CN108084054A - A kind of multi-substituted chiral alkenyl cyclopropane compound and its crystal and its preparation method and purposes - Google Patents
A kind of multi-substituted chiral alkenyl cyclopropane compound and its crystal and its preparation method and purposes Download PDFInfo
- Publication number
- CN108084054A CN108084054A CN201711168515.2A CN201711168515A CN108084054A CN 108084054 A CN108084054 A CN 108084054A CN 201711168515 A CN201711168515 A CN 201711168515A CN 108084054 A CN108084054 A CN 108084054A
- Authority
- CN
- China
- Prior art keywords
- formula
- crystal form
- compound
- compound shown
- preparation
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
-
- 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
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of multi-substituted chiral alkenyl cyclopropane compound and its crystal and its preparation method and purposes, for its structural formula as shown in formula I, the disclosure also discloses the crystal form of compound shown in formula I：The crystal form is monoclinic system, and cell parameter isα=90 °, β=90 °, γ=90 °, space group P212121, Z=4, unit cell volume isThe invention also discloses the method for preparing this crystal form, and disclose the purposes of the compounds of this invention or its crystal form or its solvate or its pharmaceutically acceptable salt in antitumor drug is prepared.
Description
Technical field
The present invention relates to a kind of multi-substituted chiral alkenyl cyclopropane compound and its crystal and its preparation method and purposes.
Background technology
Cyclopropane is widely used in the structure of complicated skeleton, has developed a series of structure by cyclopropane ring-opening reaction
The methodology system of important feature, the D-A cyclopropane open loop policies such as using cyclopropane as substrate are research very popular so far
Field.Wherein, the skeleton of chiral cyclopropane can be converted into a series of chiral skeleton by a variety of reaction types, Cyclopropanated
Occupy very important status in.Therefore, build chiral cyclopropane skeleton and determine that its accurate structure and absolute configuration have
Significance.
For same compound, it will usually there are two types of or a variety of different crystalline states, and different crystal forms is then
It would generally show different bioavilabilities, dissolution rate, rate of dissolution, stability, fusing point, color, filtrability, density and stream
Dynamic property etc..Therefore, develop dissolubility and the better crystal form of stability has very important significance.
The content of the invention
To solve the above-mentioned problems, the present invention provides a kind of multi-substituted chiral alkenyl cyclopropane compound and its crystal and
Its preparation method and purposes.
The invention discloses a kind of multi-substituted chiral alkenyl cyclopropane compounds, its structural formula is as shown in formula I：
The present invention provides a kind of methods of compound shown in formula I：It comprises the following steps：
(1) compound shown in compound shown in formula II, formula III, sodium acid carbonate, folium eucalypti thioether are added in acetonitrile, reaction knot
Beam removes solvent and obtains residue；
(2) by silicagel column on residue, eluent is eluted to obtain, solvent is removed, obtains compound shown in formula I.
In step (1), compound shown in the formula III, compound, sodium acid carbonate, the molar ratio of folium eucalypti thioether shown in formula II
For 1：1.4：1.5：0.2；And/or compound shown in the formula III and the molal volume of acetonitrile ratio are 1：0.5mmol/mL；With/
Or, the time of the reaction is 48h；And/or the temperature of the reaction is 25 ± 2 DEG C.
In step (2), the eluant, eluent of the elution is petroleum ether：Ethyl acetate=10:1；And/or the eluent is
Using thin-layered chromatography, its solvent is collected as petroleum ether：Ethyl acetate=6:1, Rf is 0.4~0.5 elution fraction.
The present invention also provides a kind of crystal form of compound shown in formula I, which is monoclinic system, and cell parameter isα=90 °, β=90 °, γ=90 °.
Further, the space group of the crystal form is P212121, Z=4, unit cell volume isAnd/or institute
State the ee values of crystal form>99%；And/or the fusing point of the crystal form is 123-125 DEG C.
The present invention provides a kind of methods for preparing compound crystal form shown in above-mentioned formula I, it comprises the following steps：
(1) according to aforementioned preparation process, compound shown in formula I is obtained；
(2) compound shown in gained formula I in step (1) is taken, is crystallized in n-hexane/isopropyl alcohol mixed solvent, obtains formula I
The crystal form of shown compound.
In step (2), the volume ratio of the isopropanol and n-hexane is 1：4.
Compound shown in above-mentioned formula I or its crystal form or its solvate or its pharmaceutically acceptable salt are anti-in preparation
Purposes in tumour medicine.
Preferably, the tumour is breast cancer or melanoma.
The present invention provides a kind of pharmaceutical compositions, it is with compound shown in above-mentioned formula I or the conjunction of its crystal form or its solvent
Object or its pharmaceutically acceptable salt are active ingredient, in addition pharmaceutically acceptable auxiliary material or auxiliary element are prepared into pharmacy
Upper common preparation.
Herein described " room temperature " is 25 ± 2 DEG C.
Beneficial effects of the present invention：The present invention provides compounds and preparation method thereof described in a kind of formula I, provide simultaneously
Its crystal form, the yield and purity of crystal form of the present invention are high, are easy to get the crystal form of the compound of high-purity, easy to operate, cost
It is low, it is very beneficial for the control of compound quality described in formula I.
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.
Description of the drawings
Fig. 1 be compound shown in formula I crystal form, stereochemical structure perspective view.
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.
Compound shown in formula II is prepared by known methods：X.Jiang,D.Fu,X.Shi,S.Wang and R.Wang,
Chem.Comm.2011,47,8289.
Compound shown in formula III is bought in this Reagent Company of Adama, and folium eucalypti thioether is bought in TCI Reagent Companies.
The preparation of 1 compound of formula I of embodiment
In reaction tube, dicyanogen methyl isophorone diene substrate II (35.5 milligrams), sodium acid carbonate (12.6 milligrams), bromine are sequentially added
For acetophenone III (19.9 milligrams) and folium eucalypti thioether (3.7 milligrams), 50 μ l acetonitriles are eventually adding as solvent.It reacts at room temperature
48h is monitored with TCL and reacted, concentrates reaction solution after the reaction was complete, with silica gel column separating purification, with petroleum ether：Ethyl acetate=
10：1 is eluant, eluent, and using thin-layered chromatography, solvent is petroleum ether：Ethyl acetate=6:1, merge Rf for 0.4~0.5 elution
Liquid removes solvent, obtains purified to get 35 milligrams of compound of formula I.
The compound being prepared is characterized, obtains its hydrogen spectrum, carbon spectrum and high-resolution data, it was demonstrated that gained compound
For compound shown in Formulas I.
1H NMR(600MHz,CDCl3):δ(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):δ(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.
The preparation of the crystal form of compound shown in 2 formula I of embodiment
35 milligrams of 1 compound of formula prepared by Example 1, in isopropanol：N-hexane=1:It is dissolved by heating in 4 (v/v) 3mL
Afterwards, room temperature is naturally cooling to, slowly volatilization crystallization, obtains 25 milligrams of the monocrystalline of Formulas I, ee values>99%, which is spread out by monocrystalline
It penetrates, crystal structural data is shown in Table 1, and stereochemical structure perspective view is shown in Fig. 1.
Crystal structural data in 1 single crystal diffraction of table
1 extracorporeal anti-tumor of experimental example is studied
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 four
Biological therapy National Key Laboratory of river 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 cell proliferation inhibition rates
Cell proliferation inhibition rate is calculated by following equation：
Cell proliferation inhibition rate (%)=(1- test groups A values/control group A value) × 100%.
All experimental datas carry out statistical analysis using SPSS 13.0.Experimental result acquires IC50 values using Probit.
2.3 experimental result
The inhibition situation that 2 crystal form I of the present invention of table grows subject cell
| MB468 | A375 | SKBR3 | MB231 | |
| IC50(μg/mL) | 36.11 | 76.22 | 54.63 | 82.87 |
It is above-mentioned the experimental results showed that, I compound of crystal form provided by the invention have antitumor activity.
To sum up, the present invention provides compound and preparation method thereof described in a kind of formula I, while its crystal form is provided, this
The yield and purity of invention crystal form are high, are easy to get the crystal form of the compound of high-purity, easy to operate, at low cost, highly beneficial
In the control of compound quality described in formula I.
Claims (10)
1. a kind of multi-substituted chiral alkenyl cyclopropane compound, it is characterised in that：Its structural formula is as shown in formula I：
2. a kind of method of compound shown in formula I：It is characterized in that：It comprises the following steps：
(1) compound shown in compound shown in formula II, formula III, sodium acid carbonate, folium eucalypti thioether being added in acetonitrile, reaction terminates,
It removes solvent and obtains residue；
(2) by silicagel column on residue, eluent is eluted to obtain, solvent is removed, obtains compound shown in formula I.
3. preparation method according to claim 2, it is characterised in that：In step (1), compound, formula shown in the formula III
Compound shown in II, sodium acid carbonate, the molar ratio of folium eucalypti thioether are 1：1.4：1.5：0.2；And/or chemical combination shown in the formula III
The molal volume of object and acetonitrile ratio is 1：0.5mmol/mL；And/or the time of the reaction is 48h；And/or the reaction
Temperature is 25 ± 2 DEG C.
4. preparation method according to claim 2, it is characterised in that：In step (2), the eluant, eluent of the elution is oil
Ether：Ethyl acetate=10:1；And/or the eluent is using thin-layered chromatography, collects its solvent as petroleum ether：Acetic acid
Ethyl ester=6:1, Rf is 0.4~0.5 elution fraction.
5. a kind of crystal form of compound shown in formula I, it is characterised in that：The crystal form is monoclinic system, and cell parameter isα=90 °, β=90 °, γ=90 °.
6. crystal form according to claim 5, it is characterised in that：The space group of the crystal form is P212121, Z=4, structure cell body
Product isAnd/or the ee values of the crystal form>99%；And/or the fusing point of the crystal form is 123-125 DEG C.
A kind of 7. method for preparing compound crystal form shown in formula I described in claim 5 or 6, it is characterised in that：It includes following
Step：
(1) according to claim 2~4 any one described in preparation method, obtain compound shown in formula I；
(2) compound shown in gained formula I in step (1) is taken, crystallizes, is obtained shown in formula I in n-hexane/isopropyl alcohol mixed solvent
The crystal form of compound.
Preferably, in step (2), the volume ratio of the isopropanol and n-hexane is 1：4.
8. compound shown in formula I described in claim 1~7 any one or its crystal form or its solvate or its pharmaceutically
Purposes of the acceptable salt in antitumor drug is prepared.
9. purposes according to claim 8, it is characterised in that：The tumour is breast cancer or melanoma.
10. a kind of pharmaceutical composition, it is characterised in that：It is with compound shown in formula I described in claim 1~7 any one or
Its crystal form or its solvate or its pharmaceutically acceptable salt are active ingredient, in addition pharmaceutically acceptable auxiliary material or auxiliary
Co-ingredients is prepared into pharmaceutically common preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711168515.2A CN108084054B (en) | 2017-11-21 | 2017-11-21 | Polysubstituted chiral alkenyl cyclopropane compound and crystal thereof, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711168515.2A CN108084054B (en) | 2017-11-21 | 2017-11-21 | Polysubstituted chiral alkenyl cyclopropane compound and crystal thereof, and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108084054A true CN108084054A (en) | 2018-05-29 |
| CN108084054B CN108084054B (en) | 2020-08-07 |
Family
ID=62172780
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711168515.2A Active CN108084054B (en) | 2017-11-21 | 2017-11-21 | Polysubstituted chiral alkenyl cyclopropane compound and crystal thereof, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108084054B (en) |
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 |
-
2017
- 2017-11-21 CN CN201711168515.2A patent/CN108084054B/en active Active
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 |
|---|
| RONG ZHOU等: "Unusual Formal [1++4] Annulation through Tandem P(NMe2)3-Mediated Cyclopropanation/Base-Catalyzed Cyclopropane Rearrangement: Facile Syntheses of Cyclopentenimines and Cyclopentenones", 《CHEM. EUR. J.》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108084054B (en) | 2020-08-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112174957B (en) | Method for synthesizing 5-selenoindolo [2,1-a ] isoquinoline-6 (5H) -ketone compound | |
| CN106632043A (en) | Licochalcone A pyrazoline derivatives with antitumor activity and synthesis method thereof | |
| CN113666824A (en) | Cannabidiol-2-propionate and application thereof | |
| CN110041222B (en) | Thymoquinone derivative, intermediate, preparation method and application thereof | |
| CN106243182B (en) | Enoxolone-hydrogen sulfide donor reagent derivatives and its synthetic method and application | |
| CN107698648B (en) | Naphthylimide derivative containing cholesterol and synthesis and application thereof | |
| CN108084054A (en) | A kind of multi-substituted chiral alkenyl cyclopropane compound and its crystal and its preparation method and purposes | |
| CN103467556B (en) | A kind of preparation method of phytosterol cinnamate | |
| CN109096357A (en) | The synthesis of the naphthalimide analog derivative of Sulfide-containing Hindered and cholesterol ester and application | |
| CN110511233B (en) | Thiazolo [2,3-b ] oxazolone compound and preparation method and application thereof | |
| CN110964032B (en) | Maotaining extract hydrogen sulfide donor derivative and preparation method and application thereof | |
| CN110964033B (en) | Oridonin 14-position hydrogen sulfide donor derivative and preparation method and application thereof | |
| Lochyński et al. | Stereochemistry of terpene derivatives. Part 3: Hydrolytic kinetic resolution as a convenient approach to chiral aminohydroxyiminocaranes with local anaesthetic activity | |
| CN108125962B (en) | Application of benzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer | |
| CN108084201B (en) | Oxoindolspirotetrahydrofuran skeleton material, crystal thereof and preparation method thereof | |
| CN108373473B (en) | Oxidized indole spiro tetrahydrofuran fluoride and crystal thereof, and preparation method and application thereof | |
| CN109705037A (en) | 4- aminoquinoline -3- carbamate derivatives and its preparation method and application | |
| Gong et al. | Synthesis, Crystal Structure and Biological Activity of 7-(4-Methylpiperazin-1-Yl)-5-[4-(Trifluoromethyl) Phenyl] pyrazolo [1, 5-a] Pyrimidine-3-Carbonitrile | |
| CN103044326A (en) | 5-bromo oxoisoaporphine, and synthesis method and application thereof | |
| CN109879873B (en) | Tetrahydrodibenzonaphthyridine compound and synthesis method and application thereof | |
| CN115215783B (en) | Propargyl substituted chiral 3-amino-3, 3-disubstituted oxindole compound, and synthetic method and application thereof | |
| CN112745310B (en) | Chromone 2-piperazine linked furazan derivative and preparation method and application thereof | |
| CN108084200B (en) | Halogenated dihydropyranopyrrolone compound and preparation method and application thereof | |
| CN110684033B (en) | Tetrahydrofuran diquinoline compound and synthesis method and application thereof | |
| CN115417857B (en) | Piperidine alkaloid in Chinese medicinal Alangium chinense and extraction purification and semisynthesis method and application thereof |
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 |