CN105272991A - Compound crystal form - Google Patents
Compound crystal form Download PDFInfo
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- CN105272991A CN105272991A CN201410415634.3A CN201410415634A CN105272991A CN 105272991 A CN105272991 A CN 105272991A CN 201410415634 A CN201410415634 A CN 201410415634A CN 105272991 A CN105272991 A CN 105272991A
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Abstract
The invention provides a new compound and a new crystal form thereof. The compound crystal form in a formula 1 has certain anti-microbial and antineoplastic activity. The formula 1 is shown in the specification. The hygroscopicity of the crystal form is not obvious, the stability is good, and great convenience is provided for the later product transportation, storage or preparation processes.
Description
Technical field
The present invention relates to a kind of compound crystal form.
Background technology
For same compound; usually have the crystalline state that two or more are different, different crystal formations then can show different bioavailabilities, dissolution rate, dissolution rate, stability, fusing point, color, filtrability, density and mobility etc. usually.Therefore, for medicine, develop solvability and the better crystal formation of stability has very important significance.
Summary of the invention
The object of the present invention is to provide a kind of new compound and new crystal thereof.
The invention provides compound as shown in Equation 1,
The invention provides the crystal formation I of compound shown in formula 1,
This crystal formation is oblique system, and spacer is P2
1, unit cell parameters is
α=90.00 °,
β=75.971 (9) °,
γ=90.00 °, Z=2, unit cell volume is
Further, the fusing point of described crystal formation is 165-166 DEG C.
Further, the ee value of described crystal formation compounds of formula I, more than 95%, is preferably 99%.
Present invention also offers the preparation method of above-mentioned crystalline form I, it comprises following operation steps:
Iodine I is added in the anhydrous acetonitrile of the tetrahydropyrans alkylol cpd 5t of allyl group replacement
2(152.3mg, 0.6mmol), sodium bicarbonate NaHCO
3(50.4mg, 0.6mmol) and potassiumiodide KI (3.3mg, 0.02mmol) stir 4 hours at .0 DEG C, add ethyl acetate (20mL) and thiosulfuric acid saturated aqueous solution of sodium (30mL) to it. aqueous phase ether (3 × 10mL) extraction that obtains will be separated and and gained organic phase solution jointly distill and be spin-dried for.Gained residue is by silica gel column chromatography (sherwood oil: ethyl acetate=20:1), thin layer detects, get target compound wash-out position, except desolventizing, add normal hexane, ultrasonic and smash to pieces with steel knife, slowly drip ethyl acetate wherein until solid color is pure white, suction filtration obtains sterling simultaneously.Sterling is placed in clean tube, and add as far as possible less ethyl acetate and make it dissolve, then it is just muddy to solution slowly to drip normal hexane, test tube, to clarification, is placed in shady and cool ventilation place to crystallization by heated solution.
Wherein, described compound 5t prepares by the following method:
Rac-3 is
racemic modification;
R1 is selected from phenyl ring, and R2 is selected from ethyl, and R3 is selected from
Concrete operation step is as follows:
Carbonyl compound shown in nitroolefin and formula 2 shown in formula 1 is under DMAP exists, and make solvent with MeCN, stirring at room temperature obtains MBH adduct rac-3; Then one kettle way adds aldehyde, catalyzer and Glacial acetic acid shown in formula 4, react under room temperature, with TLC monitoring to reacting end, concentrated and through silica gel column chromatography, PE/EA=10:1 wash-out is separated and obtains the product of chirality tetrahydropyrans alcohol shown in MBH product (S)-3 and formula 5; Described catalyzer is selected from N, N-diphenylprolinol silicon ether, L-dried meat ammonia alcohol or L-PROLINE.
MBH and Belize-Harry Hillman reaction.
Further, nitroolefin shown in formula 1: carbonyl compound shown in formula 2: DMAP: aldehyde shown in formula 4: catalyzer: 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; Preferably, nitroolefin shown in formula 1: carbonyl compound shown in formula 2: DMAP: aldehyde shown in formula 4: catalyzer: Glacial acetic acid=0.5mmol:1.0mmol:0.05mmol:1.0mmol:0.1mmol:0.1mmol.
Present invention also offers above-claimed cpd or the purposes of crystal formation in preparation treatment antibacterium or anti-tumor drug.
Further, described bacterium is staphylococcus; Preferably, described staphylococcus is streptococcus aureus or staphylococcus epidermidis.
Further, described tumour is lung cancer, prostate cancer, nonsmall-cell lung cancer, leukemia.
Formula 1 compound crystal form, possess certain antibacterial and anti-tumor activity, gained crystal formation draws moist not obvious, has good stability, for later product transport, storage or production process provide great convenience.
Below by way of embodiment, the present invention is described in further detail, but do not limit the present invention, those skilled in the art can make various change and distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Accompanying drawing explanation
The three-dimensional arrangement sciagraph of Fig. 1 crystalline form I of the present invention.
Embodiment
The preparation of embodiment 1 compound 5t
Nitroolefin 1 (0.5mmol) and the activated carbonyl compound 2 (1.0mmol) of tool are under the existence of DMAP (6.1mg, 0.05mmol), and make solvent with MeCN, stirring at room temperature 30min obtains MBH adduct rac-3.Then one kettle way adds aldehyde 4 (1.0mmol), N, N-diphenylprolinol silicon ether (32.5mg, 0.1mmol) and Glacial acetic acid (6.0mg, 0.1mmol).Reaction is at room temperature carried out, and monitors reaction process with TLC.Concentrated and silica gel column chromatography (PE/EA=10:1) is successively separated and obtains MBH product (S)-3 and chirality tetrahydropyrans alcohol product 5.
The group of R1 ~ R3 described in reaction formula, all selects according to 5t compound structure, 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 composed
13cNMR (100MHz, CDCl
3): 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 ESIHRMS: calculated value C
18h
23nO
6+ Na372.1423, measured value 372.1419.
The preparation of embodiment 2 formula 1 compound
Iodine I is added in the anhydrous acetonitrile of the tetrahydropyrans alkylol cpd 5t of allyl group replacement
2(152.3mg, 0.6mmol), sodium bicarbonate NaHCO
3(50.4mg, 0.6mmol) and potassiumiodide KI (3.3mg, 0.02mmol) stir 4 hours at .0 DEG C, add ethyl acetate (20mL) and thiosulfuric acid saturated aqueous solution of sodium (30mL) to it. aqueous phase ether (3 × 10mL) extraction that obtains will be separated and and gained organic phase solution jointly distill and be spin-dried for.Gained residue is by silica gel column chromatography (sherwood oil: ethyl acetate=20:1), thin layer detects, get target compound wash-out position, except desolventizing, add normal hexane, ultrasonic and smash to pieces with steel knife, slowly drip ethyl acetate wherein until solid color is pure white, suction filtration obtains sterling simultaneously.Sterling is placed in clean tube, and add as far as possible less ethyl acetate and make it dissolve, then it is just muddy to solution slowly to drip normal hexane, test tube, to clarification, is placed in shady and cool ventilation place to crystallization by heated solution.
White solid tetrahydropyrans alcohol product 75.1mg (yield 79%) is received to obtain in calculating, and recording its ee value by high performance liquid phase chirality CelluCoat chromatographic column is 99% (15% Virahol/normal hexane, 1mL/min), UV220nm, t
minor=21.55min, t
major=29.26min. fusing point 165-166 DEG C; Optical value [α]
d 20-151.4 (c=0.12inCH
2cl
2); Hydrogen is composed
1hNMR (400MHz, CDCl
3): 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 composed
13cNMR (100MHz, CDCl
3): 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 ESIHRMS: calculated value C
18h
22iNO
6+ Na498.0390, measured value 498.0387.
Table 1X-single crystal diffraction crystal structural data
Beneficial effect of the present invention is illustrated below by way of test example.
In following test, DMSO is all used to dissolve compound concentration by reagent.
Test example 1 Anticancer Activities
Adopt mtt assay, measure the antitumour activity of the compounds of this invention 6t, the results are shown in following table:
Table 2
Note: above-mentioned activity value is inhibiting rate is 87% if numerical value is the inhibiting rate of 0.87 medicine under this concentration.
From the above results, the compounds of this invention crystal formation has certain restraining effect to human lung carcinoma cell, prostate cancer cell, leukemia, gland cancer etc.
Test example 2 anti-microbial activity
Adopt mtt assay, measure the anti-microbial activity of the compounds of this invention 6t, the results are shown in following table:
Table 3
Mark: blank expression does not have activity.
The results showed, compound prepared by the present invention, possess certain antibacterial and anti-tumor activity, it is not obvious that gained crystal formation draws moist increase, has good stability, for later product transport, storage or production process provide great convenience.
Claims (10)
1. compound as shown in Equation 1,
2. the crystal formation I of compound shown in formula 1, is characterized in that:
This crystal formation is oblique system, and spacer is P2
1, unit cell parameters is
α=90.00 °,
β=75.971 (9) °,
γ=90.00 °, Z=2, unit cell volume is
3. crystal formation I according to claim 2, is characterized in that: the fusing point of described crystal formation is 165-166 DEG C.
4. crystal formation I according to claim 2, is characterized in that: the ee value of described crystal formation compounds of formula I, more than 95%, is preferably 99%.
5. the preparation method of crystalline form I described in claim 2-4 any one, is characterized in that: it comprises following operation steps:
Iodine, sodium bicarbonate and potassiumiodide is added in the anhydrous acetonitrile of the tetrahydropyrans alkylol cpd 5t of allyl group replacement, stir 4 hours at 0 DEG C, add ethyl acetate and thiosulfuric acid saturated aqueous solution of sodium to it, the aqueous phase ether extraction that obtains will be separated and and gained organic phase solution jointly distill and be spin-dried for; Gained residue is by silica gel column chromatography, and with sherwood oil: ethyl acetate=20:1 wash-out, thin layer is followed the tracks of, get target compound wash-out position, except desolventizing, add normal hexane, ultrasonic and smash to pieces, slowly drip ethyl acetate wherein until solid color is pure white, suction filtration obtains sterling simultaneously; Get sterling, add ethyl acetate and make it dissolve, then it is just muddy to solution slowly to drip normal hexane, test tube, to clarification, is placed in shady and cool ventilation place to crystallization by heated solution.
6. preparation method according to claim 5, is characterized in that: described compound 5t prepares by the following method:
Rac-3 is
racemic modification;
R1 is selected from phenyl ring, and R2 is selected from ethyl, and R3 is selected from
Concrete operation step is as follows:
Carbonyl compound shown in nitroolefin and formula 2 shown in formula 1 is under DMAP exists, and make solvent with MeCN, stirring at room temperature obtains MBH adduct rac-3; Then one kettle way adds aldehyde, catalyzer and Glacial acetic acid shown in formula 4, react under room temperature, with TLC monitoring to reacting end, concentrated and through silica gel column chromatography, PE/EA=10:1 wash-out is separated and obtains the product of chirality tetrahydropyrans alcohol shown in MBH product (S)-3 and formula 5; Described catalyzer is selected from N, N-diphenylprolinol silicon ether, L-dried meat ammonia alcohol or L-PROLINE.
7. synthetic method according to claim 6, is characterized in that: nitroolefin shown in formula 1: carbonyl compound shown in formula 2: DMAP: aldehyde shown in formula 4: catalyzer: 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; Preferably, nitroolefin shown in formula 1: carbonyl compound shown in formula 2: DMAP: aldehyde shown in formula 4: catalyzer: Glacial acetic acid=0.5mmol:1.0mmol:0.05mmol:1.0mmol:0.1mmol:0.1mmol.
8. compound described in claim 1-4 any one or the purposes of crystal formation in preparation treatment antibacterium or anti-tumor drug.
9. medicine according to claim 8, is characterized in that: described bacterium is staphylococcus; Preferably, described staphylococcus is streptococcus aureus or staphylococcus epidermidis.
10. medicine according to claim 8, is characterized in that: described tumour is lung cancer, prostate cancer, nonsmall-cell lung cancer, leukemia.
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| CN201410415634.3A CN105272991B (en) | 2014-06-26 | 2014-08-21 | A kind of compound crystal form |
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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 |
|---|
| ARUN K. GHOSH，等: "Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived High Affinity P2 Ligands: Structure-Activity Studies and Biological Evaluation", 《J. MED. CHEM.》 * |
| DERRICK L. J. CLIVE，等: "The Naturally Occurring Ketene Acetal Benesudon: Total Synthesis and Assignment of Relative and Absolute Stereochemistry", 《J. ORG. CHEM.》 * |
| SYED KHALID YOUSUF，等: "Highly Regio- and Stereoselective One-Pot Synthesis of Carbohydrate-Based Butyrolactones", 《ORGANIC LETTERS》 * |
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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 |
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