CN108084054B - Polysubstituted chiral alkenyl cyclopropane compound and crystal thereof, and preparation method and application thereof - Google Patents
Polysubstituted chiral alkenyl cyclopropane compound and crystal thereof, and preparation method and application thereof Download PDFInfo
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- CN108084054B CN108084054B CN201711168515.2A CN201711168515A CN108084054B CN 108084054 B CN108084054 B CN 108084054B CN 201711168515 A CN201711168515 A CN 201711168515A CN 108084054 B CN108084054 B CN 108084054B
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- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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- C—CHEMISTRY; METALLURGY
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Abstract
The invention discloses a polysubstituted chiral alkenyl cyclopropane compound, a crystal thereof, a preparation method and application thereof, wherein the structural formula is shown as a formula I, and the invention also discloses a crystal form of the compound shown as the formula I: the crystal form is monoclinic system, and the cell parameter is
α, β, γ, 90 °, space group P212121Z is 4 and the unit cell volume is
The invention also discloses a method for preparing the crystal form, and discloses application of the compound, or the crystal form, or the solvate, or the pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament.
Description
Technical Field
The invention relates to a polysubstituted chiral alkenyl cyclopropane compound, a crystal thereof, a preparation method and application thereof.
Background
Cyclopropane is widely applied to the construction of complex frameworks, and a series of methodology systems for constructing important structures are developed through the ring-opening reaction of cyclopropane, for example, the ring-opening strategy of D-A cyclopropane taking cyclopropane as a substrate is a very hot research field up to now. Among them, the skeleton of chiral cyclopropane can be converted into a series of chiral skeletons by various reaction types, and has a very important position in cyclopropane chemistry. Therefore, the construction of chiral cyclopropane skeletons and the determination of the precise structure and absolute configuration thereof are of great significance.
Two or more different crystalline states are common for the same compound, while different crystalline forms typically exhibit different bioavailability, dissolution rates, stability, melting points, color, filterability, density, and flowability, among others. Therefore, the development of a crystal form with better solubility and stability is very important.
Disclosure of Invention
In order to solve the problems, the invention provides a polysubstituted chiral alkenyl cyclopropane compound, a crystal thereof, a preparation method and application thereof.
The invention discloses a polysubstituted chiral alkenyl cyclopropane compound, which has a structural formula shown as a formula I:
the invention provides a method for preparing a compound shown as a formula I: it comprises the following steps:
(1) adding a compound shown as a formula II, a compound shown as a formula III, sodium bicarbonate and eucalyptus thioether into acetonitrile, and removing a solvent to obtain a residue after the reaction is finished;
(2) and (3) loading the residue on a silica gel column, eluting to obtain an eluent, and removing the solvent to obtain the compound shown in the formula I.
In the step (1), the molar ratio of the compound shown in the formula III to the compound shown in the formula II to the sodium bicarbonate to the eucalyptus thioether is 1: 1.4: 1.5: 0.2, and/or the molar volume ratio of the compound shown in the formula III to the acetonitrile is 1: 0.5mmol/m L, and/or the reaction time is 48 hours, and/or the reaction temperature is 25 +/-2 ℃.
In the step (2), the eluent for elution is petroleum ether: ethyl acetate 10: 1; and/or, the eluent is prepared by thin layer chromatography, and the developing solvent is petroleum ether: ethyl acetate 6:1, Rf 0.4-0.5.
The invention also provides a crystal form of the compound shown as the formula I, wherein the crystal form is a monoclinic system, and the unit cell parameter is
α＝90°，β＝90°，γ＝90°。
Further, the space group of the crystal form is P212121Z is 4 and the unit cell volume is
And/or, the crystalEe value of type>99 percent; and/or the melting point of the crystal form is 123-125 ℃.
The invention provides a method for preparing a crystal form of a compound shown in the formula I, which comprises the following steps:
(1) according to the preparation method, the compound shown as the formula I is obtained;
(2) and (2) crystallizing the compound shown in the formula I obtained in the step (1) in a n-hexane/isopropanol mixed solvent to obtain the crystal form of the compound shown in the formula I.
In the step (2), the volume ratio of the isopropanol to the n-hexane is 1: 4.
the compound shown in the formula I, or a crystal form, a solvate or a pharmaceutically acceptable salt thereof can be used for preparing the antitumor drug.
Preferably, the tumor is breast cancer or melanoma.
The invention provides a pharmaceutical composition, which is prepared into a commonly used pharmaceutical preparation by taking a compound shown as the formula I, or a crystal form, or a solvate, or a pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The normal temperature is 25 +/-2 ℃.
The invention has the beneficial effects that: the invention provides a compound shown in formula I and a preparation method thereof, and also provides a crystal form of the compound, the crystal form has high yield and purity, the crystal form of the compound with high purity can be easily obtained, the operation is simple and convenient, the cost is low, and the quality control of the compound shown in formula I is very facilitated.
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.
Drawings
FIG. 1 is a perspective view of a crystal form of a compound of formula I according to 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.
The compounds of formula II are prepared by known methods: x.jiang, d.fu, x.shi, s.wang and r.wang, chem.comm.2011,47,8289.
The compound of formula III is purchased from Hadamard reagent, and the cineole thioether is purchased from TCI reagent.
EXAMPLE 1 preparation of Compounds of formula I
Adding dicyanodiene substrate II (35.5 mg), sodium bicarbonate (12.6 mg), bromoacetophenone III (19.9 mg) and eucalyptus thioether (3.7 mg) into a reaction test tube in sequence, adding 50 mu l of acetonitrile serving as a solvent, reacting at room temperature for 48h, monitoring the reaction by using TC L, concentrating the reaction solution after the reaction is completed, separating and purifying by using a silica gel column, taking petroleum ether and ethyl acetate as an eluent, using a thin-layer chromatography, taking petroleum ether and ethyl acetate as a developing agent and 6:1, combining the eluents with Rf of 0.4-0.5, and removing the solvent to obtain a purified product, namely the compound 35 mg of the formula I.
And (3) characterizing the prepared compound to obtain a hydrogen spectrum, a carbon spectrum and high-resolution data of the compound, and confirming that the obtained compound is the compound shown in the formula I.
1H NMR(600MHz,CDCl3):(ppm):8.12–8.10(m,1H),7.92–7.81(m,4H),7.59–7.50(m,3H),7.41–7.38(m,2H),4.48–4.39(m,2H),4.11(t,J＝7.8Hz,1H),2.16(dd,J＝7.8Hz,J＝3.6Hz,1H),1.75–1.72(m,1H),1.40(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3):(ppm):194.5,172.1,168.8,136.6,134.5,133.3,132.4,128.6,128.6,128.5,128.4,112.8,112.5,90.1,63.4,40.3,36.3,26.1,14.1.
HRMS(ESI):m/z calculated forC23H18N2O3Na+:358.1419,found:358.1417.
EXAMPLE 2 preparation of the Crystal form of the Compound of formula I
After 35 mg of the compound of formula 1 prepared in example 1 was dissolved in isopropanol-n-hexane-1: 4(v/v)3m L by heating, the solution was cooled to room temperature naturally, and the crystals were evaporated slowly to obtain 25 mg of single crystals of formula I with ee value > 99%, which were diffracted by single crystals, and the crystal structure data of the crystal forms are shown in table 1, and the projection of the three-dimensional structure is shown in fig. 1.
TABLE 1 Crystal Structure data in Single Crystal diffraction
Experimental example 1 in vitro 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 key laboratory of biological treatment of Sichuan university, and the tumor cells are all frozen and stored in the national key 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/m L, uniformly inoculating into 96-well microplate, placing each group with 3 multiple wells and 100 μ l/well, placing at 37 deg.C saturation humidity and 5% CO2After 24h of incubation in an incubator, the same amount of culture medium is added to a normal control group, the tested drugs (100, 50, 25, 12.5, 6.25 mu g/m L) with concentration gradient are added, 3 multiple wells are arranged at each concentration, the experiment is carried out for 2 times in parallel, after the drugs and the cells act for 24h, 10 mu L MTT solution (5mg/m L) is added to each well, the incubation is continued for 4h, and then each well is addedAdding 100 mu L DMSO, shaking and mixing to dissolve the crystal completely, measuring the absorbance value (A value) at 490nm wavelength of microplate reader, and taking the average value of each concentration group.
2.2 measurement of cell proliferation inhibition Rate
The cell proliferation inhibition rate was calculated according to the following formula:
the cell proliferation inhibition ratio (%) (1-test group a value/control group a value) was × 100%.
All experimental data were statistically analyzed using SPSS 13.0. Experimental results IC50 values were determined using Probit.
2.3 results of the experiment
TABLE 2 inhibition of growth of test cells by form I of the present invention
| MB468 | A375 | SKBR3 | MB231 | |
| IC50(μg/mL) | 36.11 | 76.22 | 54.63 | 82.87 |
The experimental results show that the crystal form I compound provided by the invention has antitumor activity.
In conclusion, the invention provides the compound shown in the formula I and the preparation method thereof, and also provides the crystal form of the compound, the yield and the purity of the crystal form are high, the crystal form of the compound with high purity can be easily obtained, the operation is simple and convenient, the cost is low, and the quality control of the compound shown in the formula I is very favorable.
Claims (10)
1. A polysubstituted chiral alkenyl cyclopropane compound characterized in that: it has a structural formula shown in formula I:
2. a process for preparing a compound of formula I: the method is characterized in that: it comprises the following steps:
(1) adding a compound shown as a formula II, a compound shown as a formula III, sodium bicarbonate and eucalyptus thioether into acetonitrile, and removing a solvent to obtain a residue after the reaction is finished;
(2) and (3) loading the residue on a silica gel column, eluting to obtain an eluent, and removing the solvent to obtain the compound shown in the formula I.
3. The preparation method according to claim 2, wherein in the step (1), the molar ratio of the compound shown in the formula III, the compound shown in the formula II, the sodium bicarbonate and the cineole thioether is 1: 1.4: 1.5: 0.2, and/or the molar volume ratio of the compound shown in the formula III and the acetonitrile is 1 mmol: 0.5m L, and/or the reaction time is 48 hours, and/or the reaction temperature is 25 +/-2 ℃.
4. The method of claim 2, wherein: in the step (2), the eluent for elution is petroleum ether: ethyl acetate 10: 1; and/or, the eluent is prepared by thin layer chromatography, and the developing solvent is petroleum ether: ethyl acetate 6:1, Rf 0.4-0.5.
5. A crystalline form of a compound of formula i, characterized in that: the crystal form is monoclinic system, and the cell parameter is
α＝90°，β＝90°，γ＝90°；
6. The crystalline form of claim 5, characterized in that: the space group of the crystal form is P212121Z is 4 and the unit cell volume is
And/or the ee value of said crystalline form>99 percent; and/or the melting point of the crystal form is 123-125 ℃.
7. A process for preparing a crystalline form of a compound of formula i according to claim 5 or 6, characterized in that: it comprises the following steps:
(1) the preparation method according to any one of claims 2 to 4, wherein the compound shown as the formula I is obtained;
(2) and (2) crystallizing the compound shown in the formula I obtained in the step (1) in a n-hexane/isopropanol mixed solvent to obtain the crystal form of the compound shown in the formula I.
8. The method of claim 7, wherein: in the step (2), the volume ratio of the isopropanol to the n-hexane is 1: 4.
9. use of a compound of formula i, or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1, 5 to 6, in the preparation of an anti-tumor medicament; the tumor is breast cancer or melanoma.
10. A pharmaceutical combination characterized by: the compound shown as the formula I in any one of claims 1 or 5-6, or a crystal form thereof, or a pharmaceutically acceptable salt thereof is used as an active ingredient, and a pharmaceutically acceptable auxiliary material is added to prepare a pharmaceutically common preparation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4939172A (en) * | 1987-02-06 | 1990-07-03 | Roussel Uclaf | Novel cyclopropane carboxylates |
| CN102361851A (en) * | 2009-03-23 | 2012-02-22 | 住友化学株式会社 | Method for producing cyclopropanecarboxylic acid ester |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4939172A (en) * | 1987-02-06 | 1990-07-03 | Roussel Uclaf | Novel cyclopropane carboxylates |
| CN102361851A (en) * | 2009-03-23 | 2012-02-22 | 住友化学株式会社 | Method for producing cyclopropanecarboxylic acid ester |
Non-Patent Citations (1)
| Title |
|---|
| Unusual Formal [1++4] Annulation through Tandem P(NMe2)3-Mediated Cyclopropanation/Base-Catalyzed Cyclopropane Rearrangement: Facile Syntheses of Cyclopentenimines and Cyclopentenones;Rong Zhou等;《Chem. Eur. J.》;20160315;第22卷;第5883–5887页 * |
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