CN1603312A - Process for synthesis of sodium glycididazole - Google Patents
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Abstract
This invention belongs to medicine chemical technology field. This invention discloses a new synthesis technique of dry ammonia double azole natrium. The material is nitrilotriacetic acid, then it reacts with acetic anhydride in N, N-dimethyl amide, and product is got after refining and salifying with bicarbonates. The reaction yield is high, cost is low of this technique, labor intensity is reduced, and it is convenient to scale producing and environment protection.
Description
Technical field:
The invention belongs to the pharmaceutical chemistry technical field.Be specifically related to a kind of synthesis technique of sodium glycididazole.
Background technology:
Cancer is to fall ill and the mortality ratio disease with high serious threat mankind's life in the world.Oncotherapy at present still based on the operation and put, chemotherapy.The patient of tumor radiotherapy grows with each passing day in recent years, yet the tumor radiotherapy effect is not ideal enough, promptly uses the irradiation dose of maximum possible or changes illuminating method, does not still reach the radical cure purpose sometimes.
Radiosensitizer has been studied polytype compound at present since the fifties, the later stage began one's study.Wherein studying more is electrophilic compound.Britain Adams is theoretical and structure activity relationship analysis from electrophilic, has synthesized a series of nitro glyoxaline compounds, and the miaow that therefrom the filters out nitre azoles (MISO) of tremnbling is generally acknowledged in the world now radiosensitizer preferably, has carried out clinical study.But because of its neurotoxicity is big, clinical use is restricted.Metronidazole is a kind of anti-amoeba, trichomoniasis and anti-anaerobic agent, also belongs to nitro glyoxaline compound, and the seventies is developed to radiosensitizer.This compound is tremnbled with miaow, and the nitre azoles is the same to have special radiosensitizing effect to anoxic cell, but needs because of taking that dosage is big could to produce effect of enhanced sensitivity, and enhanced sensitivity is tired lower, not as the miaow nitre azoles of tremnbling, also easily causes serious neural toxic side effects simultaneously, and abandoning need not.Testing in recent years and changing metronidazole into tumor by local injection merging radiotherapy.
The inventor finds that the nitroimidazole ring is the necessary structure that produces the anoxic cell radiosensitizing effect, and its toxicity depends primarily on its distribution in vivo, easily causes characteristics such as neurotoxicity with brain intensive amount height especially.
After groping screening, successfully metronidazole and nitrilotriacetic acid(NTA) were synthesized Glycididazole in 1984, existing name Glycididazole.For improving its solubleness, again Glycididazole is made the sodium salt sodium glycididazole.
The experimental study of sodium glycididazole process physical chemistry level (ESR, E ' 7 and E1/2), molecular level (DNA chain rupture reclosing), the formation of isolated cells colony, lotus knurl (four kinds of tumours) integral level and pharmacology, toxicological test result prove that all it is the effective hypoxic cell radiation sensitizer of a kind of low toxicity.
The existing preparation method of sodium glycididazole is for being raw material with the nitrilotriacetic acid(NTA), and with acetic anhydride, products therefrom will not separate in pyridine, directly reacts with metronidazole, makes Glycididazole (acid), and then in ethanol with the sodium bicarbonate salify promptly.This method has been applied for Chinese patent, ZL89102182.5:
This technology has following weak point:
(1) pyridine toxicity is bigger, and is volatile, and the smell is awful, and difficulty is handled, reclaimed to reacted mother liquor;
(2) use the pyridine unit consumption higher.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, designs a kind of new synthesis technique, reduces cost, and reduces labor intensity.
The invention provides a kind of synthesis technique of sodium glycididazole, this technology comprises the following steps:
(1) preparation-esterification of Glycididazole
A, in 100 liters of reactors, add 6.0～8.0 kilograms of nitrilotriacetic acid(NTA)s (I, 31.4～41.8mol), 12～20 kilograms of 30 kilograms of DMF and diacetyl oxides (118～196mol), in 50～80 ℃ of insulated and stirred reactions 2～6 hours;
14.0～22.0 kilograms (81.8～128mol) in reactor, continues insulated and stirred reaction 3～7 hours in 40～80 ℃ for B, adding metronidazole;
After C, reaction finish, the logical cold water cooling of interlayer reaction feed liquid;
D, reaction solution are chilled to 30 ℃, add purified water, have been stirred to precipitation and have separated out cold putting (＜5 ℃) crystallization;
E, precipitation drying dehydration are washed to neutrality;
Get Glycididazole crude product, 9.18～13.4 kilograms of weight in wet bases, yield 47.0～51.4% after F, the centrifugation.
(2) Glycididazole is refining
A, Glycididazole crude product wet feed is put in 200 liters of reactors, added 35～65 kilograms of DMF, 50～80 kilograms of purified water and the dissolving of a small amount of strong aqua reflux, add 0.4 kilogram of activated carbon decolorizing, filtered while hot.Filtrate is put in 200 liters of crystallizers, and interlayer leads to water coolant, and feed liquid is cooled to 0～30 ℃.Stir and add 15% dilute hydrochloric acid accent pH2～5, cold putting (＜5 ℃) crystallization;
B, precipitation drying dehydration are washed till neutrality with about 200 kilograms of purified water;
C, 60～70 ℃ of oven dry, 6.09～8.04 kilograms of white powder crystallization Glycididazoles (highly finished product) (12.2～16.2mol), 116～118 ℃ of fusing points, yield 75.0～83.0%.
(3) preparation-salt-forming reaction of sodium glycididazole
A, in 100 liters of reactors, add 25～45 kilograms of purified water, 10～30 kilogram of 95% ethanol, after being warming up to 40～80 ℃, add 8.7 kilograms of (21.5mol) Glycididazoles, after stirring, add 1～4 kilogram of sodium bicarbonate powder gradually, in 40～80 ℃ of stirring and dissolving.Dissolving finishes and adds 0.5 kilogram of gac, reacts 0.5 hour.
B, filtered while hot, mother liquor are put in 200 liters of crystallizers, are cooled to 5～30 ℃, stir to add 25～75 kilograms of dehydrated alcohols, and cold putting (0～5 ℃) separated out crystallization.
C, drying collecting precipitation are with dehydrated alcohol (needing 25 kilograms approximately) washing.
D, vacuum-drying get 5.22～7.36 kilograms of sodium glycididazole crude products (9.10～12.8moL), yield 74.5～79.5%.
(4) sodium glycididazole is refining
7.6 kilograms of sodium glycididazole crude products are dropped into 50 liters of reactors, add 20～35 kilograms of purified water, 10～35 kilograms of dehydrated alcohols, be heated to 40～80 ℃ under stirring, stir and make dissolving fully, stirring adds 0.3 kilogram of activated carbon, is incubated filtered while hot after 30 minutes.Filtrate is put in 100 liters of crystallizers, is cooled to 5～30 ℃, stirs to add 25～60 kilograms of dehydrated alcohols, and cold putting (0～5 ℃) separated out crystallization.Centrifuging and collecting precipitation are put in the vacuum drying oven, in 60～70 ℃/20mmHg drying, get 4.19～6.28 kilograms of the Powdered sodium glycididazoles of class Bai Zhiwei yellow crystal, yield 80.3～85.3%.
Synthesis technique of the present invention is as follows compared with the prior art:
Synthetic new, the old process data of table 1 Glycididazole crude product relatively
| Old technology | Novel process | |
| ???020801??020802????020803 | ???010705???010711????010718 | |
| Charging capacity (kg) must be measured (kg) yield (%) outward appearance purity (%) | 20.0 20.0 20.0 25.0 26.8 25.9 48.0 51.4 49.7 light browns knot light brown knot light brown crystallization Jingjing 95.95 96.43 96.06 | 8.0 8.0 8.0 10.7 9.8 10.4 51.4 47.0 49.9 light browns knot light brown knot light brown crystallization Jingjing 98.06 98.06 98.12 |
Annotate: yield calculates with the nitrilotriacetic acid(NTA) charging capacity
New, the old process data of table 2 Glycididazole crude product refining relatively
| Old technology | Novel process | |
| ???020801????020802????020803 | ???010705????010711????010718 | |
| Charging capacity (kg) must be measured (kg) yield (%) outward appearance purity (%) | 25.0 26.8 25.9 20.8 22.5 21.8 83.2 83.9 84.2 white crystals white crystals white crystals 97.64 96.99 97.65 | 10.7 9.8 10.4 8.7 8.1 8.3 81.3 83.0 79.8 white crystals white crystals white crystals 98.96 99.14 99.13 |
Quality controlling means: HPLC method, purity＞95%.
New, the old process data of table 3 Glycididazole salt-forming reaction relatively
| Old technology | Novel process | |
| ??020801????020802????020803 | ??010705???010711?????010718 | |
| Charging capacity, (kg) must measure, (kg) yield, (%) outward appearance related substance, (%) content, (%) | 20.8 the little yellow crystal Jingjing 1.0 0.80 0.90 99.2 101.1 100.6 of the little yellow knot of 22.5 21.8 19.5 21.3 20.5 81.3 82.2 81.6 little yellow knots | 8.7 the little yellow crystal Jingjing 0.40 0.35 0.38 101.7 100.2 100.6 of the little yellow knot of 8.1 8.3 7.5 7.2 7.6 74.8 77.1 79.5 little yellow knots |
Therefore, technology of the present invention has the following advantages:
1, with the solvent of DMF substituted pyridines as esterification, the synthesis yield of Glycididazole improves, and every quality index meets the requirements, and wherein the related substance of finished product has obtained effective control.
2, the total recovery of novel process sodium glycididazole is 30.1～31.6%, and 26.3～28.6% of old technology have improved 3.0～3.8%, and the per kilogram unit consumption is reduced to 650～686 yuan by 828～864 yuan.
3, novel process greatly reduces the labour intensity of production operation, has alleviated the burden of pyridine liquid waste disposal, helps the three wastes and handles.
4, novel process pilot scale data show, the stable yield of novel process, and final product quality all can meet every regulation of sodium glycididazole national standard WS-166 (X-143)-2002.
Key intermediate Glycididazole of the present invention (acid) quality standard
Glycididazole
This product is N, two [(2-methyl-5-nitro-1H-imidazoles-1-yl)-ethoxy carbonyl methyl] glycine of N-.Press anhydride and calculate, contain C
18H
22N
8O
10Must not be less than 95.0%.
Outward appearance this product is that off-white color is to yellowish crystallization or crystalline powder; Odorless, bitter; It is dark to meet photochromic gradual change.
Solubleness this product is molten in the hot ethanol part omitted, and is almost insoluble in water or acetone.
Chromatographic purity is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
The lucifuge operation.Get the about 12.5mg of this product, the accurate title, decide, and puts in the 25ml volumetric flask, adds N, dinethylformamide 1～2ml, and jolting makes dissolving, and thin up shakes up to scale again, as need testing solution (face and use new system); Get 20 μ l and inject liquid chromatograph, the record color atlas is to 2 times of main composition peak retention time.If any impurity peaks, measure each impurity peak area in the need testing solution color atlas, press the peak area normalization method and calculate, the principal constituent peak area should be greater than 95%.
Product pharmacology of the present invention, toxicity, clinical effectiveness are as follows:
One, pharmacology, toxicity part
1, main pharmacodynamics
I chemotherapy sensitizing drug effect effect research is as follows:
A, in vitro tests
Studied the chemotherapy sensitizing effect of sodium glycididazole with conventional cell in vitro clone method of depositing alive to carboplatin, endoxan and vincristine(VCR).
(1) at first acts on cancer of the stomach SGC-790l cell strain, observe the influence that the work of sodium glycididazole pair cell is deposited with the sodium glycididazole of 0-1000 μ g/ml.The result shows, when the concentration of sodium glycididazole＜50 μ g/ml, do not have obviously influence to depositing for the work of cancer cells.The enhanced sensitivity experimental concentration of determining sodium glycididazole should not surpass 50 μ g/ml.
Use carboplatin (0.5-60 μ g/ml), endoxan (1-100 μ g/ml) and vincristine(VCR) (1-100 μ g/ml) to act on stomach cancer cell respectively then respectively, observe the influence of chemotherapeutics pair cell.The result shows: the endoxan of the carboplatin of 0.5 μ g/ml, 10 μ g/ml, the vincristine(VCR) of 1 μ g/ml can make the work of stomach cancer cell have remarkable reduction.
(2) select the sodium glycididazole of 10,30 and 50 μ g/ml, respectively with the vincristine(VCR) acting in conjunction of the endoxan of the carboplatin of 2 μ g/ml, 5 μ g/ml and 2 μ g/ml in cell, observe the chemotherapy sensitizing effect of sodium glycididazole to three kinds of chemotherapeutics.The result shows: sodium glycididazole has tangible sensitization to carboplatin and endoxan.Compare with blank, use carboplatin (2 μ g/ml) to handle separately, it is 83% that attenuating is deposited in the work of cell; After adding sodium glycididazole (10,30 and 50 μ g/ml), cell work is deposited respectively and is reduced to: 44%, 26% and 1.9%.Handle with endoxan (5 μ g/ml) separately, the work of cell is deposited and is reduced to 77%; After adding sodium glycididazole (10,30 and 50 μ g/ml), cell work is deposited respectively and is reduced to: 50%, 16% and 1.4%.Show tangible chemotherapy sensitizing effect to the alkylating agent series antineoplastic medicament.But behind the adding vincristine(VCR), do not observe the sensitization of sodium glycididazole.Therefore can confirm: sodium glycididazole has tangible chemotherapy sensitizing effect to the antitumor drug of alkylating agent class.
B, whole animal experiment
Consider the complicacy in the clinical tumor chemotherapy, comprise the tumour of various chemotherapeutics, different pathological types, different chemotherapy regimens etc., come complicacy for animal drug effect test tape.Therefore two thinkings when contrived experiment, have been selected.The one, sodium glycididazole is treated the sensitization of different tumours to typical antineoplastic alkylating agent thing; The 2nd, sodium glycididazole is to the sensitization of typical tumour with different chemotherapeutics treatments.The basic like this sodium glycididazole that can reflect is treated the chemotherapy sensitizing effect of different tumours to different chemotherapeutics.The terminal point index of observing is: tumor control rate and short-term curative effects that each is organized the variation of gross tumor volume, respectively organizes the relative rate of growth of tumour, respectively organizes.Add with behind the injection sodium glycididazole in order to investigate, whether can increase the toxic side effects of antitumor drug simultaneously, and the main toxic side effects of antitumor drug is the marrow hemopoiesis inhibition, therefore other design experiment, high spot reviews the variation of the peripheral hemogram of each treated animal during medication, and carry out statistical treatment.According to governing principle, sodium glycididazole has been selected the dosage level of high, medium and low three administrations simultaneously, has mainly selected the route of administration of clinical vein injection to carry out the observation of its sensitization.
Sodium glycididazole has selected 1000,500, high, medium and low three the dosage water intravenously administrable approach of 250mg/kg, and the result shows:
(1) compares with the blank group, use carboplatin separately, B
16Melanoma, EMT
6Mammary cancer, Lewis lung cancer and S
1804 kinds of tests of sarcoma tumour has the obvious treatment effect, shows as tumor growth rate and slows down, and the tumor growth delay fate increases, and tumor control rate increases.
Add with behind the injection sodium glycididazole of various dose (1000,500,250mg/kg), compare with carboplatin treatment group, tumor growth rate obviously slows down, and tumor growth delay fate and tumor control rate obviously increase, and the statistical significance of highly significant is arranged.To 4 kinds of test tumours, separately the tumor control rate of carboplatin treatment (after the administration the 10th day) is respectively: 25.6%, 43.9%, 18.0% and 47.0%.Add with being increased to respectively behind the injection sodium glycididazole (500mg/kg): 72.9%, 76.5%, 31.0% and 78.0%.The injection sodium glycididazole shows tangible chemotherapy sensitizing effect.
(2) compare with the blank group, 4 kinds of antineoplastic chemotherapy medicines (mitomycin, etoposide, endoxan and carboplatin) treatment Lewis lung cancer all shows the obvious treatment effect.Show as tumor growth rate and slow down, the tumor growth delay fate increases, and tumor control rate increases.
Add with behind the injection sodium glycididazole of various dose (1000,500,250mg/kg), except that the etoposide group, compare with independent mitomycin, endoxan and carboplatin treatment group, tumor growth rate further slows down, tumor growth delay fate and tumor control rate obviously increase, and the statistical significance of highly significant is arranged.
To Lewis lung cancer, separately the tumor control rate of mitomycin treatment (after the administration the 12nd day) is 31.4%, rises to 97.2% after adding the injection sodium glycididazole;
Separately the tumor control rate of endoxan treatment (after the administration the 12nd day) is 71%, rises to 94% after adding the injection sodium glycididazole; Separately the tumor control rate of carboplatin treatment (after the administration the 12nd day) is 57%, adds with being increased to behind the injection sodium glycididazole (500mg/kg): 82%.The injection sodium glycididazole shows tangible chemotherapy sensitizing effect.
The II radiosensitizing effect
Chinese hamster V with isolated culture
79Cells in vitro test S set
180, Lewis lung cancer, B
16Melanoma and EMT
6The method of four kinds of mice with tumor bulk testings of mammary cancer has proved the radiosensitizing effect of sodium glycididazole.Experiment is established the blank group simultaneously and is shone two kinds of control groups separately and experimentizes.Establishing the more sure compound of radiosensitizing effect of generally acknowledging in several documents such as Misonidazole, SR-2508 respectively experimentizes as the positive drug control group.Experimental result is all learned by statistics and is handled.Abdominal injection and two kinds of route of administration of intravenous injection have been used in the whole animal experiment, and the sodium glycididazole drug dose is established high, medium and low three dosage at least and experimentized.
(1) experiment in vitro
A. sodium glycididazole is to the IC of aerobic and anoxic cell
50Value is respectively: 35.70mmol/L and 23.50mmol/L, confirm sodium glycididazole to the toxicity of anoxic cell obviously greater than aerobic cell.
Enhanced sensitivity when b. drug level is 0.1～1.38mmol/L is 1.26～2.32 than (SER value).
C.C
1.6Value (radiation sensitization is 1.6 o'clock than the SER value, the drug level of sensitizer) is 0.418mmol/L.
D. the aerobic cell that is subjected to photograph is not shown radiosensitizing effect.
E. under same experimental conditions, compared and waited mol drug level (0.3mmol/L), the radiosensitizing effect of sodium glycididazole, Misonidazole, metronidazole.The result shows that the enhanced sensitivity of sodium glycididazole is 1.76 than (SER value), is higher than Misonidazole (1.52) and metronidazole (1.07).
(2) integral experiment
A. select Lewis lung cancer, B for use
16Melanoma, EMT
6Mammary cancer and S
180Deng four kinds of tumor models, (57.3～1032.2mg/kg) sodium glycididazoles are to the radiosensitizing effect of 0～32Gy γ line single fraction irradiation to have observed 0.1～1.8mmol/kg.The result shows with independent irradiation and compares, and adds with tumor growth rate behind the sodium glycididazole and obviously slows down, and tumor control rate increases, and the tumor growth delay fate increases, and four kinds of tumor models all obtain identical result.The SER value is most of more than 1.3.
B. sodium glycididazole is variant to the susceptibility of four kinds of tumor model radiosensitizing effects, wherein to Lewis lung cancer and B
16The melanoma better effects if some.
C. use lotus Lewis lung cancer and EMT
6The mammary cancer mouse has proved 0.1, (irradiation also has radiosensitizing effect to 57.3～573mg/kg) sodium glycididazole to 1.0mmol/kg to fractionated dose r line.
D. wait the radiosensitizing effect of gram molecular weight (0.1mmol/kg) sodium glycididazole better than the effect of enhanced sensitivity of metronidazole and SR-2508.
E. decimal continuous use 2 states (each 200mg/kg, secondary weekly) shines 0～6Gy γ line then, compares with independent irradiation, adds with behind the sodium glycididazole mouse bone marrow cells CFU-GM and CFU-S not being had tangible influence, and body weight and spleen index are not had obvious influence yet.The above results confirms that sodium glycididazole is to the no radiosensitizing effect of the more sensitive normal hematopoiesis tissue of the radiation that is subjected to photograph.
2, general pharmacology test
Use mouse and rat studies respectively the sodium intravenous back of the Glycididazole of 150～900mg/kg to neural influence.The result shows, sodium glycididazole 150～900mg/kg (450～2700mg/m
2) general behavior activity and the coordinated movement of mouse there are not obvious influence.When dosage is 300～900mg/kg (1800～5400mg/m
2) during intravenous injection, can influence the inquiry activity of rat, mainly show as and walk number of times between the grid of climbing the lattice test and reduce and hold up, modify number of times and reduce, be amount-result relation.
The Glycididazole of having observed 50～300mg/kg with cat is sodium intravenous to cardiovascular and influence respiratory system.When drug dose during, the blood pressure and the heart rate of anesthetized cat there is not obvious influence less than 100mg/kg.Electrocardiogram(ECG there is not obvious influence.When drug dose is 300mg/kg, has tangible hypotensive effect.Can be observed Electrocardiographic T ripple simultaneously increases.The dosage of 50～300mg/kg does not have obvious influence to anesthetized cat respiratory rate and amplitude.
3, acute toxicity test
With (iv) two kinds of route of administration of abdominal injection (ip) and intravenous injection, observed the acute toxic reaction of sodium glycididazole respectively to rat, mouse.
After heavy dose of (3200mg/kg) gave the mouse mainline sodium glycididazole, instability of gait, asynergia appearred in animal in one minute, jump run helter-skelter, whole-body muscle twitches, and behind the medicine 1～15 minute, animal dead occurs.It is normal that not dead person recovered after 24～48 hours.The LD of female, male mouse
50No significant difference.Through add up LD with probability-weighted unit's Return Law
50Value is the LD of 2675.89mg/kg mouse peritoneal injection
50Value is 3959.52mg/kg.
Heavy dose of (5000mg/kg) instability of gait, asynergia occurred, turns round body after giving the rat intravenous injection sodium glycididazole through several minutes, then animal lie prostrate, close one's eyes, trembling of limbs, it is dead to play beginning in 1 hour behind the medicine, after 24 hours dead animal recover normal.LD between sex
50No significant difference, LD
50Value is 2691.63mg/kg (2576.89～2811.49mg/kg).Behind the rats by intraperitoneal injection sodium glycididazole, toxic reaction is similar to intravenous injection, LD
50Value is 2911.44mg/kg (2652.13～3196.09mg/kg).
The above results shows, intravenously administrable, the LD of rat and mouse
50Value is all greater than 2g/kg, and intraperitoneal administration is to the LD of rat
50Value is greater than 2g/kg, to the LD of mouse
50Value can think that the toxic side effect of this medicine is not too big about 4g/kg.
4, systemic administration toxicity test
The injection sodium glycididazole shows rabbit auricular vein vascular stimulation test-results, in the physical abuse of the rarely seen inserting needle in injection site, does not see the significantly irritant reaction relevant with medicine, and administration group and negative control group do not have tangible difference.
Rabbit red blood corpuscle hemolytic test and to the cavy hypersensitive test result reaction that is negative.
5, long term toxicity
The laboratory animal long term toxicity test is selected SD rat and two kinds of animals of Beagle dog for use.
(1) 3 months toxicity test rats of rats by intraperitoneal injection sodium glycididazole long term toxicity test, the dosage setting is oozed soup abdominal injection MAD as high dosage to wait, with 10: 3: 1 doses of distances, in being provided with, low dose group.Abdominal injection (was equivalent to 3600mg/m in high dose group 600mg/kg/ days after 3 months continuously
2/ sky) the male rat body weight gain is subjected to slight inhibition.In all the other, low dose group (180,60mg/kg/ days, be equivalent to 1080,360mg/m
2/ sky) do not see the overt toxicity symptom that other are relevant with medicine.Serum biochemistry and routine urianlysis are not all found the abnormal results relevant with medicine, and observed value is all in range of normal value.Each internal organs of pathologic finding whole body there is no obvious pathology when administration and decubation stopped, and microscopy also finds no the toxic reaction relevant with medicine.The non-toxic reaction dosage of determining is 60mg/kg/ days (360mg/m
2/ day).
(2) long term toxicity test of 3 months toxicity test Beagle of dog intravenous drip sodium glycididazole dog be provided with 60,180,600mg/kg/ days (1200,3600,12000mg/m
2/ sky) 3 dosage groups, continuous three months of each intravenous drip administration.The result shows, the weight of animals, food ration, blood routine, serum biochemistry, routine urinalysis, electrocardiogram(ECG and fundoscopy etc. be there is no the ANOMALOUS VARIATIONS relevant with medicine.Central nervous system symptoms such as that the toxic reaction relevant with medicine-dosage that sodium glycididazole gives to be taken place behind the animal is mainly is nauseating, vomiting, slight hydrostomia, slight muscular tremor.The major cause that causes animal dead is blood circulation and central nervous system disorder, has dose-dependently.
6, mutagenicity test
(1) microorganism reverse mutation (Ames) test set of applications propylhomoserin defective type Salmonella typhimurium TA97, TA98, TA100 and TA102 are indicator microoraganism, the system mutagenicity of test 50～5000 μ g/ ware sodium glycididazoles.The result shows that four bacterial strains are adding and do not adding under the metabolism activation system condition negative result below 1000,500 μ g/ ware dosage.
(2) Mammals culturing cell gene mutation test result shows, the cell mutation rate of 20～1280 each dosage group of μ g/ml is adding and do not add under the S9 metabolism activation condition, all less than 3 times of spontaneous mutation rate.And under equal conditions, positive control ethylmethane sulfonate (EMS) and benzopyrene are respectively much larger than 3 times of spontaneous mutation rate.Therefore confirm that the Mammals culturing cell gene mutation test result of sodium glycididazole is negative.
(3) chromosomal aberration test adopts Chinese hamster lung fibroblast (CHL) experiment in vitro method, has detected sweet) the two azoles sodium of ammonia are to the influence of Mammals culturing cell chromosome aberrations rate.The result shows, under 250～1000 μ g/ml dosage, and the chromosome aberrations rate of each concentration test group and blank group there was no significant difference.Do not see that sodium glycididazole brings out the distortion of CHL cell chromosome.
(4) micronucleus test adopts sexually matured NIH mouse, and sodium glycididazole has been carried out micronucleus test in the mammalian body.The result shows that each the test group micronuclear rates of 139.9～1399mg/kg dosage and the micronuclear rates of negative control group do not have significant difference, does not show the effect that this drug-induced decimal marrow polychromatophilia micronucleus in erythrocytes increases.
7, genotoxicity
(1) general reproductive toxicity test result shows that high dose group (300mg/kg) has certain influence to the body weight gain of male mice.Middle dosage group (100mg/kg) and relative the increasing of high dose group animal testis weight, sperm motility degree have decline in various degree.Situations such as the growing of male mouse fertility, female mouse conceptual quotient and newborn mouse, nurture all there is not obvious influence.
(2) teratogenic test shows the toxicity test result of the female mouse sensitive period of teratogenesis of becoming pregnant, high dose group (1399mg/kg) absorbs tire to be increased, the tire rate of living and average nest tire number alive descend, and can cause to a certain degree the fetus mouse deformity of (total monster rate 7.42%), and certain female sodoku is arranged.In show slight maternal toxicity during dosage (279.8mg/kg), but do not have embryotoxicity and teratogenesis.
(3) perinatal toxicity test sodium glycididazole is in perinatal period and administration lactation (300mg/kg), do not have tangible influence, but some physiological development (front tooth eruption, testis descend, open ear) and the maturation of reflection growth are had retarding action going out life tire rate, nurture surviving rate, the ability of learning and memory of newborn mouse, reproductive performance.When slight maternal toxicity dosage is arranged, also can cause the newborn mouse growth retardation.
8, pharmacokinetics test
The content of sodium glycididazole and meta-bolites metronidazole thereof in employing HPLC method mensuration mouse and the rat intravenous injection sodium glycididazole artifact sample.The dependency of effect and concentration, the rate of recovery, precision are investigated after measured, and test method therefor and HPLC condition meet the pharmacokinetic requirement.The test of mouse vitro conversion shows that sodium glycididazole is all unstable in water, whole blood, liver homogenate, and is the rapidest with degraded in the blood especially.The transformation efficiency of 90min is respectively: 27.3%, 91.8% and 41.1%.The production rate of metronidazole 90min in water, whole blood, liver homogenate is respectively: 8.2%, 67.3% and 27.3%.The pharmacokinetic of mouse mainline sodium glycididazole 57.3,171.9, three dosage of 515.7mg/kg shows, sodium glycididazole transforms in the mouse body or eliminates very fast, be a compartment model, the elimination transformation period of three dosage is respectively: 0.5,0.8 and 1.0min.C
0Be respectively: 209.6,567.3 and 3102.8 μ g/ml.Area A UC under concentration one time curve is respectively: 282.4,1127.5 and 6700.8 μ gmin/ml.C
0(r is 0.992,0.993) all is proportionate with dosage with AUC.It is very fast that the meta-bolites metronidazole of sodium glycididazole reaches the peak, eliminates slowlyer, is two chamber models, and the peak time of three dosage is respectively: 0.5,1.0 and 1.2min, and eliminate the transformation period and be: 63.2,68.2 and 64.3min, C
MaxFor: 25.7,59.7 and 145.5 μ g/ml, AUC is respectively 1014.7,3914.9 and 11178.7 μ gmin/ml.C
MaxWith AUC all be proportionate (r is 0.999) with dosage.Show the first order kinetics feature.
After tissue distribution assays is found rat intravenous injection sodium glycididazole 171.9mg/kg, sodium glycididazole is distributed to rapidly in each tissue, mainly finds in the competent heart of blood flow, lung, kidney and digestive tube 2min and 5min behind the medicine, the sodium glycididazole tissue content is the highest, and 20min reduces significantly.Its metabolite metronidazole is higher at 2min and 5min at the content of each tissue, is higher than the Glycididazole sodium content of corresponding time, and behind the 20min, each tissue content descends.
Behind the rat intravenous injection sodium glycididazole 171.9mg/kg, the drainage of sodium glycididazole is based on urine, the former medicine of excretory accounts for 8.4% of administration total amount from urine, and the drainage of metronidazole and another unknown metabolite accounts for 33.4% and 39.2% respectively, promptly gets rid of 81% of administration total amount altogether from urine.Bile excretion is less, and sodium glycididazole and metronidazole account for 11.5% and 10.1% respectively.Excrement is drained few, and sodium glycididazole and metronidazole account for 0.14% and 0.06% of dosage respectively.The average protein binding rate of sodium glycididazole only is 14.2 ± 2.2%.
Two, clinical part (radiosensitizing effect)
1, I clinical trial phase
(1) intravenous route gives injection sodium glycididazole dosage and reaches 900mg/m
2, to peripheral hemogram, basic vital signs such as breathing, pulse, blood pressure, body temperature, renal function etc. do not have obviously influence.
(2) dosage reaches 900mg/m
2, Electrocardiographic variations such as sinus tachycardia, the change of ST section can appear in part patient, can be used as an index of the monitoring drug toxicity of clinical use.
(3) dosage reaches 900mg/m
2, the liver dysfunction that ALT raises can appear in part patient, should note monitoring patient's liver function when using this medicine for a long time.
(4) dosage reaches 900mg/m
2, patient's neural system is not had tangible influence.
(5) untoward reaction relevant with medication mainly contains the change of gastral nausea and vomiting and constipation and heart function.
(6) preliminary radiocurable results suggest, this medicine has radiosensitizing effect preferably to the anoxic cell in the tumor tissues.
(7) take all factors into consideration pharmacokinetics and preclinical result of study, the recommended dose of II phase clinical study is 800mg/m
2
2, clinical fs test of II phase
This step-by-step test is adopted at random, the design of double blinding, parallel control, goes into to organize incidence, oesophagus and the lung tumors that 218 examples make a definite diagnosis altogether and carries out radiocurable patient.Because a variety of causes comes off and rejects 13 examples, effectively adds up 205 of cases.Test group is used injection sodium glycididazole (800mg/m in the conventional planning treatment
2), control group uses placebo.The result shows:
(1) the injection sodium glycididazole has sure radiation sensitization curative effect to the radiotherapy of tumor of head and neck, the esophageal carcinoma and lung cancer, shows as the irradiation dose that increases tumor control rate, reduces CR and PR, improves CR or patient's CR+PR percentage.Present data prompting can increase the remission time of CR, PR.
(2) rate (CR leads) but the tumour of using injection sodium glycididazole highly significant to improve tumor of head and neck, the esophageal carcinoma and lung cancer disappears entirely.
(3) the tumor of head and neck curative effect SER value that reaches CR and PR is respectively: 1.27 and 1.31; Local control rate is brought up to 62.75% (P=0.001) by 39.18% of independent radiotherapy group during the Dt4000cGy of the esophageal carcinoma and lung cancer; Two groups the rate that disappears is entirely brought up to 55.9% (P=0.001) by 30.9% of independent radiotherapy group, shows tangible radiosensitizing effect.
(4) radiation therapy session are used the injection sodium glycididazole, and the dosage of use reaches 800mg/m
2/ time, to use continuously 21 times, patient's tolerance is good.
(5) dosage (800mg/m of the clinical use of recommendation
2/ time, 3 times weekly, continuous 6～7 weeks) adverse reaction rate that occurs compares with independent irradiation, and the adverse reaction rate of not observing the injection sodium glycididazole increases.
(6) case of indivedual dysfunction of livers is used the result who occurs the liver function obvious damage behind this medicine.Whether should strictly limit this medicine of use to the dysfunction of liver patient, reach a conclusion after remaining to continue to enlarge case load.
(7) I phase clinical research observation arrives, and when the dosage that uses the injection sodium glycididazole was big, individual patients can be observed Electrocardiographic change, shows as tachycardia, the change of T ripple etc.The II clinical trial phase is observed no statistics difference between two groups of this situations, but in should testing on a large scale afterwards, notes observing patient's electrocardiogram(ECG and heart function, so that draw clear and definite conclusion.
3, clinical subordinate phase test of II phase
This step-by-step test is adopted at random, the design of parallel control, goes into to organize incidence, oesophagus and the lung tumors that 411 examples make a definite diagnosis altogether and carries out radiocurable patient.Because a variety of causes comes off and rejects 9 examples, effectively adds up 402 of cases.Test group is used injection sodium glycididazole (800mg/m in the conventional planning treatment
2), (test group: ratio control group) was established independent radiocurable control group in 2: 1 at random.In validity and the security of having observed the injection sodium glycididazole in a big way.The result shows:
(1) the injection sodium glycididazole has sure radiosensitizing effect to the radiotherapy of tumor of head and neck, the esophageal carcinoma and lung cancer, shows as the irradiation dose that increases tumor control rate, reduces CR and PR, improves CR or patient's CR+PR percentage.
(2) (CR) rate (P=0.003) but the tumour of using injection sodium glycididazole highly significant to improve tumor of head and neck, the esophageal carcinoma and lung cancer disappears entirely.
(3) the tumor of head and neck metastasis curative effect SER value that reaches CR and PR is respectively: 1.39 and 1.26; Local control rate is brought up to 54.76% (P=0.012) by 41.22% of independent radiotherapy group during the Dt4000cGy of the esophageal carcinoma and lung cancer; Two groups the rate that disappears is entirely brought up to 44.0% (P=0.003) by 28.2% of independent radiotherapy group, shows tangible radiosensitizing effect.
(4) radiation therapy session are used the injection sodium glycididazole, and the dosage of use reaches 800mg/m
2/ time, to use continuously 21 times, patient's tolerance is good.
(5) dosage (800mg/m of the clinical use of recommendation
2/ time, 3 times weekly, continuous 6～7 weeks) adverse reaction rate that occurs compares with independent irradiation, and the adverse reaction rate of not observing the injection sodium glycididazole increases.
(6) behind the use injection sodium glycididazole, the esophageal carcinoma, the radiocurable skin of tumor of head and neck, mucous membrane untoward reaction there is the trend of minimizing.
(7) use the injection sodium glycididazole after, although the laboratory indexes of liver function is all in range of normal value generally, have untoward reaction before and after part test person's medication to show the change aspect of liver function.In conjunction with the test-results of fs, should pay attention to monitoring during life-time service this product to liver function.This medicine of patient Ying Shen of dysfunction of liver.
(8) I phase clinical research observation arrives, and when the dosage that uses the injection sodium glycididazole was big, a few patients can be observed the change of electrocardiogram(ECG or heart function, shows as tachycardia, ECG T wave change etc.Clinical first, second step-by-step test of II phase through randomized, double-blind and contrast at random proves, the routine number of the ECG change that electrocardiogram(ECG is normal before the treatment, the treatment back is relevant with myocardial ischemia and rhythm abnormality, no difference of science of statistics between two groups.Confirm that this medicine does not have obvious influence to electrocardiogram(ECG.
(9) do not observe tangible gastral untoward reaction after use this product, renal function and electrocardiogram(ECG are not had obvious influence.
(10) do not observe tangible neural toxic side effects after use this product.
Embodiment:
Preparation-the esterification of embodiment 1, Glycididazole
A, in 100 liters of reactors, add 6.0 kilograms of nitrilotriacetic acid(NTA)s (I, 31.4mol), DMF30 kilogram and 12 kilograms of diacetyl oxides (118mol), in 50 ℃ of insulated and stirred reactions 6 hours;
B, adding metronidazole 14.0 kilograms (81.8mol) continue insulated and stirred reaction 7 hours in 40 ℃ in reactor;
After C, reaction finish, the logical cold water cooling of interlayer reaction feed liquid;
D, reaction solution are chilled to 30 ℃, add purified water, have been stirred to precipitation and have separated out, and cold putting (＜5 ℃) separated out crystallization;
E, precipitation drying dehydration are washed to neutrality;
Get Glycididazole crude product, 9.18 kilograms of weight in wet bases, yield 47.0% after F, the centrifugation.
Preparation-the esterification of embodiment 2, Glycididazole
A, in 100 liters of reactors, add 7.0 kilograms of nitrilotriacetic acid(NTA)s (I, 36.6mol), DMF30 kilogram and 16 kilograms of diacetyl oxides (157mol), in 65 ℃ of insulated and stirred reactions 4 hours;
B, adding metronidazole 18.0 kilograms (105mol) continue insulated and stirred reaction 5 hours in 60 ℃ in reactor;
After C, reaction finish, the logical cold water cooling of interlayer reaction feed liquid;
D, reaction solution are chilled to 30 ℃, add purified water, have been stirred to precipitation and have separated out, and cold putting (＜5 ℃) separated out crystallization;
E, precipitation drying dehydration are washed to neutrality;
Get Glycididazole crude product, 11.3 kilograms of weight in wet bases, yield 49.6% after F, the centrifugation.
Preparation-the esterification of embodiment 3, Glycididazole
A, in 100 liters of reactors, add 8.0 kilograms of nitrilotriacetic acid(NTA)s (I, 41.8mol), DMF30 kilogram and 20 kilograms of diacetyl oxides (196mol), in 80 ℃ of insulated and stirred reactions 2 hours;
B, adding metronidazole 22.0 kilograms (128mol) continue insulated and stirred reaction 3 hours in 80 ℃ in reactor;
After C, reaction finish, the logical cold water cooling of interlayer reaction feed liquid;
D, reaction solution are chilled to 30 ℃, add purified water, have been stirred to precipitation and have separated out, and cold putting (＜5 ℃) separated out crystallization;
E, precipitation drying dehydration are washed to neutrality;
Get Glycididazole crude product, 13.4 kilograms of weight in wet bases, yield 51.4% after F, the centrifugation.
Embodiment 4, Glycididazole are made with extra care
A, 9.18 kilograms of Glycididazole crude product wet feeds are put in 200 liters of reactors, added 35 kilograms of DMF, 80 kilograms of purified water and the dissolving of a small amount of strong aqua reflux, add 0.4 kilogram of activated carbon decolorizing, filtered while hot.Filtrate is put in 200 liters of crystallizers, and interlayer leads to water coolant, and feed liquid is cooled to 0 ℃.Stir adding 15% dilute hydrochloric acid and transfer pH2～5, cold putting (＜5 ℃) separated out crystallization;
B, precipitation drying dehydration are washed till neutrality with about 200 kilograms of purified water;
C, 60～70 ℃ of oven dry get 6.09 kilograms of white powder crystallization Glycididazoles (highly finished product) (12.9mol), 116～118 ℃ of fusing points, yield 83.0%.
Embodiment 5, Glycididazole are made with extra care
A, 11.3 kilograms of Glycididazole crude product wet feeds are put in 200 liters of reactors, added the dissolving that refluxes of 50 kilograms of DMF, 65 kilograms of purified water and a small amount of strong aqua, add 0.4 kilogram of activated carbon decolorizing, filtered while hot.Filtrate is put in 200 liters of crystallizers, and interlayer leads to water coolant, and feed liquid is cooled to 15 ℃.Stir adding 15% dilute hydrochloric acid and transfer pH2～5, cold putting (＜5 ℃) separated out crystallization;
B, precipitation drying dehydration are washed till neutrality with about 200 kilograms of purified water;
C, 60～70 ℃ of oven dry get 7.14 kilograms of white powder crystallization Glycididazoles (highly finished product) (14.3mol), 116～118 ℃ of fusing points, yield 79.0%.
Embodiment 6, Glycididazole are made with extra care
A, 13.4 kilograms of Glycididazole crude product wet feeds are put in 200 liters of reactors, added the dissolving that refluxes of 65 kilograms of DMF, 50 kilograms of purified water and a small amount of strong aqua, add 0.4 kilogram of activated carbon decolorizing, filtered while hot.Filtrate is put in 200 liters of crystallizers, and interlayer leads to water coolant, and feed liquid is cooled to 30 ℃.Stir adding 15% dilute hydrochloric acid and transfer pH2～5, cold putting (＜5 ℃) separated out crystallization;
B, precipitation drying dehydration are washed till neutrality with about 200 kilograms of purified water;
C, 60～70 ℃ of oven dry get 8.04 kilograms of white powder crystallization Glycididazoles (highly finished product) (16.2mol), 116～118 ℃ of fusing points, yield 75.0%.
Preparation-the salt-forming reaction of embodiment 7, sodium glycididazole
A, in 100 liters of reactors, add 25 kilograms of purified water, 30 kilogram of 95% ethanol, be warming up to 80 ℃ after, add 6.09 kilograms of (12.9mol) Glycididazoles, after stirring, add 1.0 kilograms of sodium bicarbonate powder gradually, in 80 ℃ of stirring and dissolving.Dissolving finishes and adds 0.5 kilogram of gac, reacts 0.5 hour.
B, filtered while hot, mother liquor are put in 200 liters of crystallizers, are cooled to about 30 ℃, stir to add 25 kilograms of dehydrated alcohols, and cold putting (0～5 ℃) separated out crystallization.
C, drying collecting precipitation are with dehydrated alcohol (needing 25 kilograms approximately) washing.
D, vacuum-drying get 5.22 kilograms of sodium glycididazole crude products (9.11moL), yield 74.5%.
Preparation-the salt-forming reaction of embodiment 8, sodium glycididazole
A, in 100 liters of reactors, add 35 kilograms of purified water, 20 kilogram of 95% ethanol, be warming up to 60 ℃ after, add 7.14 kilograms of (14.3mol) Glycididazoles, after stirring, add 2.5 kilograms of sodium bicarbonate powder gradually, in 60 ℃ of stirring and dissolving.Dissolving finishes and adds 0.5 kilogram of gac, reacts 0.5 hour.
B, filtered while hot, mother liquor are put in 200 liters of crystallizers, are cooled to about 17 ℃, stir to add 50 kilograms of dehydrated alcohols, and cold putting (＜5 ℃) separated out crystallization.
C, drying collecting precipitation are with dehydrated alcohol (needing 25 kilograms approximately) washing.
D, vacuum-drying get 6.33 kilograms of sodium glycididazole crude products (10.6moL), yield 77.0%.
Preparation-the salt-forming reaction of embodiment 9, sodium glycididazole
A, in 100 liters of reactors, add 45 kilograms of purified water, 10 kilogram of 95% ethanol, be warming up to 40 ℃ after, add 8.04 kilograms of (16.2mol) Glycididazoles, after stirring, add 4.0 kilograms of sodium bicarbonate powder gradually, in 40 ℃ of stirring and dissolving.Dissolving finishes and adds 0.5 kilogram of gac, reacts 0.5 hour.
B, filtered while hot, mother liquor are put in 200 liters of crystallizers, are cooled to about 5 ℃, stir to add 75 kilograms of dehydrated alcohols, and cold putting (0～5 ℃) separated out crystallization.
C, drying collecting precipitation are with dehydrated alcohol (needing 25 kilograms approximately) washing.
D, vacuum-drying get 7.36 kilograms of sodium glycididazole crude products (12.3moL), yield 79.5%.
Making with extra care of embodiment 10, sodium glycididazole
5.22 kilograms of sodium glycididazole crude products are dropped into 50 liters of reactors, add 20 kilograms of purified water, 30 kilograms of dehydrated alcohols, be heated to 80 ℃ under stirring, stir and make dissolving fully, stirring adds 0.3 kilogram of activated carbon, is incubated filtered while hot after 30 minutes.Filtrate is put in 100 liters of crystallizers, is cooled to 30 ℃, stirs to add 25 kilograms of dehydrated alcohols, and cold putting (0～5 ℃) separated out crystallization.Centrifuging and collecting precipitation are put in the vacuum drying oven, in 60～70 ℃/20mmHg drying, get 4.19 kilograms of the Powdered sodium glycididazoles of class Bai Zhiwei yellow crystal, yield 80.3%.
Making with extra care of embodiment 11, sodium glycididazole
6.33 kilograms of sodium glycididazole crude products are dropped into 50 liters of reactors, add 27 kilograms of purified water, 20 kilograms of dehydrated alcohols, be heated to 60 ℃ under stirring, stir and make dissolving fully, stirring adds 0.3 kilogram of activated carbon, is incubated filtered while hot after 30 minutes.Filtrate is put in 100 liters of crystallizers, is cooled to 17 ℃, stirs to add 45 kilograms of dehydrated alcohols, and cold putting (0～5 ℃) separated out crystallization.Centrifuging and collecting precipitation are put in the vacuum drying oven, in 60～70 ℃/20mmHg drying, get 5.25 kilograms of the Powdered sodium glycididazoles of class Bai Zhiwei yellow crystal, yield 83.0%.
Making with extra care of embodiment 12, sodium glycididazole
7.36 kilograms of sodium glycididazole crude products are dropped into 50 liters of reactors, add 35 kilograms of purified water, 10 kilograms of dehydrated alcohols, be heated to 40 ℃ under stirring, stir and make dissolving fully, stirring adds 0.3 kilogram of activated carbon, is incubated filtered while hot after 30 minutes.Filtrate is put in 100 liters of crystallizers, is cooled to 5 ℃, stirs to add 65 kilograms of dehydrated alcohols, and cold putting (0～5 ℃) separated out crystallization.Centrifuging and collecting precipitation are put in the vacuum drying oven, in 60～70 ℃/20mmHg drying, get 6.28 kilograms of the Powdered sodium glycididazoles of class Bai Zhiwei yellow crystal, yield 85.3%.
Claims (2)
1, a kind of sodium glycididazole synthesis technique is characterized in that this technology comprises the following steps:
(1) preparation-esterification of Glycididazole
A, in 100 liters of reactors, add 6.0～8.0 kilograms of nitrilotriacetic acid(NTA)s (I, 31.4～41.8mol), 12～20 kilograms of 30 kilograms of DMF and diacetyl oxides (118～196mol), in 50～80 ℃ of insulated and stirred reactions 2～6 hours;
14.0～22.0 kilograms (81.8～128mol) in reactor, continues insulated and stirred reaction 3～7 hours in 40～80 ℃ for B, adding metronidazole;
After C, reaction finish, the logical cold water cooling of interlayer reaction feed liquid;
D, reaction solution are chilled to 30 ℃, add purified water, have been stirred to precipitation and have separated out, cold putting＜5 ℃, 12 hours;
E, precipitation drying dehydration are washed to neutrality;
Get Glycididazole crude product, 9.18～13.4 kilograms of weight in wet bases, yield 47.0～51.4% after F, the centrifugation;
(2) Glycididazole is refining
A, Glycididazole crude product wet feed is put in 200 liters of reactors, added 35～65 kilograms of DMF, 50～80 kilograms of purified water and the dissolving of a small amount of strong aqua reflux, add 0.4 kilogram of activated carbon decolorizing, filtered while hot.Filtrate is put in 200 liters of crystallizers, and interlayer leads to water coolant, and feed liquid is cooled to 0～30 ℃.Stir and add 15% dilute hydrochloric acid accent pH2～5, cold putting (＜5 ℃) crystallization;
B, precipitation drying dehydration are washed till neutrality with about 200 kilograms of purified water;
C, 60～70 ℃ of oven dry, 6.09～8.04 kilograms of white powder crystallization Glycididazoles (highly finished product) (12.2～16.2mol), 116～118 ℃ of fusing points, yield 75.0～83.0%;
(3) preparation-salt-forming reaction of sodium glycididazole
A, in 100 liters of reactors, add 25～45 kilograms of purified water, 10～30 kilogram of 95% ethanol, after being warming up to 40～80 ℃, add 8.7 kilograms of (21.5mol) Glycididazoles, after stirring, add 1～4 kilogram of sodium bicarbonate powder gradually, in 40～80 ℃ of stirring and dissolving.Dissolving finishes and adds 0.5 kilogram of gac, reacts 0.5 hour;
B, filtered while hot, mother liquor are put in 200 liters of crystallizers, are cooled to 5～30 ℃, stir to add 25～75 kilograms of dehydrated alcohols, and cold putting (0～5 ℃) separated out crystallization;
C, drying collecting precipitation are with dehydrated alcohol (needing 25 kilograms approximately) washing;
D, vacuum-drying get 5.22～7.36 kilograms of sodium glycididazole crude products (9.10～12.8moL), yield 74.5～79.5%;
(4) sodium glycididazole is refining
7.6 kilograms of sodium glycididazole crude products are dropped into 50 liters of reactors, add 20～35 kilograms of purified water, 10～35 kilograms of dehydrated alcohols, be heated to 40～80 ℃ under stirring, stirring makes dissolving fully, stir and add 0.3 kilogram of activated carbon, be incubated filtered while hot after 30 minutes, filtrate is put in 100 liters of crystallizers, be cooled to 5～30 ℃, stir 25～60 kilograms of adding dehydrated alcohols, cold putting (0～5 ℃) separated out crystallization, centrifuging and collecting precipitation are put in the vacuum drying oven, in 60～70 ℃/20mmHg drying, get 4.19～6.28 kilograms of the Powdered sodium glycididazoles of class Bai Zhiwei yellow crystal, yield 80.3～85.3%.
2, a kind of sodium glycididazole that makes by the described method of claim 1 has application in chemotherapy sensitizing and the radiation sensitization medicine in preparation.
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| CN102190626A (en) * | 2010-03-15 | 2011-09-21 | 南京莱因医药科技有限公司 | Synthesis method of sodium glycididazole |
| CN104356070A (en) * | 2014-12-05 | 2015-02-18 | 江苏艾凡生物医药有限公司 | Synthesis method of sodium glycididazole |
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| CN1270062A (en) * | 1999-04-08 | 2000-10-18 | 广州山河药业股份有限公司 | Glycobiazole metal salt as synergist for radiotherapy or chemicotherapy and its preparing process and application |
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| CN102190626A (en) * | 2010-03-15 | 2011-09-21 | 南京莱因医药科技有限公司 | Synthesis method of sodium glycididazole |
| CN104356070A (en) * | 2014-12-05 | 2015-02-18 | 江苏艾凡生物医药有限公司 | Synthesis method of sodium glycididazole |
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