also provides the purposes of above-claimed cpd or its crystal form in antitumor drug is prepared.
Further, the tumour is breast cancer, melanoma.
The experimental results showed that：A series of halogenated dihydropyran and pyrroles's ketone compound has been prepared in the present invention, prepares
Method is easy, reaction is mild, high income, and with antitumor activity, has a vast market application prospect.
Obviously, the above according to the present invention according to the ordinary technical knowledge and customary means of this field, is not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically the above of the present invention
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
Specific embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercial product.
C1-C3Alkyl refer to methyl, ethyl, propyl.
Et in structural formula of compound represents ethyl, and Me represents methyl, and Bn represents benzyl；PMB is represented to methoxy-benzyl.
The preparation of embodiment 1, the compounds of this invention
Raw material
Quinine set squaric amide catalyst：Structure isPurchased from Daicel drug chiral technology (on
Sea) Co., Ltd
General synthetic routes：
Wherein, X is fluorine, chlorine, bromine, iodine；L1For nothing or vinyl；Ring A is naphthalene nucleus, phenyl ring, thiphene ring；R1For benzyl, C1-
C8Alkyl or (CH2)n-O-Bn；N is 1~5 integer；R2For benzyl, pi-allyl, to methoxybenzyl；R3、R4Separately
Selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxyl group.
Following compound has been prepared：
1st, the preparation of compound 4a
1. taking the round-bottomed flask of a 150mL, the benzene methanamine of 30mmol amounts is measured respectively, the absolute ethyl alcohol of 10mL and is waited
The ethyl acrylate of equivalent, stirs 16h at room temperature.Weigh the diethy-aceto oxalate and 1.5 times of equivalents of 1.0 times of equivalents of benzene methanamine
Sodium ethoxide is added in the reaction solution of the first step, and adds 10mL absolute ethyl alcohols, system is moved in 90 DEG C of oil bath pan and flowed back instead
Answer 1h.Post processing：Vacuum is spin-dried for the absolute ethyl alcohol in reaction solution, and 70mL deionized waters are added in after being cooled to room temperature, are added dense
Hydrochloric acid regulation system pH=1, system heat release at this time, therefore move in ice bath and cool down, there is white-yellowish solid precipitation at this time.Topple over supernatant
Liquid is drying to obtain compound shown in formula 1-5.
2. the 20%HCl solution of compound shown in the formula 1-5 of 36mmol, the benzaldehyde of 36mmol amounts, 112.5ml are added in
Into 55ml absolute ethyl alcohols, 4h is reacted at 90 DEG C, is cooled to 25 ± 2 DEG C, filters to obtain residue, adds in ethyl acetate, at 90 DEG C
It places to solution and clarifies, be cooled to 25 ± 2 DEG C, compound shown in formula (1) is precipitated to obtain.
3. with compound (0.1mmol) shown in alpha-chloro benzenpropanal (0.3mmol) and formula (1) for raw material, sequentially add anti-
Test tube is answered, 1ml chlorobenzenes is added in and does solvent and quinine set squaric amide catalyst (0.01mmol).16h is reacted at room temperature, is used
Thin-layer chromatography monitoring reaction, is waited after the completion of reacting, concentrated solvent, obtained crude product is purified using column chromatography, uses petroleum ether：
Dichloromethane：Ethyl acetate=4：4：1 separation is to get compound 4a, white solid, yield 95%, dr values 90：10, ee values
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.
2nd, the preparation of compound 4b
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into p-tolualdehyde to get compound
4b, white solid, yield 95%, dr values 87：13, ee values 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.
3rd, the preparation of compound 4c
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into 4-Fluorobenzaldehyde to get compound
4c, white solid, yield 99%, dr values 88：12, ee values 99%.
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.
4th, the preparation of compound 4d
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into 4-chloro-benzaldehyde to get compound
4d, white solid, yield 98%, dr values 87：13, ee values 99%.
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.
5th, the preparation of compound 4e
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into p-bromobenzaldehyde to get compound
4e, white solid, yield 96%, dr values 90：10, ee values 97%.
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.
6th, the preparation of compound 4f
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into paranitrobenzaldehyde to get chemical combination
Object 4f, white solid, yield 99%, dr values 91：9, ee values 99%.
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.
7th, the preparation of compound 4g
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into o-chlorobenzaldehyde to get compound
4g, white solid, yield 99%, dr values 96：4, ee values 95%.
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.
8th, the preparation of compound 4h
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into a tolualdehyde to get compound
4h, white solid, yield 90%, dr values 91：9, ee values 99%.
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.
9th, the preparation of compound 4i
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into a methoxybenzaldehyde to get chemical combination
Object 4i, white solid, yield 76%, dr values 85：15, ee values 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.
10th, the preparation of compound 4j
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into m chlorobenzaldehyde to get compound
4j, white solid, yield 99%, dr values 88：12, ee values 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.
11st, the preparation of compound 4k
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into 3-bromobenzaldehyde to get compound
4k, white solid, yield 98%, dr values 87：13, ee values 99%.
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.
12nd, the preparation of compound 4l
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into 2,4- dichlorobenzaldehydes to get change
Close object 4l, white solid, yield 99%, dr values 96：4, ee values 99%.
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.
13rd, the preparation of compound 4m
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into 2- naphthaldehydes to get compound 4m,
White solid, yield 90%, dr values 90：10, ee values 99%.
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.
14th, the preparation of compound 4n
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into thiophenecarboxaldehyde to get compound 4n,
White solid, yield 98%, dr values 85：, e15e values 99%.
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.
15th, the preparation of compound 4o
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into 1- naphthaldehydes to get compound 4o,
White solid, yield 92%, dr values 93：7, ee values 99%.
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.
16th, the preparation of compound 4p
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into cinnamic acid to get compound 4p, in vain
Color solid, yield 99%, dr values 88：12, ee values 98%.
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.
17th, the preparation of compound 4q
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into cinnamic acid to get compound 4q, in vain
Color solid, yield 98%, dr values 86：14, ee values 99%.
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.
18th, the preparation of compound 4r
Preparation method with compound 4a, only need to by step 1. in benzene methanamine be replaced into methoxy-benzyl amine, step is 2.
In benzaldehyde be replaced into benzenpropanal to get compound 4r, white solid, yield 95%, dr values 88：12, ee values 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.
19th, the preparation of compound 4s
Preparation method with compound 4a, only need to by step 1. in benzene methanamine be replaced into allylamine to get compound 4s, in vain
Color solid, yield 92%, dr values 90：10, ee values 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.
20th, the preparation of compound 4t
Preparation method with compound 4a, only need to by step 3. in alpha-chloro benzenpropanal be replaced into 2- chlorine hexanals to get change
Close object 4t, white solid, yield 93%, dr values 95：5, ee values 99%.
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.
21st, the preparation of compound 4u
Preparation method with compound 4a, only need to by step 3. in alpha-chloro benzenpropanal be replaced into 2- chlorine enanthaldehyde to get change
Close object 4u, white solid, yield 93%, dr values 95：5, ee values 99%.
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.
22nd, the preparation of compound 4v
Preparation method with compound 4a, only need to by step 3. in alpha-chloro benzenpropanal be replaced into chloro benzyloxy butyraldehyde, i.e.,
Obtain compound 4v, white solid, yield 96%, dr values 95：5, ee values 99%.
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.
23rd, the preparation of compound 4w
Preparation method with compound 4a, only need to by step 3. in alpha-chloro benzenpropanal be replaced into alpha-brominated benzenpropanal, i.e.,
Obtain compound 4w, white solid, yield 93%, dr values 94：6, ee values 98%.
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.
24th, the preparation of compound 4x
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into p-methyl hydrocinnamaldehyde, step 3. in
Alpha-chloro benzenpropanal be replaced into alpha-brominated benzenpropanal to get compound 4x, white solid, yield 89%, dr values 96：4, ee values
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.
25th, the preparation of compound 4y
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into bromobenzene propionic aldehyde, step 3. in
Alpha-chloro benzenpropanal is replaced into alpha-brominated benzenpropanal to get compound 4y, white solid, yield 90%, dr values 95：5, ee values
98%.
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.
26th, the preparation of compound 4z
Preparation method with compound 4a, only need to by step 2. in benzaldehyde be replaced into 2,4- dichlorobenzaldehydes, step is 3.
In alpha-chloro benzenpropanal be replaced into alpha-brominated benzenpropanal to get compound 4z, white solid, yield 99%, dr values 96：4, ee
Value 98%.
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.
27th, the preparation of compound 6a
Preparation method with compound 4a, only need to by step 3. in alpha-chloro benzenpropanal change 3-phenylpropion aldehyde into get chemical combination
Object 6a, white solid, yield 80%, dr values 90：10, ee values 97%.
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.
28th, the preparation of compound 6b
Preparation method with compound 4a, only need to by step 3. in alpha-chloro benzenpropanal change benzyloxy butyraldehyde into get chemical combination
Object 6b, white solid, yield 82%, dr values 88：12, ee values 98%.
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.
Beneficial effects of the present invention are illustrated below by way of test example.
Test example 1, antitumor research
1st, experimental tumor cell line
Human breast carcinoma MB468 cell lines, human breast carcinoma SKBR3 cell lines, human breast carcinoma MB231 cell lines, mouse black
Plain knurl A375 cell lines are provided by biological therapy National Key Laboratory of Sichuan University, and more than tumour cell is frozen in Sichuan
Biological therapy National Key Laboratory of university.
2nd, experimental method
The preparation and processing of 2.1 cells
4 kinds of tumour cells are incubated at the RPMI-1640 culture solutions containing 10% inactivation newborn calf serum, 37 DEG C, 5%
CO280% cell fusion is grown in incubator, is digested with 0.1% trypsin solution, single cell suspension is made, adjusts cell concentration
For 5 × 104/mL, be uniformly inoculated in 96 hole microtest plates, every group of 3 multiple holes, 100 μ l/ holes, put 37 DEG C of saturated humidities,
5%CO2In incubator after culture for 24 hours, Normal group adds in the culture solution containing equivalent；Add in the test medicine of concentration gradient
(100,50,25,12.5,6.25 μ g/mL), each concentration set 3 multiple holes, and experiment is 2 times parallel.Treat drug with cytosis for 24 hours
Afterwards, 10 μ L MTT solution (5mg/mL) are added in per hole, continues to add in 100 μ L DMSO per hole after cultivating 4h, vibrates mixing, make knot
Brilliant object fully dissolves, its absorbance (A values) is surveyed at microplate reader 490nm wavelength, and each concentration group takes its average value.
The measure of 2.2 Cytostatic to tumor cell rates
Cell proliferation inhibition rate is calculated by following equation：Cell proliferation inhibition rate (%)=(1- test groups A values/control group
A values) × 100%.All experimental datas carry out statistical analysis using SPSS 13.0.Experimental result acquires IC using Probit50
Value.
3rd, experimental result
The inhibition situation that 1 the compounds of this invention of table grows subject cell
The experimental results showed that the compounds of this invention has antitumous effect, wherein, the antitumous effect of compound 25 is most
It is good.
In conclusion a series of halogenated dihydropyran and pyrroles's ketone compound, preparation method has been prepared in the present invention
Simplicity reacts mild, high income, and with antitumor activity, has a vast market application prospect.
Claims (10)
1. a kind of halogenated dihydropyran and pyrroles's ketone compound or its crystal form as shown in formula (I)：
Wherein, X is fluorine, chlorine, bromine, iodine；
L1For nothing or vinyl；
Ring A is naphthalene nucleus, phenyl ring, thiphene ring；
R1For benzyl, C1-C8Alkyl or (CH2)n-O-Bn；N is 1~5 integer；
R2For benzyl, pi-allyl, to methoxybenzyl；
R3、R4Separately selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxyl group.
2. compound according to claim 1 or its crystal form, the compound is one of following compound：
3. the preparation method of the compound of claim 1 or 2 or its crystal form, it is characterised in that：Comprise the following steps：
(1) ethyl acrylate shown in compound shown in modus ponens (1-1) and formula (1-2), in 25 ± 2 DEG C, react 16 in ethanol ±
After 2h, diethy-aceto oxalate, sodium ethoxide shown in formula (1-4) are added in, to get compound shown in formula (1-5) after 90 ± 2 DEG C of reactions；
(2) compound shown in modus ponens (1-5) and compound shown in formula (1-6), react at 90 ± 3 DEG C up to chemical combination shown in formula (1)
Object,
(3) compound shown in modus ponens (1) and compound shown in formula (2), using chlorobenzene as solvent, squaric amide is catalyst, 25 ± 3
Reaction is to get compound shown in formula (I) at DEG C.
4. preparation method according to claim 3, it is characterised in that：X is fluorine, chlorine, bromine, iodine；L1For nothing or vinyl；Ring A
For naphthalene nucleus, phenyl ring, thiphene ring；R1For benzyl, C1-C8Alkyl or (CH2)n-O-Bn；N is 1~5 integer；R2For benzyl, alkene
Propyl, to methoxybenzyl；R3、R4Separately selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkyl, nitro, methoxyl group.
5. the method according to claim 3 or 4, it is characterised in that：In step (1), compound, propylene shown in formula (1-1)
The molar ratio of acetoacetic ester, diethy-aceto oxalate and sodium ethoxide is 1：1：1：1.5.
6. according to claim 3-5 any one of them methods, it is characterised in that：In step (2), compound shown in formula (1-5)
Molar ratio with compound shown in formula (1-6) is 1:1.
7. according to claim 3-6 any one of them preparation methods, it is characterised in that：In step (3), chemical combination shown in formula (1)
Object is 10 with compound shown in formula (2) and the molar ratio of squaric amide:30:1.
8. according to claim 3-7 any one of them methods, it is characterised in that：In step (3), the squaric amide structure is such as
Under：
9. the purposes of the compound of claim 1 or 2 or its crystal form in antitumor drug is prepared.
10. purposes according to claim 9, it is characterised in that：The tumour is breast cancer, melanoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711296699.0A CN108084200B (en) | 2017-12-08 | 2017-12-08 | Halogenated dihydropyranopyrrolone compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711296699.0A CN108084200B (en) | 2017-12-08 | 2017-12-08 | Halogenated dihydropyranopyrrolone compound and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108084200A true CN108084200A (en) | 2018-05-29 |
| CN108084200B CN108084200B (en) | 2020-04-24 |
Family
ID=62174898
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711296699.0A Active CN108084200B (en) | 2017-12-08 | 2017-12-08 | Halogenated dihydropyranopyrrolone compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108084200B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010054278A2 (en) * | 2008-11-10 | 2010-05-14 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| WO2015095052A1 (en) * | 2013-12-17 | 2015-06-25 | Controlled Chemicals, Inc. | Isoindolin-1-ones as macrophage migration inhibitory factor (mif) inhibitors |
| CN105541853A (en) * | 2016-02-04 | 2016-05-04 | 成都大学 | Polysubstituted type gamma-pyranopyrrolidone compound as well as preparation method and application thereof |
-
2017
- 2017-12-08 CN CN201711296699.0A patent/CN108084200B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010054278A2 (en) * | 2008-11-10 | 2010-05-14 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| WO2015095052A1 (en) * | 2013-12-17 | 2015-06-25 | Controlled Chemicals, Inc. | Isoindolin-1-ones as macrophage migration inhibitory factor (mif) inhibitors |
| CN105541853A (en) * | 2016-02-04 | 2016-05-04 | 成都大学 | Polysubstituted type gamma-pyranopyrrolidone compound as well as preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| QIANG LI ET AL.: "Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of a-Haloaldehydes", 《ANGEW.CHEM.INT.ED.》 * |
| TRI H. V. HUYNH ET AL.: "Structure−Activity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and Absolute Configurational", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108084200B (en) | 2020-04-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102126934B (en) | Paraterphenyl derivative and application thereof in preparation of antitumor medicaments | |
| CN113603653B (en) | Synthesis method of selenooxazolidine-2, 4-dione promoted by visible light | |
| CN110183373A (en) | A kind of optical activity 1- (hetero) aryl indole derivatives and its preparation method and application | |
| CN108084200A (en) | A kind of halogenated dihydropyran and pyrroles's ketone compound and its preparation method and application | |
| CN109574906A (en) | A kind of preparation method of 3,3 '-two Indoleacetic esters | |
| Camps et al. | A total synthesis of methylenomycin B | |
| CN108864089B (en) | Indolopyridone drug molecule and preparation method and application thereof | |
| CN113603694B (en) | 1, 2-diketone compound and preparation method and application thereof | |
| CN113072481B (en) | Indolo-cyclobutane skeleton compound, synthesis method and application | |
| CN110698426B (en) | Method for preparing 1, 3-benzothiazole derivative by efficient catalysis of potassium tert-butoxide | |
| CN110590771B (en) | [1,5-a ] -pyridylimidazole-1-nitrile and chemical synthesis method thereof | |
| CN106866514B (en) | A kind of method that Aqueous phase synthesizes the halogenated -3- substituted hydrocarbon radical sulfonyl pyridine of 2- and its intermediate | |
| CN115093315B (en) | Synthesis method of 2-benzylidene-3-cyclohexenone compound | |
| CN108129418A (en) | Phenthazine-dithiocarbamates derivative and its preparation method and application | |
| CN117143066A (en) | Synthesis method of selenylbenzoxepin compound | |
| CN111072606B (en) | Octahydrobenzofuran derivative, preparation method and application thereof | |
| CN108822060B (en) | 3-aryl substituted oxetane and preparation method thereof | |
| CN116217611B (en) | Cyclobutanone derivative, preparation method and application | |
| CN103980153B (en) | Dibenzoyl amine compound with anti-tumor activity and its preparation method and application | |
| CN112430205B (en) | Preparation method of arylpyrrole compound | |
| CN112125838B (en) | Trifluoromethylated aniline compound and application thereof | |
| CN112250639B (en) | Heterocyclic substituted arylamine compound and preparation method and application thereof | |
| CN101555248A (en) | Method for preparing poly-substituted 1, 5-naphthyridine compound | |
| CN103848756A (en) | Preparation method of teriflunomide and intermediate thereof | |
| CN113582933A (en) | Preparation method of medical intermediate 4-chloro-5-cyanopyrimidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |