CN108117494A - M-dicyanobenzene compound and preparation method thereof and pharmaceutical composition - Google Patents
M-dicyanobenzene compound and preparation method thereof and pharmaceutical composition Download PDFInfo
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- CN108117494A CN108117494A CN201611078280.3A CN201611078280A CN108117494A CN 108117494 A CN108117494 A CN 108117494A CN 201611078280 A CN201611078280 A CN 201611078280A CN 108117494 A CN108117494 A CN 108117494A
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- dicyanobenzene
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- -1 M-dicyanobenzene compound Chemical class 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 13
- LAQPNDIUHRHNCV-UHFFFAOYSA-N isophthalonitrile Chemical compound N#CC1=CC=CC(C#N)=C1 LAQPNDIUHRHNCV-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000002329 infrared spectrum Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 238000004321 preservation Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 150000001555 benzenes Chemical class 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical class N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 3
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 239000013078 crystal Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 9
- 230000006641 stabilisation Effects 0.000 abstract 1
- 238000011105 stabilization Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 13
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 8
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 8
- 239000008108 microcrystalline cellulose Substances 0.000 description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229920002785 Croscarmellose sodium Chemical group 0.000 description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 229960001681 croscarmellose sodium Drugs 0.000 description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 5
- 239000007888 film coating Substances 0.000 description 5
- 238000009501 film coating Methods 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 229920000036 polyvinylpyrrolidone Chemical group 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 229940069328 povidone Drugs 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 229960001021 lactose monohydrate Drugs 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 235000020985 whole grains Nutrition 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000007580 dry-mixing Methods 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
-
- 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
Abstract
The present invention relates to field of medicaments, more particularly to one kind 2,4,5 trichlorines 6 ((2,4,6 trichloro-benzenes amido) m-dicyanobenzene compound and preparation method thereof and contain above-mentioned 2,4,5 trichlorine, the 6 (pharmaceutical composition of (2,4,6 trichloro-benzenes amido) m-dicyanobenzene compound.This 2,4,5 trichlorines 6 ((2,4,6 trichloro-benzenes amidos) m-dicyanobenzene compound X x ray diffractions 2 θ of angle of diffraction to have diffraction maximum on 9.84 ± 0.2 degree, 19.66 ± 0.2 degree, 21.94 ± 0.2 degree, 22.80 ± 0.2 degree, 25.08 ± 0.2 degree, 31.19 ± 0.2 degree, with good crystal form, property stabilization, it easily prepares, is suitable as medicinal.
Description
Technical field
The present invention relates to field of medicaments, more particularly to a kind of 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) isophthalic two
Nitrile compound and preparation method thereof and contain above-mentioned tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compounds
Pharmaceutical composition.
Background technology
((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is (such as by the tri- chloro- 6- of 2,4,5- of existing preparation
Disclosed in WO2013135147) certain hygroscopicity is respectively provided with, there is relatively low heap density and poor mobility, be unfavorable for medicine
The working process of object preparation, and with potential drug stability problems, it is not particularly suited for field of medicaments.
The content of the invention
It is contemplated that overcome tri- chloro- 6- of 2,4,5- of the prior art ((2,4,6- trichloro-benzenes amido) m-dicyanobenzenes
The problem of object is not particularly suited for field of medicaments is closed, providing one kind has good crystal form, and property is stablized, and easily prepares, is suitable as
Medicinal tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compounds.
To achieve the above object, the present invention uses following technical scheme：
The present invention provides a kind of 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compounds, in X-
2 θ of angle of diffraction of x ray diffraction for 9.84 ± 0.2 degree, 19.66 ± 0.2 degree, 21.94 ± 0.2 degree, 22.80 ± 0.2 degree,
There is diffraction maximum on 25.08 ± 0.2 degree, 31.19 ± 0.2 degree.
In some embodiments, 2,4,5- tri- chloro- 6- (in X-ray spread out by (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound
2 θ of angle of diffraction penetrated for 9.84 ± 0.2 degree, 12.51 ± 0.2 degree, 11.71 ± 0.2 degree, 14.72 ± 0.2 degree, 14.88 ± 0.2
Degree, 18.33 ± 0.2 degree, 19.12 ± 0.2 degree, 19.66 ± 0.2 degree, 20.19 ± 0.2 degree, 20.86 ± 0.2 degree, 21.94 ±
0.2 degree, 22.80 ± 0.2 degree, 24.61 ± 0.2 degree, 25.08 ± 0.2 degree, 25.41 ± 0.2 degree, 25.75 ± 0.2 degree, 28.09
± 0.2 degree, 28.45 ± 0.2 degree, 29.62 ± 0.2 degree, 30.32 ± 0.2 degree, 31.19 ± 0.2 degree, 31.93 ± 0.2 degree,
There is diffraction maximum on 33.10 ± 0.2 degree.
In some embodiments, (fusing point of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is 2,4,5- tri- chloro- 6-
250-257℃。
In some embodiments, ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is in infrared spectrum by 2,4,5- tri- chloro- 6-
Wavelength 3351.21cm-1、3073.79cm-1、2916.39cm-1、2849.80cm-1、2229.57cm-1、1560.66cm-1、
1479.61cm-1、1407.23cm-1、1381.98cm-1、1213.29cm-1、1137.06cm-1、866.87cm-1、820.24cm-1、
793.86cm-1、738.35cm-1、454.25cm-1、420.76cm-1On have absworption peak.
The present invention additionally provides a kind of tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compounds simultaneously
Preparation method, step include will contain unformed 2,4, the 5- tri- chloro- 6- (changes of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene
It closes object to mix with solvent, dissolve by heating, cooling crystallization, above-mentioned 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) isophthalic are made
Dinitrile compound；It is described to contain unformed 2,4,5- trichlorines
(compound of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene and the mass volume ratio w/v of solvent are 1g to -6-：
10-120ml。
In some embodiments, solvent is selected from one or more of alcohol, substituted benzene, ester, cyanogen class solvent.
In some embodiments, the temperature of heating is 30-120 DEG C.
In some embodiments, step includes that unformed 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) isophthalic will be contained
The compound of dintrile is placed in reactor, adds in solvent, and agitating and heating makes its dissolving, when heat preservation 0.5-2 is small, is cooled to 10-15
DEG C stirring and crystallizing filters, washing, dry above-mentioned 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene chemical combination
Object.
In some embodiments, when the time of crystallization is 0.5-6 small.
The present invention additionally provides a kind of pharmaceutical composition simultaneously, including above-mentioned 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes
Amido) m-dicyanobenzene compound.
The beneficial effects of the present invention are：
The present inventor has found that the reason for WO2013135147 is not suitable for field of medicaments is it by studying for a long period of time
((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is containing unformed to 2,4, the 5- tri- chloro- 6- prepared, and unformed is contained
Amount ratio is difficult to control, and affects pharmaceutical preparation processing.And this hair is surprisingly obtained by studying for a long period of time for the present inventor
The bright chloro- 6- in 2,4,5- tri- with good crystal form ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound, of the invention 2,4,
((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound has good physicochemical property to tri- chloro- 6- of 5-, and property is stablized, particularly profit
In the working process of pharmaceutical preparation, it is more suitable for medicinal.And the preparation method of the present invention is simple, easily prepares.
Description of the drawings
Fig. 1 is tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene chemical combination prepared by the embodiment of the present invention 1
X-ray diffraction (XRD) figure of object；
Fig. 2 is tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene chemical combination prepared by the embodiment of the present invention 1
The infrared spectrogram of object；
Fig. 3 is tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene chemical combination prepared by the embodiment of the present invention 1
The differential scanning calorimetry analysis (DSC) of object, thermogravimetric analysis (TGA) figure.
Specific embodiment
The embodiment of the present invention is described below in detail, specific embodiments described below is exemplary, it is intended to for solving
The present invention is released, and is not considered as limiting the invention.
The present invention provides a kind of 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compounds, in X-
2 θ of angle of diffraction of x ray diffraction for 9.84 ± 0.2 degree, 19.66 ± 0.2 degree, 21.94 ± 0.2 degree, 22.80 ± 0.2 degree,
There is diffraction maximum on 25.08 ± 0.2 degree, 31.19 ± 0.2 degree.
In some embodiments, 2,4,5- tri- chloro- 6- (in X-ray spread out by (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound
2 θ of angle of diffraction penetrated for 9.84 ± 0.2 degree, 12.51 ± 0.2 degree, 11.71 ± 0.2 degree, 14.72 ± 0.2 degree, 14.88 ± 0.2
Degree, 18.33 ± 0.2 degree, 19.12 ± 0.2 degree, 19.66 ± 0.2 degree, 20.19 ± 0.2 degree, 20.86 ± 0.2 degree, 21.94 ±
0.2 degree, 22.80 ± 0.2 degree, 24.61 ± 0.2 degree, 25.08 ± 0.2 degree, 25.41 ± 0.2 degree, 25.75 ± 0.2 degree, 28.09
± 0.2 degree, 28.45 ± 0.2 degree, 29.62 ± 0.2 degree, 30.32 ± 0.2 degree, 31.19 ± 0.2 degree, 31.93 ± 0.2 degree,
There is diffraction maximum on 33.10 ± 0.2 degree, substance crystal form is good, and property is stablized, particularly the working process beneficial to pharmaceutical preparation, more suitable
Cooperate to be medicinal.Specific 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzenes in the present invention preferably embodiment
The X-ray diffraction of compound is as shown in Fig. 1 and table 1.
Table 1
Wherein, X-ray diffraction of the invention test is used equipped with position sensing detector (OED) and one as X
The survey that the advanced diffractometers of Bruker D8 of the Cu anodes (CuK α 1 are radiated, λ=1.5406A, 40kV, 40mA) of radiographic source carry out
Amount.
In some embodiments, (fusing point of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is 2,4,5- tri- chloro- 6-
250-257℃。
In some embodiments, ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is in infrared spectrum by 2,4,5- tri- chloro- 6-
Wavelength 3351.21cm-1、3073.79cm-1、2916.39cm-1、2849.80cm-1、2229.57cm-1、1560.66cm-1、
1479.61cm-1、1407.23cm-1、1381.98cm-1、1213.29cm-1、1137.06cm-1、866.87cm-1、820.24cm-1、
793.86cm-1、738.35cm-1、454.25cm-1、420.76cm-1On have absworption peak, it was demonstrated that substance 2,4, tri- chloro- 6- of 5-
((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound.
Wherein, examination of infrared spectrum is using SHIMADZU FTIR-8400 type Fourier turn infrared instrument.
The present invention additionally provides a kind of tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compounds simultaneously
Preparation method, step include will contain unformed 2,4, the 5- tri- chloro- 6- (changes of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene
It closes object to mix with solvent, dissolve by heating, cooling crystallization, above-mentioned 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) isophthalic are made
Dinitrile compound；It is described containing unformed tri- chloro- 6- of 2,4,5- (compound of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene with it is molten
The mass volume ratio w/v of agent is 1g：10-120ml.
It is preferred that solvent is selected from one or more of alcohol, substituted benzene, ester, cyanogen class solvent.
It is preferred that the temperature of heating is 30-120 DEG C.
It is preferred that filtered after crystallization, solvent washing, dry target crystal.Wherein, filtering, solvent washing, dry method
It is known to the skilled person, details are not described herein.
Following steps specifically may be employed to be prepared：
By containing unformed tri- chloro- 6- of 2,4,5-, (compound of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene is placed in reaction
In device, add in solvent, agitating and heating makes its dissolving, when heat preservation 0.5-2 is small, be cooled to 10-15 DEG C of stirring and crystallizing 0.5-6 it is small when,
Filtering, washing, dry above-mentioned 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compounds.
The present invention additionally provides a kind of pharmaceutical composition simultaneously, including above-mentioned 2,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes
Amido) m-dicyanobenzene compound.Pharmaceutical composition can also contain one or more inert carriers and/or diluent, wherein, it is lazy
Property supporting agent and diluent can be not limited to microcrystalline cellulose, lactose, magnesium stearate etc..Pharmaceutical composition can also contain more
Kind drug, drug can be not limited to taxol, cis-platinum, adriamycin etc..
((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is applied to pharmaceutical composition to the tri- chloro- 6- of 2,4,5- of the present invention
During object, mode commonly used in the art may be employed in specific configuration mode, such as is directly administered, and can also be configured to containing 2,4,5-
(tablet of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is, for example, the circular tablet of film coating to three chloro- 6-, can
2 containing 50mg, 100mg and 200mg, 4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound, it is orally available
Discharge active component is administered.
Containing tri- chloro- 6- of 2,4,5-, (tablet of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound, which can also contain, to be filled out
Fill agent, disintegrant, adhesive, lubricant, coating agent etc..It specifically can be by tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido)
The groups such as m-dicyanobenzene compound, microcrystalline cellulose, lactose, croscarmellose sodium, povidone, magnesium stearate, Opadry
Into.
In some embodiments, wet granulation, dry-mixing, tablet press and method for coating film preparation can be used to contain
Tri- chloro- 6- of the 50mg and 100mg 2,4,5- (tablets of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound.Specifically, can be with
Bulk pharmaceutical chemicals, lactose monohydrate, microcrystalline cellulose and the croscarmellose sodium of formula ratio are weighed, is placed in high shear mixing
It is uniformly mixed in granulator.Uniformly mixed material is transferred in fluid bed, fluidisation is sprayed into using povidone aqueous solution is prepared
Bed granulation, in 40 ± 3 DEG C of fluidized bed drying 45 minutes.By particle obtained through 80 mesh sieve whole grains, add in microcrystalline cellulose and
Croscarmellose sodium mixture mixes 20 minutes in mixer, remixes 3 minutes after adding in magnesium stearate, tablet press machine
Compacting obtains uncoated plain piece.Opadry is dissolved in pure water, film coating suspension is prepared under stirring.It is right in coating pan
Tablet carries out film coating (weight increase about 3%).
It is specific embodiment provided by the invention below, to illustrate the selection of said program and its various conditions.This hair
Agents useful for same is pure using analysis purchased in market in bright embodiment.
Embodiment 1：
The present embodiment is used for tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) the m-dicyanobenzene chemical combination for illustrating the present invention
Object.
In 100mL single port bottles, add in 0.5g and contain unformed 2,4,5- tri- chloro- 6- (between (2,4,6- trichloro-benzenes amido)
Benzene dinitrile compound (using WO2013135147 embodiment 1 method it is homemade), 60mL ethyl alcohol, 80 DEG C be heated to reflux until
Solution is clarified, and when heat preservation 1 is small, stops heating, be cooled to 15 DEG C of stirring and crystallizings 3 it is small when, filtering, the washing of a small amount of ethyl alcohol, room temperature does
It is dry to obtain pale solid crystal 0.31g, yield 62.0%.
Using equipped with position sensing detector (OED) and one as x-ray source Cu anodes (CuK α 1 are radiated, λ=
1.5406A, 40kV, 40mA) the advanced diffractometers of Bruker D8 carry out X-ray diffraction (XRD) and test, test result such as attached drawing
1 and table 1.
Examination of infrared spectrum, test are carried out using SHIMADZU FTIR-8400 type Fourier turn infrareds instrument
The results are shown in Figure 2.
DSC (differential scanning calorimetry analysis), TGA (thermogravimetric analysis) measurement are carried out using NETZSCH STA 449F3, risen
Warm 5 DEG C/min of rate, N2Atmosphere, test result are as shown in Figure 3.
Embodiment 2：
The present embodiment is used for tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) the m-dicyanobenzene chemical combination for illustrating the present invention
Object.
In 100mL single port bottles, add in 0.5g and contain unformed 2,4,5- tri- chloro- 6- (between (2,4,6- trichloro-benzenes amido)
Benzene dinitrile compound (using WO2013135147 embodiment 1 method it is homemade), 50mL methanol, 80 DEG C be heated to reflux until
Solution is clarified, and when heat preservation 1 is small, stops heating, be cooled to 15 DEG C of stirring and crystallizings 3 it is small when, filtering, the washing of a small amount of methanol, room temperature does
It is dry to obtain pale solid crystal 0.13g, yield 26.0%.
XRD tests, examination of infrared spectrum and DSC, TGA test are carried out using method same as Example 1, as a result with reality
It is similar to apply example 1.
Embodiment 3：
The present embodiment is used for tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) the m-dicyanobenzene chemical combination for illustrating the present invention
Object.
In 100mL single port bottles, add in 0.5g and contain unformed 2,4,5- tri- chloro- 6- (between (2,4,6- trichloro-benzenes amido)
Benzene dinitrile compound (using WO2013135147 embodiment 1 method it is homemade), 20mL acetonitriles, 85 DEG C be heated to reflux until
Solution is clarified, and when heat preservation 1 is small, stops heating, be cooled to 14 DEG C of stirring and crystallizings 3 it is small when, filtering, the washing of a small amount of acetonitrile, room temperature does
It is dry to obtain pale solid crystal 0.40g, yield 80.0%.
XRD tests, examination of infrared spectrum and DSC, TGA test are carried out using method same as Example 1, as a result with reality
It is similar to apply example 1.
Embodiment 4：
The present embodiment is used for tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) the m-dicyanobenzene chemical combination for illustrating the present invention
Object.
In 100mL single port bottles, add in 1.0g and contain unformed 2,4,5- tri- chloro- 6- (between (2,4,6- trichloro-benzenes amido)
Benzene dinitrile compound (homemade using the method for the embodiment 1 of WO2013135147), 10mL ethyl acetate, 85 DEG C are heated to reflux
Until solution is clarified, when heat preservation 1 is small, stop heating, be cooled to 14 DEG C of stirring and crystallizings 3 it is small when, filtering, a small amount of ethyl acetate washes
It washs, drying at room temperature obtains pale solid crystal 0.21g, yield 21.0%.
XRD tests, examination of infrared spectrum and DSC, TGA test are carried out using method same as Example 1, as a result with reality
It is similar to apply example 1.
Embodiment 5：
The present embodiment is used for tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) the m-dicyanobenzene chemical combination for illustrating the present invention
Object.
In 100mL single port bottles, add in 1.0g and contain unformed 2,4,5- tri- chloro- 6- (between (2,4,6- trichloro-benzenes amido)
Benzene dinitrile compound (homemade using the method for the embodiment 1 of WO2013135147), 15mL toluene, 120 DEG C are heated to reflux directly
Clarified to solution, when heat preservation 1 is small, stop heating, be cooled to 14 DEG C of stirring and crystallizings 3 it is small when, filtering, the washing of a small amount of toluene, room temperature
Dry pale solid crystal 0.83g, yield 83.0%.
XRD tests, examination of infrared spectrum and DSC, TGA test are carried out using method same as Example 1, as a result with reality
It is similar to apply example 1.
Embodiment 6-15：
Embodiment 6-15 is used to illustrate that the present invention's contains tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) isophthalic two
The tablet of nitrile compound, embodiment 6-15 correspond respectively to include chemical combination obtained by the embodiment 1-5 of 50.00mg and 100mg dosage
The tablet of object.
Weigh tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene chemical combination of formula ratio as shown in Table 2
Object, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium are placed in high shear mixing granulator and mix
It is even.Uniformly mixed material is transferred in fluid bed, fluidized bed granulation is sprayed into using povidone aqueous solution is prepared, 40 ± 3
DEG C fluidized bed drying 45 minutes.By particle obtained through 80 mesh sieve whole grains, microcrystalline cellulose and cross-linked carboxymethyl fiber are added in
Plain sodium mixture mixes 20 minutes in mixer, is remixed 3 minutes after adding in magnesium stearate, and tablet press machine compacting obtains uncoated
Plain piece.Opadry is dissolved in pure water, film coating suspension is prepared under stirring.Film bag is carried out to tablet in coating pan
Clothing (weight increase about 3%).
Table 2
Comparative example
Weigh tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene chemical combination of formula ratio as shown in table 3
Object, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium are placed in high shear mixing granulator and mix
It is even.Uniformly mixed material is transferred in fluid bed, fluidized bed granulation is sprayed into using povidone aqueous solution is prepared, 40 ± 3
DEG C fluidized bed drying 45 minutes.By particle obtained through 80 mesh sieve whole grains, microcrystalline cellulose and cross-linked carboxymethyl fiber are added in
Plain sodium mixture mixes 20 minutes in mixer, is remixed 3 minutes after adding in magnesium stearate, and tablet press machine compacting obtains uncoated
Plain piece.Opadry is dissolved in pure water, film coating suspension is prepared under stirring.Film bag is carried out to tablet in coating pan
Clothing (weight increase about 3%).
Table 3
Medicinal tablet corresponding to embodiment 6-15, compared with the preparation process of the medicinal tablet of comparative example, embodiment 6-
15 is more easy to operate, the good fluidity of material, and entire process operation process is there is no difficulty, and the tablet yields of preparation is high, and yield
Also it is high.And the material in comparative example is easy to moisture absorption, the poor fluidity of material, operating characteristics is poor, and the tablet yields of preparation is low.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or the spy for combining the embodiment or example description
Point is contained at least one embodiment of the present invention or example.In the present specification, schematic expression of the above terms is not
Centainly refer to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be any
One or more embodiments or example in combine in an appropriate manner.
Although the embodiment of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, those of ordinary skill in the art are not departing from the principle of the present invention and objective
In the case of above-described embodiment can be changed within the scope of the invention, change, replace and modification.
Claims (10)
1. one kind 2,4, tri- chloro- 6- of 5- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound, which is characterized in that described 2,4,
((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is 9.84 ± 0.2 in 2 θ of angle of diffraction of X-ray diffraction to tri- chloro- 6- of 5-
Degree, 19.66 ± 0.2 degree, 21.94 ± 0.2 degree, 22.80 ± 0.2 degree, 25.08 ± 0.2 degree, have diffraction on 31.19 ± 0.2 degree
Peak.
2. according to claim 12,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound, spies
Sign is that ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is in the angle of diffraction of X-ray diffraction by described 2,4,5- tri- chloro- 6-
Spend 2 θ for 9.84 ± 0.2 degree, 12.51 ± 0.2 degree, 11.71 ± 0.2 degree, 14.72 ± 0.2 degree, 14.88 ± 0.2 degree, 18.33 ±
0.2 degree, 19.12 ± 0.2 degree, 19.66 ± 0.2 degree, 20.19 ± 0.2 degree, 20.86 ± 0.2 degree, 21.94 ± 0.2 degree, 22.80
± 0.2 degree, 24.61 ± 0.2 degree, 25.08 ± 0.2 degree, 25.41 ± 0.2 degree, 25.75 ± 0.2 degree, 28.09 ± 0.2 degree,
28.45 ± 0.2 degree, 29.62 ± 0.2 degree, 30.32 ± 0.2 degree, 31.19 ± 0.2 degree, 31.93 ± 0.2 degree, 33.10 ± 0.2 degree
On have diffraction maximum.
3. according to claim 12,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound, spies
Sign is that (fusing point of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is 250-257 DEG C to described 2,4,5- tri- chloro- 6-.
4. according to claim 12,4,5- tri- chloro- 6- ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound, spies
Sign is that ((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound is in the wavelength of infrared spectrum by described 2,4,5- tri- chloro- 6-
3351.21cm-1、3073.79cm-1、2916.39cm-1、2849.80cm-1、2229.57cm-1、1560.66cm-1、
1479.61cm-1、1407.23cm-1、1381.98cm-1、1213.29cm-1、1137.06cm-1、866.87cm-1、820.24cm-1、
793.86cm-1、738.35cm-1、454.25cm-1、420.76cm-1On have absworption peak.
5. one kind 2,4, (preparation method of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound, feature exist tri- chloro- 6- of 5-
In step includes that unformed 2,4, the 5- tri- chloro- 6- (compounds and solvent of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene will be contained
Mixing dissolves by heating, cooling crystallization, and 2,4, the 5- tri- chloro- 6- ((2,4,6- tri- as described in claim 1-4 any one are made
Chloroanilino) m-dicyanobenzene compound；It is described to contain unformed tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) isophthalic two
The compound of nitrile and the mass volume ratio w/v of solvent are 1g：10-120ml.
6. preparation method according to claim 5, which is characterized in that it is molten that the solvent is selected from alcohol, substituted benzene, ester, cyanogen class
One or more of agent.
7. preparation method according to claim 5, which is characterized in that the temperature of the heating is 30-120 DEG C.
8. preparation method according to claim 5, which is characterized in that the step includes that unformed 2,4,5- tri- will be contained
(compound of (2,4,6- trichloro-benzenes amido) m-dicyanobenzene is placed in reactor chloro- 6-, adds in solvent, and agitating and heating makes its molten
Solution when heat preservation 0.5-2 is small, is cooled to 10-15 DEG C of stirring and crystallizing, filters, and washing is dry such as claim 1-4 any one
Described tri- chloro- 6- of 2,4,5- ((2,4,6- trichloro-benzenes amido) the m-dicyanobenzene compounds.
9. preparation method according to claim 5, which is characterized in that when the time of the crystallization is 0.5-6 small.
10. a kind of pharmaceutical composition, which is characterized in that including 2,4, the 5- tri- chloro- 6- as described in claim 1-4 any one
((2,4,6- trichloro-benzenes amido) m-dicyanobenzene compound.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012171484A1 (en) * | 2011-06-17 | 2012-12-20 | 中国中化股份有限公司 | Substituted cyanoaniline compounds, preparation and use thereof |
| WO2013135147A1 (en) * | 2012-03-14 | 2013-09-19 | 中国中化股份有限公司 | Use of substituted diphenylamine compounds in preparing anti-tumour drugs |
-
2016
- 2016-11-29 CN CN201611078280.3A patent/CN108117494A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012171484A1 (en) * | 2011-06-17 | 2012-12-20 | 中国中化股份有限公司 | Substituted cyanoaniline compounds, preparation and use thereof |
| WO2013135147A1 (en) * | 2012-03-14 | 2013-09-19 | 中国中化股份有限公司 | Use of substituted diphenylamine compounds in preparing anti-tumour drugs |
Non-Patent Citations (1)
| Title |
|---|
| AI-YING GUAN等: "Design, Synthesis, and Structure−Activity Relationship of Novel Aniline Derivatives of Chlorothalonil", 《J. AGRIC. FOOD CHEM.》 * |
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