CN100358910C - Glucose phosphonic amide crystals and preparation process and use thereof - Google Patents
Glucose phosphonic amide crystals and preparation process and use thereof Download PDFInfo
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Abstract
The present invention relates to a crystal of N, N'-di-(2-chloroethyl) phosphoryl diamino acid-beta-D-glucopyranosyl ester(glufosfamide). The space group of the crystal is P1, the unit cell parameter a is equal to 5.841(1), the unit cell parameter b is equal to 7.813(1), the unit cell parameter c is equal to 18.271(2) angstroms, the unit cell parameter alpha is equal to 95.795(1), the unit cell parameter beta is equal to 93.442(1), and the unit cell parameter gamma is equal to 89.925(1) degree. The unit cell volume V is equal to 828.0(2) angstrom<3>, and the molecular number z in the unit cell is equal to 1. The present invention also relates to a method for preparing the N, N'-di-(2-chloroethyl) phosphoryl diamino acid-beta-D-glucopyranosyl ester crystal by using one or a plurality of solvents. The glufosfamide crystal of the present invention has the advantages of easy preparation and high stability. The glufosfamide crystal is suitable for industrialized production and storage. The present invention also relates to the application of the crystal at the aspect of antitumor drugs.
Description
Technical field
The present invention relates to a kind of crystallization of Glufosfamide, the present invention also relates to described crystalline preparation method and application thereof.
Background technology
Glufosfamide (Glufosfamide), chemical name N, N '-two (2-chloroethyl) phosphoryl diamine acid-β-D-glucopyranosyl ester (N, N '-bis (2-chloroethyl) phosphorodiamidate acid β-D-Glucopyranosyl ester), be a kind of novel alkylating agent, belonging to phosphamide nitrogen mustards derivative, is that active part by alkylide is connected with a glucose molecule and gets.Its mechanism of action meets the characteristics of alkylating agent, for irreversible interchain commissure takes place inducing DNA, has caused the dna double chain break, and then has caused apoptosis, plays the effect that suppresses growth of tumour cell.
Experiment shows in the body, and Glufosfamide suppresses active suitable with the ifosfamide mustargen to mouse L-1210, people KB tumour cell, leukemia of children.Experiment in vitro shows, anti-mouse P
388Cell, rat L5222 cell and AH13r hepatoma, anti-mouse Ehrlich ascitic tumor, mouse melanin tumour b16 and the antitumor action that carries out on the nude mice that the human tumour heterogeneity transplants all demonstrate higher activity in testing, and especially human mammary, lung tumors and melanoma are had remarkable anti-knurl effect.
Glufosfamide is the novel alkylating agent by the exploitation of the U.S. hundred spies (Baxter) medical company, now carries out clinical study by U.S. Threshold drugmaker.Be mainly used in the irremediable advanced pancreatic cancer of operation, and multiple solid tumor is all had antitumor activity.On November 15th, 2004, drugmaker announced that it is fast passage product that FDA has specified drug candidate Glufosfamide (Glufosfamide) injection of its exploitation.This product is carrying out the III clinical trial phase of single drug first-line treatment advanced pancreatic cancer at present, and plan carries out treating with the gemcitabine drug combination II clinical trial phase of advanced pancreatic cancer.At present, this product is not at home and abroad still gone public, and just carries out II, III phase clinical study at different indications abroad.
German patent DE 3835772 and US 5,622,936 grades have disclosed the preparation method of Glufosfamide, and what it was prepared all is amorphous form, and its physicals is unfavorable for the stable of product, mass preparation and subsequent applications.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of glucose phosphonic amide crystals and preparation method thereof and application are provided.
A kind of glucose phosphonic amide crystals comprises the powder art X-ray diffraction that uses CuK α radiation, represents with 2 θ angles and spacing (d value) basically at the following N that characteristic peak is arranged everywhere, N '-two (2-chloroethyl) phosphoryl diamine acid-β-D-glucopyranosyl ester:
2 θ angle spacings (d value)
4.82 18.31
9.70 9.11
17.52 5.06
20.44 4.34
21.74 4.08
24.10 3.69
25.86 3.44
34.58 2.59。
The mensuration of relevant above-mentioned characteristic peak need to prove, when (2 θ value) identifies one independently during the XRD spike in certain position, mean that this peak is this 2 θ value ± 0.1, when (2 θ value) this means that this peak is this 2 θ value ± 0.3 when identifying an XRD broad peak in certain position.The diffractogram that is obtained by compound crystal is distinctive to a given crystal habit, though some weak or very weak diffraction peaks may always not occur in the diffractogram that the crystallization of different batches obtains.The relative intensity of bands of a spectrum (especially low angle X ray incident value (low 2 θ)) may be changed by factor such as the difference of condition determination, crystal habit, therefore, the relative intensity of diffraction peak at crystal habit be not to be distinctive, more it should be noted the relative position at peak rather than their relative intensity on the contrary, to determine this crystalline form.
Glucose phosphonic amide crystals of the present invention, its spacer are P1, unit cell parameters a=5.841 (1), b=7.813 (1), c=18.271 (2) , α=95.795 (1), β=93.442 (1), γ=89.925 (1) °.Unit cell volume V=828.0 (2)
3, molecule number z=1 in the structure cell.
The preparation method of crystallization Glufosfamide of the present invention, step is as follows:
(1) Glufosfamide crude product 20-50 ℃ is dissolved among the crystallization solvent I, add the crystallization solvent II again after perhaps being dissolved in crystallization solvent I, perhaps be dissolved in the mixed solvent of crystallization solvent I and crystallization solvent II, the mass volume ratio m of Glufosfamide crude product and crystallization solvent: v is 1: 1-100, and the volume ratio of crystallization solvent I and crystallization solvent II is 1: 1-100;
Described crystallization solvent I is selected from the following solvents one or more: aliphatic ketone kind solvent, aromatic ketone kind solvent, fatty alcohol kind solvent, aromatic alcohols kind solvent;
Described crystallization solvent II is selected from the following solvents one or more: fat hydrocarbon solvent, aromatic hydrocarbon solvent, halogenated hydrocarbon solvent, aliphatic ester kind solvent, aromatic ester kind solvent, aliphatic ether kind solvent, aromatic oxide kind solvent;
(2)-20 ℃-50 ℃ placed crystallization 2-48 hour;
(3) suction filtration, 20-50 ℃ vacuum-drying get the Glufosfamide white crystals.
Glufosfamide crude product in the above-mentioned steps (1) is any existing known technology preparation, and its purity is not had special requirement.
The aliphatic category ketone solvent of crystallization solvent I is selected from acetone, butanone, pentanone in the above-mentioned steps (1), the aromatic ketone kind solvent is selected from benzophenone, methyl phenyl ketone, the fatty alcohol kind solvent is selected from methyl alcohol, ethanol, Virahol, butanols, and the aromatic alcohols kind solvent is selected from phenylcarbinol, phenylethyl alcohol.
Fat hydrocarbon solvent in the above-mentioned steps (1) in the crystallization solvent II is selected from normal hexane, hexanaphthene or normal heptane, and aromatic hydrocarbon solvent is selected from benzene, toluene or dimethylbenzene, and halogenated hydrocarbon solvent is selected from methylene dichloride, trichloromethane or ethylene dichloride; The aliphatic ester kind solvent is selected from ethyl acetate, isopropyl acetate, butylacetate, Isoamyl Acetate FCC or ethyl propionate, and the aromatic ester kind solvent is selected from methyl benzoate, ethyl benzoate or isobutyl benzoate; The aliphatic ether kind solvent is selected from ether, isopropyl ether, tetrahydrofuran (THF) or dioxane, and the aromatic oxide kind solvent is selected from methyl-phenoxide or phenyl ethyl ether.
The glucose phosphonic amide crystals product purity that the inventive method obtains is more than 98.5%.
The crystallization of the inventive method preparation has following advantage:
(1) has the performance of carrying out the large-scale industry preparation.For example, have good fusing point or flowability.The fusing point of glucose phosphonic amide crystals is stablized (106 ℃-111 ℃), good fluidity, operability and large-scale industry manufacturing when helping pharmaceutical preparation to produce.
(2) have satisfactory stability, be convenient to produce, transport and store.The results showed that glucose phosphonic amide crystals is stored under 2-8 ℃ of condition and kept 18 months, every quality index all meets the quality standard of this medicine.
The pharmaceutical applications of crystallization Glufosfamide of the present invention is used to prepare antitumor drug.
Mouse presses down the knurl experiment:
With the mouse tumor is bearing mouse model, the Glufosfamide intraperitoneal injection, dosage 50,100,150,200mg/kg, the next day 1 time, successive administration 5 times; Mouse S180 sarcoma, Lewis lung cancer, B16 melanoma all there is remarkable antitumor action (tumour inhibiting rate＞40%, P＜0.05); When medication during to 200mg/kg, the Glufosfamide the weight of animals descends about 19%; The basically identical as a result of repeated experiments.Restraining effect to Lewis lung cancer is the strongest, and tumour inhibiting rate can reach 95%, obviously is better than contrasting medicine CPM.Glufosfamide is Lewis lung cancer＞S180 sarcoma＞B16 melanoma to mouse entity knurl tumor-inhibiting action intensity, and tangible dose-effect relationship is arranged; Dosage does not have obvious antitumor action during for 50mg/kg.
A kind of pharmaceutical composition comprises described crystallization Glufosfamide and pharmaceutical carrier.Can be made into injection or oral preparations such as powder injection, tablet, capsule, granule, suspensoid.Pharmaceutical carrier comprises N.F,USP MANNITOL, lactose, cyclodextrin, starch, Microcrystalline Cellulose, Vltra tears, Magnesium Stearate, talcum powder and the known pharmaceutical excipient of other present technique fields personnel.
Description of drawings
The structure of Fig. 1 glucose phosphonic amide crystals and atom numbering figure.
The accumulation graph of Fig. 2 glucose phosphonic amide crystals unit cell.
Fig. 3 Glufosfamide powder x-ray diffraction figure.Sweep parameter: 3.0/80.0/0.02/0.15 (second), and Cu (40KV, 150mA); Among the figure 1,2,9,13,14,16,18,19,27 peaks are characteristic peaks.
Embodiment
The following examples will be further explained the present invention, but the present invention is not limited only to these embodiment, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done in the claim scope and adjust also should be thought and belongs to scope of the present invention.
Embodiment 1.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, adds acetone 50ml in 20-50 ℃ of dissolving, is placed to-20 ℃ of-50 ℃ of crystallizatioies, and after 24 hours, suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Described glucose phosphonic amide crystals, molecular weight are 383.17, and crystal density is 1.537g/cm
3, being the water white transparency sheet, diffraction experiment belongs to triclinic(crystalline)system with crystallographic dimension 0.02 * 0.40 * 0.50mm, spacer is P1, unit cell parameters a=5.841 (1), b=7.813 (1), c=18.271 (2) , α=95.795 (1), β=93.442 (1), γ=89.925 (1) °.Unit cell volume V=828.0 (2)
3, molecule number z=1 in the structure cell.
The atomic coordinate parameter of table 1 glucose phosphonic amide crystals and the equivalent temperature factor
| X | Y | Z | Biso | |
| CL1 | .2847 | .5422 | .2359 | 9.6(4) |
| CL2 | 1.4076(8) | 1.0487(8) | .2621(5) | 6.5(3) |
| P1 | .7758(5) | .7665(5) | .0866(8) | 3.0(2) |
| N1 | .8705(2) | .9608(7) | .1127(7) | 4.7(6) |
| N2 | .7149(9) | .6851(7) | .1619(6) | 4.1(5) |
| O1 | .5919(3) | 1.0447(1) | -.0085(4) | 3.2(3) |
| O2 | .5347(3) | .7996(1) | .0440(4) | 3.1(4) |
| O3 | .2118(4) | .6882(2) | -.0760(5) | 3.6(4) |
| O4 | .0754(3) | .9478(2) | -.1695(5) | 3.6(4) |
| O5 | .4431(4) | 1.1869(2) | -.1882(5) | 3.7(4) |
| O6 | .9090(6) | 1.2998(4) | -.0014(6) | 5.0(5) |
| O7 | .9295(5) | .6497(2) | .0431(5) | 3.8(4) |
| C1 | .5305(9) | .8688(7) | -.0249(6) | 2.9(5) |
| C2 | .2836(9) | .8618(8) | -.0616(7) | 3.4(6) |
| C3 | .3007(8) | .9435(6) | -.1327(6) | 2.7(5) |
| C4 | .4016(8) | 1.1262(7) | -.1186(6) | 2.9(5) |
| C5 | .6270(9) | 1.1246(6) | -.0726(6) | 3.0(5) |
| C6 | .6934(4) | 1.3138(8) | -.0431(8) | 4.0(6) |
| C7 | 1.1220(4) | .9801(2) | .1443(8) | 4.4(6) |
| C8 | 1.1180(3) | 1.0310(3) | .2236(9) | 7.7(3) |
| C9 | .6810(3) | .5051(3) | .1679(9) | 5.3(8) |
| C10 | .4370(4) | .4480(3) | .1571(1) | 9.0(3) |
| CL1’ | -1.1964(7) | 1.3424(7) | -.6379(4) | 5.9(2) |
| CL2′ | -.0818(1) | .8375(8) | -.6112(4) | 8.6(3) |
| P1’ | -.5713(5) | 1.1368(5) | -.4613(9) | 3.0(2) |
| N1’ | -.6758(1) | 1.3178(5) | -.4872(6) | 3.8(5) |
| N2’ | -.5071(1) | 1.0218(6) | -.5369(6) | 4.1(5) |
| O1’ | -.3865(1) | 1.4564(1) | -.3677(4) | 3.3(4) |
| O2’ | -.3283(1) | 1.1890(1) | -.4190(4) | 3.1(4) |
| O3’ | -.0012(1) | 1.1312(2) | -.2985(4) | 3.7(4) |
| O4’ | .1299(1) | 1.4367(3) | -.2054(5) | 3.9(4) |
| O5’ | -.2319(1) | 1.6900(2) | -.1875(4) | 3.6(4) |
| O6’ | -.7048(1) | 1.7131(5) | -.3736(6) | 5.25() |
| O7’ | -.7222(4) | 1.0389(3) | -.4153(5) | 3.6(4) |
| C1’ | -.3229(9) | 1.2909(7) | -.3489(7) | 3.1(5) |
| C2’ | -.0811(9) | 1.3008(8) | -.3142(6) | 3.3(6) |
| C3’ | -.0945(8) | 1.4170(6) | -.2420(6) | 2.7(5) |
| C4’ | -.1945(2) | 1.5939(8) | -.2558(6) | 3.3(5) |
| C5’ | -.4227(9) | 1.5736(6) | -.3028(6) | 3.0(5) |
| C6’ | -.4938(3) | 1.7415(2) | -.3303(7) | 3.9(6) |
| C7’ | -.9159(4) | 1.322(2) | -.5201(8) | 4.3(7) |
| C8’ | -.9250(4) | 1.3530(3) | -.5967(9) | 6.7(1) |
| C9’ | -.4730(3) | .8367(2) | -.5422(9) | 5.6(8) |
| C10’ | -.2270(4) | .7830(3) | -.5326(1) | 7.7(1) |
| HN1 | .799 | 1.001 | .076 | 3.2 |
| HN2 | .638 | .756 | .205 | 3.2 |
| HO3 | .194 | .668 | -.013 | 3.2 |
| HO4 | .071 | .990 | -.216 | 3.2 |
| HO5 | .304 | 1.296 | -.196 | 3.2 |
| HO6 | .925 | 1.250 | -.069 | 3.2 |
| H1 | .649 | .802 | -.062 | 3.8 |
| H2 | .170 | .936 | -.026 | 4.2 |
| H3 | .415 | .865 | -.168 | 3.8 |
| H4 | .281 | 1.210 | -.088 | 3.7 |
| H5 | .763 | 1.063 | -.106 | 4.0 |
| H6A | .563 | 1.371 | -.009 | 4.9 |
| H6B | .711 | 1.392 | -.089 | 4.9 |
| H7A | 1.213 | 1.071 | .117 | 5.3 |
| H7B | 1.208 | .854 | .135 | 5.3 |
| H8A | 1.032 | 1.157 | .232 | 8.3 |
| H8B | 1.021 | .941 | .25 1 | 8.3 |
| H9A | .787 | .434 | .129 | 7.1 |
| H9B | .743 | .479 | .223 | 7.1 |
| H10A | .358 | .488 | .104 | 9.9 |
| H10B | .423 | .305 | .150 | 9.9 |
| HN1’ | -.725 | 1.457 | -.483 | 3.2 |
| HN2’ | -.424 | 1.123 | -.569 | 3.2 |
| HO3’ | .020 | 1.089 | -.345 | 3.2 |
| HO4’ | .087 | 1.443 | -.160 | 3.2 |
| HO5’ | -.244 | 1.575 | -.174 | 3.2 |
| HO6’ | -.775 | 1.850 | -.381 | 3.2 |
| H1’ | -.442 | 1.241 | -.312 | 4.0 |
| H2’ | .033 | 1.357 | -.350 | 4.1 |
| H3’ | -.209 | 1.357 | -.208 | 3.4 |
| H4’ | -.076 | 1.662 | -.286 | 3.9 |
| H5’ | -.556 | 1.526 | -.270 | 3.6 |
| H6’A | -.362 | 1.787 | -.363 | 5.1 |
| H6’B | -.516 | 1.838 | -.283 | 5.1 |
| H7’A | -1.013 | 1.424 | -.490 | 5.3 |
| H7’B | -1.002 | 1.200 | -.515 | 5.3 |
| H8’A | -.847 | 1.476 | -.603 | 7.1 |
| H8’B | -.818 | 1.253 | -.627 | 7.1 |
| H9’A | -.575 | .784 | -.503 | 6.6 |
| H9’B | -.537 | .785 | -.598 | 6.6 |
| H10’A | -.144 | .850 | -.481 | 9.0 |
| H10’B | -.210 | .645 | -.527 | 9.0 |
The structure of described glucose phosphonic amide crystals and atom numbering are as shown in Figure 1.
The accumulation graph of the unit cell of described glucose phosphonic amide crystals as shown in Figure 2.
The powder x-ray diffraction figure of described glucose phosphonic amide crystals as shown in Figure 3.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, adds ethanol 50ml in 20-50 ℃ of dissolving, is placed to-20 ℃ of-50 ℃ of crystallizatioies, and after 2-48 hour, suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, adds butanone 50ml in 20-50 ℃ of dissolving, adds normal hexane 500ml and is placed to-20 ℃ of-50 ℃ of crystallizatioies, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Embodiment 4.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, adds methyl alcohol 50ml in 20-50 ℃ of dissolving, adds hexanaphthene 500ml and is placed to-20 ℃ of-50 ℃ of crystallizatioies, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Embodiment 5.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, adds acetone 50ml in 20-50 ℃ of dissolving, adds ethyl acetate 500ml and is placed to-20 ℃ of-50 ℃ of crystallizatioies, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Embodiment 6.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, adds phenylcarbinol 50ml in 20-50 ℃ of dissolving, adds butylacetate 500ml and is placed to-20 ℃ of-50 ℃ of 0 crystallizatioies, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Embodiment 7.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, adds phenylcarbinol 50ml in 20-50 ℃ of dissolving, adds ether 500ml and is placed to-20 ℃ of-50 ℃ of crystallizatioies, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Embodiment 8.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, adds phenylethyl alcohol 50ml in 20-50 ℃ of dissolving, adds methylene dichloride 500ml and is placed to-20 ℃ of-50 ℃ of crystallizatioies, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, and add acetone: (v: v=1: 8) 450ml is placed to-20 ℃ of-50 ℃ of crystallizatioies in 20-50 ℃ of dissolving to ethyl acetate, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, and add methyl alcohol: (v: v=1: 8) 450ml is placed to-20 ℃ of-50 ℃ of crystallizatioies in 20-50 ℃ of dissolving to methylene dichloride, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Embodiment 11.
Glufosfamide crude product 10g adds in the 500ml three-necked bottle, and add ethanol: (v: v=1: 8) 450ml is placed to-20 ℃ of-50 ℃ of crystallizatioies in 20-50 ℃ of dissolving to trichloromethane, and suction filtration, 20-50 ℃ vacuum-drying promptly get the Glufosfamide white crystals.
Claims (10)
1. glucose phosphonic amide crystals comprises the powder x-ray diffraction that uses CuK α radiation, represents with 2 θ angles and spacing (d value) basically at the following N that characteristic peak is arranged everywhere, N '-two (2-chloroethyl) phosphoryl diamine acid-β-D-glucopyranosyl ester:
2 θ angle spacings (d value)
4.82 18.31
9.70 9.11
17.52 5.06
20.44 4.34
21.74 4.08
24.10 3.69
25.86 3.44
34.58 2.59。
2. glucose phosphonic amide crystals according to claim 1 is characterized in that, its spacer is P1, unit cell parameters a=5.841 (1), b=7.813 (1), c=18.271 (2) , α=95.795 (1), β=93.442 (1), γ=89.925 (1) °, unit cell volume V=828.0 (2)
3, molecule number z=1 in the structure cell.
3. glucose phosphonic amide crystals according to claim 1 is characterized in that it belongs to triclinic(crystalline)system.
4. glucose phosphonic amide crystals according to claim 3 is characterized in that profile is the water white transparency sheet, is of a size of 0.02 * 0.40 * 0.50mm.
5. the preparation method of the described glucose phosphonic amide crystals of claim 1, step is as follows:
(1) Glufosfamide crude product 20-50 ℃ is dissolved among the crystallization solvent I, add the crystallization solvent II again after perhaps being dissolved in crystallization solvent I, perhaps be dissolved in the mixed solvent of crystallization solvent I and crystallization solvent II, the mass volume ratio m of Glufosfamide crude product and crystallization solvent: v is 1: 1-100, and the volume ratio of crystallization solvent I and crystallization solvent II is 1: 1-100;
Described crystallization solvent I is selected from the following solvents one or more: aliphatic ketone kind solvent, aromatic ketone kind solvent, fatty alcohol kind solvent, aromatic alcohols kind solvent;
Described crystallization solvent II is selected from the following solvents one or more: fat hydrocarbon solvent, aromatic hydrocarbon solvent, halogenated hydrocarbon solvent, aliphatic ester kind solvent, aromatic ester kind solvent, aliphatic ether kind solvent, aromatic oxide kind solvent;
(2)-20 crystallization was placed in ℃-50 ℃ of placements 2-48 hour;
(3) suction filtration, 20-50 ℃ vacuum-drying get the Glufosfamide white crystals.
6. according to the preparation method of the glucose phosphonic amide crystals described in the claim 5, it is characterized in that, the mass volume ratio m of glufosfamide crude product and crystallization solvent in the step (1): v is 1: 1-50, the volume ratio of crystallization solvent I and crystallization solvent II is 1: 1-50.
7. according to the preparation method of the glucose phosphonic amide crystals described in the claim 5, it is characterized in that, the aliphatic category ketone solvent of crystallization solvent I is selected from acetone, butanone or pentanone in the step (1), the aromatic ketone kind solvent is selected from benzophenone or methyl phenyl ketone, the fatty alcohol kind solvent is selected from methyl alcohol, ethanol, Virahol or butanols, and the aromatic alcohols kind solvent is selected from phenylcarbinol or phenylethyl alcohol.
8, according to the preparation method of the glucose phosphonic amide crystals described in the claim 5, it is characterized in that, fat hydrocarbon solvent in the step (1) in the crystallization solvent II is selected from normal hexane, hexanaphthene or normal heptane, aromatic hydrocarbon solvent is selected from benzene, toluene or dimethylbenzene, and halogenated hydrocarbon solvent is selected from methylene dichloride, trichloromethane or ethylene dichloride; The aliphatic ester kind solvent is selected from ethyl acetate, isopropyl acetate, butylacetate, Isoamyl Acetate FCC or ethyl propionate, and the aromatic ester kind solvent is selected from methyl benzoate, ethyl benzoate or isobutyl benzoate; The aliphatic ether kind solvent is selected from ether, isopropyl ether, tetrahydrofuran (THF) or dioxane, and the aromatic oxide kind solvent is selected from methyl-phenoxide or phenyl ethyl ether.
9. the pharmaceutical applications of the described glucose phosphonic amide crystals of claim 1 is used to prepare antitumor drug.
10. a pharmaceutical composition comprises described glucose phosphonic amide crystals of claim 1 and pharmaceutical carrier.
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|---|---|---|---|---|
| US5622936A (en) * | 1988-10-20 | 1997-04-22 | Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts | Tumor inhibiting saccharide conjugates |
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