CN102558130A - 2-(4-fluorine phenyl)-3-nitryl-8-ethyoxyl-2H-benzopyran chiral compound and preparation method and application thereof - Google Patents
2-(4-fluorine phenyl)-3-nitryl-8-ethyoxyl-2H-benzopyran chiral compound and preparation method and application thereof Download PDFInfo
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- CN102558130A CN102558130A CN2012100050444A CN201210005044A CN102558130A CN 102558130 A CN102558130 A CN 102558130A CN 2012100050444 A CN2012100050444 A CN 2012100050444A CN 201210005044 A CN201210005044 A CN 201210005044A CN 102558130 A CN102558130 A CN 102558130A
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Abstract
The invention relates to a 2-(4-fluorine phenyl)-3-nitryl-8-ethyoxyl-2H-benzopyran chiral compound and a preparation method and the application thereof and specifically discloses a ((R)-XM002S (formula I)) and an (S)-XM002S (formula II) of the chiral compound and the preparation method of the chiral compound. The application of the chiral compound in preparation of anti-tumor medicine is further disclosed.
Description
Technical field
The invention belongs to medical technical field, be specifically related to single enantiomer (the R)-XM002S of chipal compounds 2-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene with (S)-XM002S and preparation method thereof and application.
Background technology
According to prior art, if contain chiral centre or asymmetric center in a molecule, then this molecule is a chiral molecules.If only contain a chiral centre in the molecule, then there is optical direction pair of opposite enantiomorph molecule (levo form and dextrorotatory form) in this molecule.The material that the levo form of equivalent and dextrorotatory form are formed is called racemic modification.About 60% has 1 or 1 above chiral centre in the common drug, and about 50% belongs to chiral drug in listed 2050 medicines of USP.The different enantiomorphs of chiral drug often have different stereoselectivities with the effect of biomacromolecule, and then show very big difference in pharmacodynamics, pharmacokinetics and toxicology.For example (S)-Proprasylyte is a kind of receptor blocking agent, be used to treat heart trouble, and (R)-Proprasylyte has the inhibition sexuality, is a kind of male contraceptive pill; (S)-Ibuprofen BP/EP is a non-steroidal analgesic-antipyretic efficiently, and (R)-Ibuprofen BP/EP do not have pharmacologically active basically; (R)-Thalidomide (having another name called " thalidomide ") has and alleviates the gestation reaction effect, and (S)-Thalidomide is a kind of powerful teratogen.Therefore, obtaining optically pure chipal compounds all is very important for chemistry, biology or pharmacy.FDA (FDA) regulation: pharmacy industry must be guaranteed activity and all process tests respectively of toxicity of its two enantiomers before a racemic new drug is introduced to the market.Use high optically pure monomer to become the requirement and the trend of pharmaceutical development as specifics.
Chinese patent file CN101849934A (CN201010181572.6) discloses the application of compound 2-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene as phosphatidylinositol--3-kinase inhibitor.Compound 2-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene (XM002S) is a racemic modification compound, and its single enantiomer (R)-XM002S or (S)-XM002S does not appear in the newspapers with the associated biomolecule activity as the synthetic of new compound entity.
Summary of the invention
The present invention aims to provide single enantiomer (R)-XM002S, (S)-XM002S and the preparation method of a kind of 2-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene chipal compounds;
The present invention also provides (R)-XM002S, the application of (S)-XM002S in the preparation antitumor drug.
The technical scheme that the present invention adopts is following:
Terminological interpretation:
XM002S:2-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene,
(R)-XM002S: (2R)-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene, be the levo form of XM002S.
(S)-XM002S: (2S)-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene, be the dextrorotatory form of XM002S.
[α]
20 D: under 20 ℃ of temperature, sodium light, contain the specific rotation that the 1mL solution of 1g solute is measured in the liquid-holding pipe of long 1dm.
DCC:N, N '-dicyclohexyl carbon imide.
The DMAP:4-Dimethylamino pyridine.
1, single enantiomer (the R)-XM002S of 2-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene (XM002S) chipal compounds or (S)-XM002S
Chipal compounds 2-of the present invention (4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene (XM002S) molecular formula is: C
17H
14FNO
4, molecular weight is 315.3, [α] of its levo form (R)-XM002S
20 D=-158 ° (chloroform), structure is suc as formula shown in the I; [α] of its dextrorotatory form (S)-XM002S
20 D=+152 ° (chloroform), structure is suc as formula shown in the II;
2, the preparation method of (R)-XM002S or (S)-XM002S
The compounds of this invention (R)-XM002S, (S)-XM002S split preparation and get through chemistry, and resolution reagent is (S)-(+)-α-methoxyphenylacetic acid.
With racemic modification [2-(4-fluorophenyl)-3-nitro-8-hydroxyl-2H-chromene] (compound 1) is initial feed; Obtain a pair of diastereomer 2a, 2b with the chiral carboxylic acids condensation; Slough carboxylic acid then respectively and obtain a pair of enantiomer 3a, 3b, prepare (R)-XM002S, (S)-XM002S through hydroxyethylization at last.
2a: (2R)-(4-fluorophenyl)-3-nitro-8-[(S)-α-anisole acetoxyl group]-the 2H-chromene;
2b: (2S)-(4-fluorophenyl)-3-nitro-8-[(S)-α-anisole acetoxyl group]-the 2H-chromene;
3a: (2R)-(4-fluorophenyl)-3-nitro-8-hydroxyl-2H-chromene;
3b: (2S)-(4-fluorophenyl)-3-nitro-8-hydroxyl-2H-chromene;
Reaction scheme is following:
Reaction reagent and condition: a) (S)-(+)-α-methoxyphenylacetic acid, DCC, DMAP, CHCl
3B) MeNH
2, CH
2Cl
2C) CH
3CH
2I, K
2CO
3
According to the present invention, (R)-preparation method of XM002S or (S)-XM002S, comprise that step is following:
(1) get [2-(4-fluorophenyl)-3-nitro-8-hydroxyl-2H-chromene] (compound 1) and be dissolved in the chloroform, adding DCC, DMAP reach (S)-(+)-α-methoxyphenylacetic acid stirring at room 20-24 hour; Filter, filtrate decompression concentrates; Ethyl acetate extraction is after column chromatography gets compound 2a and compound 2b;
(2) the compound 2a and the compound 2b that step (1) are made are dissolved in respectively in the dichloromethane solution, add aqueous methylamine solution, and stirring at room 1 hour is regulated pH to 6.0 with acetic acid; With ethyl acetate extraction after column chromatography respectively compound 3a, compound 3b;
(3) the compound 3a, the compound 3b that step (2) are made are dissolved in N respectively, in the dinethylformamide, add Anhydrous potassium carbonate and iodoethane, stirring at room 16 hours; After ethyl acetate extraction, get (R)-XM002S or (S)-XM002S through column chromatography respectively.
According to (R)-XM002S of the present invention or (S)-and the preparation method of XM002S, preferred scheme, step is following:
1) claims that 10 mmoles get compound 1 and be dissolved in 80 milliliters of chloroforms, add 15 mmole DCC, 4 mmole DMAP, 15 mmoles (S)-(+)-α-methoxyphenylacetic acid, stirring at room 24 hours; Filter, filtrate decompression concentrates; Ethyl acetate extraction is after column chromatography gets compound 2a1.50 gram and compound 2b1.55 gram;
2) the 4.66 mmole compound 2a that step (1) made are dissolved in 50 milliliters of dichloromethane solutions, add 10 milliliters of aqueous methylamine solutions, and stirring at room 1 hour is regulated pH to 6.0 with acetic acid; With ethyl acetate extraction after column chromatography gets 3a 0.90 gram;
3.14 mmole compound 3a are dissolved in 20 milliliters of N, in the dinethylformamide, add 6.28 mmole Anhydrous potassium carbonates, 3.77 mmole iodoethane, stirring at room 16 hours; After ethyl acetate extraction, get (R)-XM002S0.74 gram through column chromatography.
3) the 4.43 mmole compound 2b that step (1) made are dissolved in 50 milliliters of dichloromethane solutions, add 10 milliliters of aqueous methylamine solutions, and stirring at room 1 hour is regulated pH to 6.0 with acetic acid; After ethyl acetate extraction, column chromatography gets 3b 0.83 gram;
2.89 mmole compound 3b are dissolved in 20 milliliters of N, in the dinethylformamide, add Anhydrous potassium carbonate 0.80 gram again, 3.47 mmole iodoethane, stirring at room 16 hours.After ethyl acetate extraction, get (S)-XM002S 0.65 gram through column chromatography.
3, the application of (R)-XM002S or (S)-XM002S
Chipal compounds of the present invention (R)-XM002S or (S)-XM002S is used to prepare antitumor drug, especially as the application of leukemia cell and myeloma cell's suppressor factor.
A kind of antitumor medicine composition comprises compound according to the invention or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.Described anti-tumor drug preferably is meant the medicine of anti-leukemia medicine and/or anti-myeloma.
According to the present invention, chipal compounds of the present invention (R)-XM002S or (S)-XM002S can become pharmaceutical composition with conventional medicine carrier or vehicle group.But this pharmaceutical composition administered through oral or parenteral route administration.Pharmaceutical composition of the present invention can be prepared into various formulations by this area ordinary method, includes but not limited to tablet, capsule, solution, suspension-s, granule or injection etc., oral administration or parenteral route administration.
Excellent results of the present invention:
1, the present invention prepares single enantiomer (R)-XM002S of racemic modification XM002S or (S)-XM002S through chemical method for splitting.
2, the present invention to (R)-XM002S or (S)-activity that XM002S suppresses pernicious myelomatosis and leukemia cell carried out experimental verification, clear and definite chipal compounds (R)-XM002S or (S)-XM002S has an obvious suppression effect to leukemia cell and myeloma cell's.Can be same as the preparation antitumor drug.
Description of drawings
Fig. 1 is that myeloma cell LP1 gives the cell survival rate figure after (R)-XM002S or (S)-XM002S is hatched among the embodiment 3, and X-coordinate is: drug level, and unit: μ M, ordinate zou is: the cell survival percentage;
Fig. 2 is that myeloma cell OPM-2 gives the cell survival rate figure after (R)-XM002S or (S)-XM002S is hatched among the embodiment 3, and X-coordinate is: drug level, and unit: μ M, ordinate zou is: the cell survival percentage;
Fig. 3 is that leukemia cell K562 gives the cell survival rate figure after (R)-XM002S or (S)-XM002S is hatched among the embodiment 3, and X-coordinate is: drug level, and unit: μ M, ordinate zou is: the cell survival percentage;
Fig. 4 is that leukemia cell Jurkat cell gives the cell survival rate figure after (R)-XM002S or (S)-XM002S is hatched among the embodiment 3, and X-coordinate is: drug level, unit: μ M, ordinate zou is: the cell survival percentage.
Embodiment
Help to understand the present invention through following instance, but can not limit content of the present invention.Do not specify among the embodiment all according to prior art.
Embodiment 1: (R)-and the preparation of XM002S
Take by weighing compound 1 (2.86 grams, 10 mmoles) and be dissolved in 80 milliliters of chloroforms, add DCC (3.09 grams, 15 mmoles), DMAP (0.49 gram, 4 mmoles), (S)-(+)-and α-methoxyphenylacetic acid (2.49 grams, 15 mmoles), stirring at room 24 hours; Filter, filtrate decompression concentrates; Ethyl acetate extraction is after column chromatography gets compound 2a (1.50 gram) and compound 2b (1.55 gram);
Compound 2a (2.03 grams, 4.66 mmoles) is dissolved in 50 milliliters of dichloromethane solutions, adds 10 milliliters of aqueous methylamine solutions, stirring at room 1 hour is regulated pH to 6.0 with acetic acid; With ethyl acetate extraction after column chromatography gets 3a (0.90 gram);
Compound 3a (0.90 gram, 3.14 mmoles) is dissolved in 20 milliliters of N, in the dinethylformamide, adds Anhydrous potassium carbonate (0.87 gram, 6.28 mmoles), iodoethane (0.59 gram, 3.77 mmoles), stirring at room 16 hours; After ethyl acetate extraction, get (R)-XM002S (0.74 gram), optical purity＞99.9% through column chromatography.
Embodiment 2: (S)-and the preparation of XM002S
Compound 2b (1.93 grams, 4.43 mmoles) is dissolved in 50 milliliters of dichloromethane solutions, adds 10 milliliters of aqueous methylamine solutions, stirring at room 1 hour is regulated pH to 6.0 with acetic acid.After ethyl acetate extraction, column chromatography gets 3b (0.83 gram);
Compound 3b (0.83 gram, 2.89 mmoles) is dissolved in 20 milliliters of N, in the dinethylformamide, adds Anhydrous potassium carbonate (0.80 gram) again, iodoethane (0.54 gram, 3.47 mmoles), stirring at room 16 hours.After ethyl acetate extraction, get (S)-XM002S (0.65 gram), optical purity＞99.5% through column chromatography.
Experimental example 3: (R)-XM002S, (S)-XM002S suppress pernicious myelomatosis and leukemia cell's increment experiment
Terminological interpretation:
MTT:3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt, trade(brand)name: tetrazolium bromide; DMSO: DMSO 99.8MIN..
Test material and method:
Experiment material: LP1 cell, OPM-2 cell, K562 cell, Jurkat cell, 96 orifice plates, MTT, 10%DMSO (volume ratio).
The LP1 cell, the OPM-2 cell, the K562 cell, the Jurkat cell is provided by the Tang Zhong of University Of Suzhou English Blood Center.
Concrete operations are following:
Respectively with myeloma cell strain LP1, myeloma cell strain OPM-2, leukemia cell line K562, leukemia cell line Jurkat cell is inoculated in 96 orifice plates with 10000/milliliter density uniformly, adds the cell of 100 microlitres in every hole.Cell culture environment is 37 ℃, 5% carbonic acid gas (volume ratio), with (R)-XM002S or (S)-XM002S is with 0; 0.25,0.5,1; 2,4,8 micromolar concentration gradients join in the cell of 100 microlitres successively; After hatching 72 hours, add the MTT liquid of 10 microlitres in every hole, continue to cultivate after 3～4 hours; Add 100 microlitre 10%DMSO again and make the crystallisate dissolving, detect each hole OD value (the detection wavelength is 570nm) with ELIASA after 4 hours, obtain Fig. 1 (LP1), Fig. 2 (OPM-2), Fig. 3 (K562), Fig. 4 (Jurkat) respectively.
Above-mentioned experimental result shows:
Compound (R)-XM002S with (S)-XM002S all can effectively suppress the myeloma cell (LP1, OPM-2) and the leukemia cell (K562, increment Jurkat) can be applicable to prepare in the medicine of treating tumour.
Claims (6)
1. chipal compounds 2-(4-fluorophenyl)-3-nitro-8-oxyethyl group-2H-chromene (XM002S) molecular formula is: C
17H
14FNO
4, molecular weight is 315.3, [α] of its levo form (R)-XM002S
20 D=-158 °, structure is suc as formula shown in the I; [α] of its dextrorotatory form (S)-XM002S
20 D=+152 °, structure is suc as formula shown in the II;
2. the preparation method of chipal compounds as claimed in claim 1 (R)-XM002S or (S)-XM002S; It is characterized in that with racemic modification [2-(4-fluorophenyl)-3-nitro-8-hydroxyl-2H-chromene] (1) be initial feed; Obtain a pair of diastereomer (2a), (2b) with the chiral carboxylic acids condensation; Slough carboxylic acid then respectively and obtain a pair of enantiomer (3a), (3b), at last through hydroxyethylization prepare (R)-XM002S with (S)-XM002S;
Reaction scheme is following:
Reaction reagent and condition: a) (S)-(+)-α-methoxyphenylacetic acid, DCC, DMAP, CHCl
3B) MeNH
2, CH
2Cl
2C) CH
3CH
2I, K
2CO
3
3. preparation method as claimed in claim 2 is characterized in that comprising that step is following:
(1) get [2-(4-fluorophenyl)-3-nitro-8-hydroxyl-2H-chromene] (1) and be dissolved in the chloroform, adding DCC, DMAP reach (S)-(+)-α-methoxyphenylacetic acid stirring at room 20-24 hour; Filter, filtrate decompression concentrates; Ethyl acetate extraction is after column chromatography gets compound 2a and compound 2b;
(2) the compound 2a and the compound 2b that step (1) are made are dissolved in respectively in the dichloromethane solution, add aqueous methylamine solution, and stirring at room 1 hour is regulated pH to 6.0 with acetic acid; With ethyl acetate extraction after column chromatography respectively compound 3a, compound 3b;
(3) the compound 3a, the compound 3b that step (2) are made are dissolved in N respectively, in the dinethylformamide, add Anhydrous potassium carbonate and iodoethane, stirring at room 16 hours; After ethyl acetate extraction, get (R)-XM002S or (S)-XM002S through column chromatography respectively.
4. like claim 2 or 3 described preparing methods, it is characterized in that comprising that step is following:
1) claims that 10 mmoles get compound 1 and be dissolved in 80 milliliters of chloroforms, add 15 mmole DCC, 4 mmole DMAP, 15 mmoles (S)-(+)-α-methoxyphenylacetic acid, stirring at room 24 hours; Filter, filtrate decompression concentrates; Ethyl acetate extraction is after column chromatography gets compound 2a1.50 gram and compound 2b1.55 gram;
2) the 4.66 mmole compound 2a that step (1) made are dissolved in 50 milliliters of dichloromethane solutions, add 10 milliliters of aqueous methylamine solutions, and stirring at room 1 hour is regulated pH to 6.0 with acetic acid; With ethyl acetate extraction after column chromatography gets 3a 0.90 gram;
3.14 mmole compound 3a are dissolved in 20 milliliters of N, in the dinethylformamide, add 6.28 mmole Anhydrous potassium carbonates, 3.77 mmole iodoethane, stirring at room 16 hours; After ethyl acetate extraction, get (R)-XM002S0.74 gram through column chromatography;
3) the 4.43 mmole compound 2b that step (1) made are dissolved in 50 milliliters of dichloromethane solutions, add 10 milliliters of aqueous methylamine solutions, and stirring at room 1 hour is regulated pH to 6.0 with acetic acid; After ethyl acetate extraction, column chromatography gets 3b 0.83 gram;
2.89 mmole compound 3b are dissolved in 20 milliliters of N, in the dinethylformamide, add Anhydrous potassium carbonate 0.80 gram again, 3.47 mmole iodoethane, stirring at room 16 hours; After ethyl acetate extraction, get (S)-XM002S 0.65 gram through column chromatography.
5. an antitumor medicine composition comprises the said compound of claim 1 or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.
6. the said compound of claim 1 is used to prepare antitumor drug, special application as leukemia cell and myeloma cell's suppressor factor.
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| CN2012100050444A CN102558130A (en) | 2012-01-09 | 2012-01-09 | 2-(4-fluorine phenyl)-3-nitryl-8-ethyoxyl-2H-benzopyran chiral compound and preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104606189A (en) * | 2015-01-08 | 2015-05-13 | 苏州大学 | Application of compound to preparation of mTOR inhibitor |
| CN106543131A (en) * | 2016-11-02 | 2017-03-29 | 山东大学齐鲁医院 | PI3K/Akt signal pathway inhibitor S14161 of 18F labellings and its preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101849934A (en) * | 2010-05-25 | 2010-10-06 | 苏州大学 | Phosphatidylinositol-3-kinase inhibitor and application thereof |
| CN101857584A (en) * | 2010-04-22 | 2010-10-13 | 广东德鑫制药有限公司 | Hydroxyl flavanoid compound and application thereof |
-
2012
- 2012-01-09 CN CN2012100050444A patent/CN102558130A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101857584A (en) * | 2010-04-22 | 2010-10-13 | 广东德鑫制药有限公司 | Hydroxyl flavanoid compound and application thereof |
| CN101849934A (en) * | 2010-05-25 | 2010-10-06 | 苏州大学 | Phosphatidylinositol-3-kinase inhibitor and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| XINLIANG MAO ET AL.: "A small-molecule inhibitor of D-cyclin transactivation displays preclinical efficacy in myeloma and leukemia via phosphoinositide 3-kinase pathway", 《BLOOD》, vol. 117, no. 6, 6 December 2010 (2010-12-06), pages 1986 - 1997 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104606189A (en) * | 2015-01-08 | 2015-05-13 | 苏州大学 | Application of compound to preparation of mTOR inhibitor |
| CN106543131A (en) * | 2016-11-02 | 2017-03-29 | 山东大学齐鲁医院 | PI3K/Akt signal pathway inhibitor S14161 of 18F labellings and its preparation method and application |
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Application publication date: 20120711 |