CN105272991B - A kind of compound crystal form - Google Patents
A kind of compound crystal form Download PDFInfo
- Publication number
- CN105272991B CN105272991B CN201410415634.3A CN201410415634A CN105272991B CN 105272991 B CN105272991 B CN 105272991B CN 201410415634 A CN201410415634 A CN 201410415634A CN 105272991 B CN105272991 B CN 105272991B
- Authority
- CN
- China
- Prior art keywords
- formula
- crystal formation
- compound
- catalyst
- staphylococcus
- 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.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of new compound and its novel crystal forms.The compound crystal form of formula 1, possesses certain antibacterial and antitumor activity, gained crystal formation draw it is moist not substantially, have good stability, great convenience provided for later product transport, storage or production process.
Description
Technical field
The present invention relates to a kind of compound crystal form.
Background technology
For same compound, it will usually have two or more different crystalline states, and different crystal formation is then
Different bioavilabilities, dissolution rate, rate of dissolution, stability, fusing point, color, filtrability, density and stream would generally be shown
Dynamic property etc..Therefore, for medicine, develop dissolubility and the more preferable crystal formation of stability has very important significance.
The content of the invention
It is an object of the invention to provide a kind of new compound and its novel crystal forms.
The invention provides compound as shown in Equation 1,
The invention provides the crystal formation I of compound shown in formula 1,
The crystal formation is monoclinic system, and space group is P21, cell parameter isα=90.00 °,β=75.971 (9) °,γ=90.00 °, Z=2, unit cell volume is
Further, the fusing point of the crystal formation is 165-166 DEG C.
Further, the ee values of the crystal formation compounds of formula I are more than 95%, and preferably 99%.
Present invention also offers the preparation method of above-mentioned crystal formation I, it includes following operating procedure：
Iodine I is added in the oxinane alcoholic compound 5t replaced to pi-allyl anhydrous acetonitrile2(152.3mg,
0.6mmol), sodium acid carbonate NaHCO3Stirred at (50.4mg, 0.6mmol) and .0 DEG C of KI KI (3.3mg, 0.02mmol)
4 hours, add ethyl acetate (20mL) and thiosulfuric acid saturated aqueous solution of sodium (30mL) to it and use isolated aqueous phase
Ether (3 × 10mL) extraction is simultaneously distilled and is spin-dried for gained organic phase solution jointly.Gained residue passes through silica gel column chromatography (oil
Ether：Ethyl acetate=20:1), thin layer is detected, takes object to elute position, removes solvent, adds n-hexane, and ultrasound is simultaneously used simultaneously
Steel knife is smashed to pieces, ethyl acetate is slowly added dropwise thereto until solid color is pure white, suction filtration obtains sterling.Sterling is placed in dry
In net test tube, add as far as possible that ethyl acetate dissolves it less, then be slowly added dropwise that n-hexane is just muddy to solution, heated solution is extremely
Clarification, test tube is placed at shady and cool ventilation to crystallizing precipitation.
Wherein, the compound 5t is prepared by the following method：
Rac-3 isRacemic modification；
R1 is selected from phenyl ring, and R2 is selected from ethyl, and R3 is selected from
Concrete operation step is as follows：
Carbonyls makees solvent with MeCN, is stirred at room temperature in the presence of DMAP shown in nitroolefin shown in formula 1 and formula 2
Obtain MBH addition compound products rac-3；Then one kettle way adds aldehyde, catalyst and glacial acetic acid shown in formula 4, is reacted at room temperature, uses
TLC, which is monitored to reaction, to be terminated, and is concentrated and through silica gel column chromatography, PE/EA=10：The 1 isolated MBH products (S) -3 of elution and formula
Chiral oxinane alcohol product shown in 5t；The catalyst is selected from N, N- diphenylprolinol silicon ether, L- dried meat ammonia alcohol or L- dried meat ammonia
Acid.
MBH is Belize-Harry Hillman reaction.
Further, nitroolefin shown in formula 1：Carbonyls shown in formula 2：DMAP：Aldehyde shown in formula 4：Catalyst：Ice vinegar
Acid=0.5-1.0mmol:1.0mmol：0.05-0.2mmol：1.0-2.0mmol：0.1-0.3mmol：0.1-0.2mmol；It is preferred that
Ground, nitroolefin shown in formula 1:Carbonyls shown in formula 2：DMAP：Aldehyde shown in formula 4：Catalyst：Glacial acetic acid=0.5mmol:
1.0mmol：0.05mmol：1.0mmol：0.1mmol：0.1mmol.
Present invention also offers the purposes of above-claimed cpd or crystal formation in treatment antibacterium or anti-tumor drug is prepared.
Further, the bacterium is staphylococcus；It is preferred that, the staphylococcus is staphylococcus aureus or epidermis
Staphylococcus.
Further, the tumour is lung cancer, prostate cancer, non-small cell lung cancer, leukaemia.
The compound crystal form of formula 1, possesses certain antibacterial and antitumor activity, gained crystal formation draw it is moist not substantially,
Have good stability, great convenience is provided for later product transport, storage or production process.
Below by way of embodiment, the present invention is described in further detail, but is not intended to limit the present invention, ability
Field technique personnel can be variously modified and deform according to the present invention, without departing from the spirit of the present invention, all should belong to this
Invention scope of the following claims.
Brief description of the drawings
The stereochemical structure perspective view of Fig. 1 crystal formations I of the present invention.
Embodiment
The compound 5t of embodiment 1 preparation
Nitroolefin 1 (0.5mmol) and active carbonyls 2 (1.0mmol) DMAP (6.1mg,
In the presence of 0.05mmol), solvent is done with MeCN, 30min is stirred at room temperature and obtains MBH addition compound products rac-3.Then one kettle way adds
Enter aldehyde 4 (1.0mmol), N, N- diphenylprolinol silicon ethers (32.5mg, 0.1mmol) and glacial acetic acid (6.0mg, 0.1mmol).Instead
It should at room temperature carry out, reaction process is monitored with TLC.Concentrate and silica gel column chromatography (PE/EA=10：1) the isolated MBH of priority
Product (S) -3 and chiral oxinane alcohol product 5.
R1~R3 groups described in reaction equation, are selected all in accordance with 5t compound structures, and gained compound is as follows：
7.31-7.22 (m, 3H), 7.12 (d, J=7.2Hz, 2H), 5.39 (dd, J=6.8Hz, J=4.0Hz, 1H),
5.23 (dd, J=10.0Hz, J=6.0Hz, 1H), 5.10 (d, J=5.6Hz, 1H), 4.76 (d, J=9.6Hz, 1H), 4.29-
4.22 (m, 2H), 4.00-3.84 (m, 1H), 3.30 (t, J=11.2Hz, 1H), 2.80-2.73 (m, 1H), 1.50 (s, 3H),
1.40 (s, 3H), 1.24 (t, J=7.2Hz, 3H) ppm；Carbon is composed13C NMR(100MHz,CDCl3):δ=167.94,137.74,
137.22,128.63,128.08,127.74,121.13,97.12,89.30,68.95,62.31,47.24,44.25,25.72,
18.31,13.85ppm；High resolution mass spectrum ESI HRMS:Calculated value C18H23NO6+ Na 372.1423, measured value 372.1419.
The preparation of the compound of 2 formula of embodiment 1
Iodine I is added in the oxinane alcoholic compound 5t replaced to pi-allyl anhydrous acetonitrile2(152.3mg,
0.6mmol), sodium acid carbonate NaHCO3Stirred at (50.4mg, 0.6mmol) and .0 DEG C of KI KI (3.3mg, 0.02mmol)
4 hours, add ethyl acetate (20mL) and thiosulfuric acid saturated aqueous solution of sodium (30mL) to it and use isolated aqueous phase
Ether (3 × 10mL) extraction is simultaneously distilled and is spin-dried for gained organic phase solution jointly.Gained residue passes through silica gel column chromatography (oil
Ether：Ethyl acetate=20:1), thin layer is detected, takes object to elute position, removes solvent, adds n-hexane, and ultrasound is simultaneously used simultaneously
Steel knife is smashed to pieces, ethyl acetate is slowly added dropwise thereto until solid color is pure white, suction filtration obtains sterling.Sterling is placed in dry
In net test tube, add as far as possible that ethyl acetate dissolves it less, then be slowly added dropwise that n-hexane is just muddy to solution, heated solution is extremely
Clarification, test tube is placed at shady and cool ventilation to crystallizing precipitation.
White solid oxinane alcohol product 75.1mg (yield 79%) is received to obtain in calculating, chiral by efficient liquid phase
CelluCoat chromatographic columns measure its ee value for 99% (15% isopropanol/n-hexane, 1mL/min), UV220nm, tminor=
21.55min,tmajor165-166 DEG C of=29.26min. fusing points；Optical value [α]D 20- 151.4 (c=0.12in CH2Cl2)；Hydrogen
Spectrum1H NMR(400MHz,CDCl3):δ=7.39-7.31 (m, 3H), 7.27 (d, J=7.6Hz, 2H), 5.44 (d, J=8.0Hz,
1H), 5.27-5.20 (m, 2H), 4.21 (dd, J=14.4Hz, J=7.2Hz, 2H), 3.85 (d, J=12.0Hz, 1H), 3.75
(t, J=11.2Hz, 1H), 2.37-2.29 (m, 1H), 1.51 (s, 3H), 1.37 (s, 3H), 1.27 (t, J=7.2Hz, 3H)
ppm；Carbon is composed13C NMR(100MHz,CDCl3):δ=167.32,134.32,128.92,128.63,128.45,99.78,
86.28,84.87,73.86,62.40,52.10,45.47,30.92,26.72,25.81,13.83ppm；High resolution mass spectrum ESI
HRMS:Calculated value C18H22INO6+ Na 498.0390, measured value 498.0387.
The X- single crystal diffraction crystal structural datas of table 1
Beneficial effects of the present invention are illustrated below by way of test example.
In following experiments, by reagent dissolves compound concentration with DMSO.
The Anticancer Activities of test example 1
Using mtt assay, the compounds of this invention 6t active anticancer is determined, as a result be see the table below：
Table 2
Note：Above-mentioned activity value is inhibiting rate, and inhibiting rate of the medicine under the concentration is 87% if numerical value is 0.87.
From the above results, the compounds of this invention crystal formation is to human lung carcinoma cell, prostate gland cancer cell, leukaemia, gland cancer
Etc. there is certain inhibitory action.
The antibacterial activity of test example 2
Using mtt assay, the compounds of this invention 6t antibacterial activity is determined, as a result be see the table below：
Table 3
Mark：Blank is represented without activity.
The results showed, the compound for preparing of the present invention possesses certain antibacterial and antitumor activity, and gained crystal formation draws wet
Property increase it is unobvious, have good stability, for later product transport, storage or production process provide great convenience.
Claims (13)
1. compound as shown in Equation 1,
2. the crystal formation I of compound shown in formula 1, it is characterised in that：
The crystal formation is monoclinic system, and space group is P21, cell parameter isα=90.00 °,β
=75.971 (9) °,γ=90.00 °, Z=2, unit cell volume is
3. crystal formation I according to claim 2, it is characterised in that：The fusing point of the crystal formation is 165-166 DEG C.
4. crystal formation I according to claim 2, it is characterised in that：The ee values of the crystal formation compounds of formula I 95% with
On.
5. crystal formation I according to claim 4, it is characterised in that：The ee values of the crystal formation compounds of formula I are 99%.
6. the preparation method of crystal formation I described in claim 2-5 any one, it is characterised in that：It includes following operating procedure：
Iodine, sodium acid carbonate and iodine are added in the oxinane alcoholic compound 5t replaced to pi-allyl anhydrous acetonitrile
Change and stirred 4 hours at potassium, 0 DEG C, ethyl acetate and thiosulfuric acid saturated aqueous solution of sodium are added to it, by isolated aqueous phase
Distill and be spin-dried for jointly with ether extraction and with gained organic phase solution；Gained residue is by silica gel column chromatography, with petroleum ether：Second
Acetoacetic ester=20:1 elution, thin layer tracking, takes object to elute position, removes solvent, adds n-hexane, and ultrasound is simultaneously smash simultaneously
It is broken, ethyl acetate is slowly added dropwise thereto until solid color is pure white, suction filtration obtains sterling；Sterling is taken, adding ethyl acetate makes
It is dissolved, then to be slowly added dropwise n-hexane just muddy to solution, and test tube is placed at shady and cool ventilation to tying to clarifying by heated solution
Partial crystallization goes out.
7. preparation method according to claim 6, it is characterised in that：The compound 5t is prepared by the following method：
Rac-3 isRacemic modification；
R1 is selected from phenyl ring, and R2 is selected from ethyl, and R3 is selected from
Concrete operation step is as follows：
Carbonyls makees solvent with MeCN, is stirred at room temperature and obtains in the presence of DMAP shown in nitroolefin shown in formula 1 and formula 2
MBH addition compound products rac-3；Then one kettle way adds aldehyde, catalyst and glacial acetic acid shown in formula 4, is reacted at room temperature, uses TLC
Monitoring to reaction terminates, and concentrates and through silica gel column chromatography, PE/EA=10：The 1 isolated MBH products (S) -3 of elution and formula 5t institutes
Show chiral oxinane alcohol product；The catalyst is selected from N, N- diphenylprolinol silicon ether, L- dried meat ammonia alcohol or L-PROLINE.
8. synthetic method according to claim 7, it is characterised in that：Nitroolefin shown in formula 1：Carbonyl compound shown in formula 2
Thing：DMAP：Aldehyde shown in formula 4：Catalyst：Glacial acetic acid=0.5-1.0mmol:1.0mmol：0.05-0.2mmol：1.0-
2.0mmol：0.1-0.3mmol：0.1-0.2mmol.
9. synthetic method according to claim 8, it is characterised in that：Nitroolefin shown in formula 1:Carbonyl compound shown in formula 2
Thing：DMAP：Aldehyde shown in formula 4：Catalyst：Glacial acetic acid=0.5mmol:1.0mmol：0.05mmol：1.0mmol：0.1mmol：
0.1mmol。
10. compound described in claim 1 or the crystal formation I described in claim 2-4 any one prepare treatment antibacterium or
Purposes in anti-tumor drug.
11. purposes according to claim 10, it is characterised in that：The bacterium is staphylococcus.
12. purposes according to claim 11, it is characterised in that：The staphylococcus is staphylococcus aureus or epidermis
Staphylococcus.
13. purposes according to claim 10, it is characterised in that：The tumour is lung cancer, prostate cancer, non-small cell lung
Cancer, leukaemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410415634.3A CN105272991B (en) | 2014-06-26 | 2014-08-21 | A kind of compound crystal form |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2014102988148 | 2014-06-26 | ||
| CN201410298814 | 2014-06-26 | ||
| CN201410415634.3A CN105272991B (en) | 2014-06-26 | 2014-08-21 | A kind of compound crystal form |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105272991A CN105272991A (en) | 2016-01-27 |
| CN105272991B true CN105272991B (en) | 2017-11-07 |
Family
ID=55142885
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410415634.3A Expired - Fee Related CN105272991B (en) | 2014-06-26 | 2014-08-21 | A kind of compound crystal form |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105272991B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1184474A (en) * | 1995-04-19 | 1998-06-10 | 沃泰克斯药物股份有限公司 | Oxygenated-heterocycle containing sulfonamide inhibitors of aspartyl protease |
| WO1999067417A2 (en) * | 1998-06-23 | 1999-12-29 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Fitness assay and associated methods |
| CN102143965A (en) * | 2008-09-08 | 2011-08-03 | 贝林格尔.英格海姆国际有限公司 | Pyrazolopyrimidines and their use for the treatment of CNS disorders |
| WO2013103874A1 (en) * | 2012-01-05 | 2013-07-11 | Lasya, Inc. | Skin lightening compositions |
-
2014
- 2014-08-21 CN CN201410415634.3A patent/CN105272991B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1184474A (en) * | 1995-04-19 | 1998-06-10 | 沃泰克斯药物股份有限公司 | Oxygenated-heterocycle containing sulfonamide inhibitors of aspartyl protease |
| WO1999067417A2 (en) * | 1998-06-23 | 1999-12-29 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Fitness assay and associated methods |
| CN102143965A (en) * | 2008-09-08 | 2011-08-03 | 贝林格尔.英格海姆国际有限公司 | Pyrazolopyrimidines and their use for the treatment of CNS disorders |
| WO2013103874A1 (en) * | 2012-01-05 | 2013-07-11 | Lasya, Inc. | Skin lightening compositions |
Non-Patent Citations (3)
| Title |
|---|
| Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived High Affinity P2 Ligands: Structure-Activity Studies and Biological Evaluation;Arun K. Ghosh，等;《J. Med. Chem.》;20101231;第54卷;第622-634页 * |
| Highly Regio- and Stereoselective One-Pot Synthesis of Carbohydrate-Based Butyrolactones;Syed Khalid Yousuf，等;《ORGANIC LETTERS》;20110118;第13卷(第4期);第576-579页 * |
| The Naturally Occurring Ketene Acetal Benesudon: Total Synthesis and Assignment of Relative and Absolute Stereochemistry;Derrick L. J. Clive，等;《J. Org. Chem.》;20080802;第73卷;第6743-6752页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105272991A (en) | 2016-01-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106365986A (en) | Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam | |
| CN102348706A (en) | Process for producing pyripyropene derivative | |
| CN102947312A (en) | Process for producing pyripyropene derivatives | |
| CN105130927A (en) | Phenyl-nitrogen alkadienone derivative as well as preparation method and application thereof | |
| Yoon et al. | Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine based approach | |
| CN105949118A (en) | Preparation method of 2-aryl quinoline derivatives | |
| CN106810560A (en) | A kind of synthetic method of 8 azepine cumarin and its application in antineoplastic | |
| JP6010605B2 (en) | Chroman derivatives | |
| CN105272991B (en) | A kind of compound crystal form | |
| CN102180914A (en) | Preparation method of 2-deoxidizing-D-glucose | |
| Kumar et al. | A simple and efficient enantioselective route to 2, 6-disubstituted piperidines: synthesis of (2R, 6S)-isosolenopsin A and (2S, 6R)-isosolenopsin | |
| CN103304478B (en) | Alkaloidal intermediate of one class synthesis renieramycins type and preparation method thereof | |
| CN103374049B (en) | One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid | |
| CN103254187B (en) | A kind of preparation method of Taxane derivative | |
| CN107365301B (en) | Synthesis method of crizotinib and preparation method of intermediate thereof | |
| CN104892499B (en) | A kind of synthetic method of 2 pyridinone derivatives | |
| CN101270119B (en) | Technique for purifying spherosinin from leguminosae pointvetch or milk vetch | |
| CN103483354B (en) | One class chromone compounds and preparation method thereof and antitumor with the application in enzyme inhibitor medicine in preparation | |
| CN102020619A (en) | Method for separating cephalomannine from taxol | |
| CN101787003A (en) | Preparation method of 5,6-epoxy-5,6-dihydro-beta-ionol | |
| Yamano et al. | Total synthesis of lycopene-5, 6-diol and γ-carotene-5′, 6′-diol stereoisomers and their HPLC separation | |
| CN109369606A (en) | A kind of preparation method of the pungent class compound of acetylation dibenzo -1,3- dioxane and the application as antibacterials | |
| CN104387221A (en) | Synthesis method of peretinoin decarboxylative body impurities | |
| CN104844681A (en) | L-crystal form eplerenone refining method | |
| CN102399228B (en) | Preparation method of N-alkyl polyhydroxypiperidine derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191211 Address after: 610000 No.3, 11th floor, Jilong building, no.589, east section of Jinfu Road, Chengdu cross strait science and Technology Industrial Development Park, Wenjiang District, Chengdu, Sichuan Province Patentee after: Sichuan hongtaizhongcheng Medical Equipment Co.,Ltd. Address before: 611137 No. 1166, Willow Road, Wenjiang District, Sichuan, Chengdu Patentee before: Chengdu University of Traditional Chinese Medicine |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171107 Termination date: 20210821 |