CN105153238B - A kind of preparation method of Miboplatin - Google Patents
A kind of preparation method of Miboplatin Download PDFInfo
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Abstract
The invention provides a kind of antitumor medicament platinum (Miriplatin) preparation method：The mixed solution of dimethylformamide and n-butanol is prepared, heating adds Miboplatin crude product, and insulated and stirred obtains Miboplatin crude product solution to being completely dissolved；After solution clarification, add activated carbon and continue insulated and stirred, filtrate is collected in filtering；Filtrate cools, and adds toluene, insulated and stirred；After reaction terminates, cool again, separate out crystal, growing the grain；Growing the grain terminates to continue slow cooling, and growing the grain, suction filtration washs, dries, obtain Miboplatin fine work.The preparation method that the present invention is provided is simple to operate, and yield is higher, and Miboplatin purity reaches more than 99.9%, and maximum single miscellaneous control is below 0.1%, and total miscellaneous control is within 0.2%.
Description
Technical field
The present invention relates to a kind of preparation method of platinum series antineoplastic medicament, more particularly to Miboplatin.
Background technology
Hepatocellular carcinoma is one of most common, recurrence rate very high malignant tumour in the world, occupies global malignant tumour hair
The 5th of sick rate, the cause of the death the 3rd, and in growth trend year by year, more than 62.6 ten thousand person/year, China's number of the infected accounts for the whole world
The 55% of total number of the infected.The characteristics of incidence of hepatocellular carcinoma is generally that HCV or hepatitis type B virus persistent infection cause
Chronic hepatitis, hepatic sclerosis and finally develop into hepatocellular carcinoma.Clinically generally controlled using surgical operations such as hepatotomy, transplanting
Treat；The internal medicine local treatments such as radio-frequency ablation procedure, Percutaneous microwave coagulation therapy, percutaneous Ethanol Injection therapy；It is dynamic through conduit liver
Arteries and veins Chemoembolization (TACE), transcatheter arterial infusion treatment；Systemic chemotherapy.Wherein, TACE is although only can not implement outer
Just used when section's operation or internal medicine local treatment, but the ratio in treating first is 29.6%, recurs and controls in liver
53.3% is accounted in treatment, its critical role has some idea of.TACE is to move the mixture of cancer therapy drug and lipiodol from liver
Injection focus in arteries and veins, while injecting the embolization materials such as gelfoam blocks artery, cuts off artery blood flow, reaches and cause neoplasm necrosis
Purpose.Cancer therapy drug for TACE has doxorubicin hydrochloride, epirubicin hydrochloride, mitomycin, cis-platinum, Zinostatin stimalamer
Deng.Wherein, platinum-containing anticancer drug cis-platinum is widely used because of its efficient active anticancer with broad spectrum anticancer effect, to hepatocellular carcinoma
Also good clinical effectiveness is shown, but its water miscible feature causes it using the physically stable that lipiodol is carrier
Property is severely impacted；Zinostatin stimalamer is unique as with lipiodol fatty-acid ethyl ester (ethyl ester of
Iodinated poppy-seed oil fatty acid) got the Green Light for carrier, by the cancer therapy drug of arteria hepatica drug administration by injection
, approved from antitumous effect after listing in 1994, but the medicine presence may cause arteria hepatica injury of blood vessel, to liver and gall system
The problems such as influence of system is irreversible, has an impact, drug safety has hidden danger to treatment and prognosis later.Therefore, find and iodine
Change the medicine that poppy seed oil aliphatic acid ethyl ester compatibility is high, anticancer effect is small no less than Zinostatin stimalamer, prognosis safety, hidden danger
Thing turns into the fresh target of medicament research and development.
Miboplatin (english name Miriplatin, CAS 141977-79-9), chemical name is：Cis- [(1R, 2R) -1,2-
Cyclohexanediamine-N, N '] double myristoyl epoxides close platinum monohydrates, be by SUMITOMO CHEMICAL Pharmaceutical Co., Ltd develop it is a kind of new
Liposoluble platinum (II) series antineoplastic medicament, code name is SM-11355.The kind is in 2009 in the granted listing of Japan, and clinic is main
It is used for the treatment of liver cancer.The characteristics of Miboplatin is fat-soluble good, and toxic side effect is small.Miboplatin-lipiodol emulsion is to advanced liver cancer
Effective percentage 56%, toxicity is mainly neutropenia and total bilirubin rise, and patient can be resistant to well.
Research shows, Miboplatin keeps stable after being mixed with distal embolization agent Lipiodol, Miboplatin/Lipiodol both bolts
Plug supply artery of the tumor can slowly discharge anticarcinogen again, optionally in liver cancer tissue, long-time can be kept to have by extended stationary periods
The drug concentration of effect, embolism complements each other with chemotherapy, promotes mutually, while also effectively reducing other platinum series antineoplastic medicaments
The shortcoming of toxic side effect acutely with generation drug resistance.
Miboplatin-Lipiodol trans-hepatic arteries are subjected to embolism chemical therapeutic and treat inoperable hepatocellular carcinoma patient, with
Cis-platinum-the Lipiodol or styrene maleic acid brand-new rhzomorph-Lipiodol of document report add the curative effect of gelfoam close to and
Toxicity is obviously reduced.Certain dose of therapeutic equivalence is thrown, Miboplatin-Lipiodol Cmax is cis-platinum-Lipiodol
1/300；And both reach that Cmax time is 8-37 days and 10-60 minutes.In addition, pharmacokinetics shows, Miboplatin is swollen
The drug concentration of tumor tissue is six times of nonneoplastic tissue.Miboplatin-Lipiodol is by avoiding the peak valley effect of drug concentration (prominent
Release effect) and play continual and steady effect, and the synergy for the lipid targeted system imitated due to structure, make patient obtain compared with
High curative effect and lower toxic side effect.
The preparation method of the Miboplatin of currently available technology report mainly has following several：
European patent 0193936A1 (Priority Patent JP43869/85) is disclosed, and is with 1,2- diamines butylcyclohexanes
Initiation material, with chloroplatinous acid nak response be made two chloro- 1,2- diamines butylcyclohexanes close after platinum obtained with nitric acid silver reaction dinitro-
1,2- diamines butylcyclohexane closes platinum, filters off precipitation, is then added into the aqueous suspension containing Sodium myristate, room temperature
Lucifuge reacted for three weeks, filtered out solid, washes, is dried under reduced pressure and produces Miboplatin crude product.
The preparation technology is for initiation material, containing substantial amounts of suitable in Miboplatin crude product with 1, the 2- diamines butylcyclohexane of mixing
Trans isomer and enantiomter, and gained Miboplatin has a small amount of silver ion residual.
The method of international monopoly WO94/14470 reports, is that cis-[two iodo- (1R, 2R) -1,2- cyclohexanediamine] is closed into platinum
(II) it is suspended in chloroform and reacts with myristic acid silver, remove after the silver iodide formed, concentrating filter liquor processing obtains Miboplatin.
Due to initiation material it is cis-[two iodo- (1R, 2R) -1,2- cyclohexanediamine] closes platinum (II) and myristic acid is silver-colored in chlorine
It is almost insoluble in imitative, cause the reaction to carry out extremely slow, and product purity is relatively low, is not suitable for industrialized production.In addition, passing through the party
The Miboplatin that method is prepared has a small amount of silver ion residual, while also having harmful chloroform residual.
Method disclosed in Japan Patent JP11315088 and JP2004083508, be in water by it is cis-[dichloro- (1R,
2R) -1,2- cyclohexanediamine] close platinum and nitric acid silver reaction and obtain cis-[dinitric acid (1R, 2R) -1,2- cyclohexanediamine] to close platinum molten
Liquid, is then added to myristic acid, chloroform and Strong oxdiative nak response, and post processing obtains Miboplatin.
Water is insoluble in because myristic acid is dissolved in chloroform, so reaction is substantially carried out in two-phase, the reaction time is long,
And yield is low.Multi-solvents are added in course of reaction, and use the larger chloroform of toxicity, post processing trouble is unfavorable for final production
Product it is refined.
Preparation method disclosed in Chinese patent 201010185779.0, is with cis-[two iodo- ((1R, 2R) -1,2- hexamethylenes
Diamines)] platinum (II) (Cycloplatin) is closed for reactant, by ion exchange generation dihydroxy compounds after being hydrolyzed through silver nitrate, then with
Positive ten tetra-carbonic reacts about 3~5 hours at 50~60 DEG C, and obtained white solid is filtrated to get into Miboplatin solid.The party
Method is related to the steps such as multiple times of filtration, ion exchange, troublesome poeration and reduces product yield.In addition, silver nitrate consumption is big, increase
Financial cost, and the Miboplatin for preparing has a small amount of silver ion residual.
The preparation technology that Chinese patent 201010039194.8 is disclosed is with cis-[two iodo- ((1R, 2R) -1,2- hexamethylenes
Diamines)] platinum (II) (Cycloplatin) is closed for reactant, after addition suitable quantity of water stirs, mercurous nitrate is slowly added to, at 50~60 DEG C
Lower reaction about 3~5 hours, filtering adds positive ten tetra-carbonics solution, reacts post processing in about 6~7 hours and obtains Miboplatin solid.Should
Method has been used to human body and environment harmful mercurous nitrate, limits large-scale production.
Synthetic method disclosed in Chinese patent 201010249760.8, is with cis-[dinitric acid (1R, 2R) -1,2- hexamethylenes
Diamines] close platinum (II) solution and myristate and react in a solvent and obtain Miboplatin crude product.The Miboplatin meeting that this method is prepared
There is a small amount of silver ion residual.
J.Coord.Chem.1993,29：The preparation method of 1-6 reports, be by potassium chloroplatinite and KI with (1R,
2R) -1,2- diamines butylcyclohexane reaction, is made two iodo- (1R, 2R) -1,2- diamines butylcyclohexanes and closes platinum, then by tetradecylic acid sodium
With nitric acid silver reaction, tetradecylic acid silver is made.Two iodo- (1R, 2R) -1,2- diamines butylcyclohexanes close platinum and tetradecylic acid silver in chloroform
Reaction, is made Miboplatin.In the preparation technology, two iodo- (1R, 2R) -1,2- diamines butylcyclohexanes close platinum and tetradecylic acid silver is shown in that light is easy
Discoloration is decomposed, it is not easy to maintain.In addition, the difficulty of this method control silver ion is larger, the Miboplatin prepared has a small amount of silver
Ion residues and harmful solvent chloroform is used.
Chinese Journal of New Drugs, 2011,20 (17)：1715-1717 report synthetic method, be in water by it is cis-[(1R,
2R) -1,2- cyclohexanediamine-diiodo-] close platinum (Cycloplatin) with silver nitrate in 60 DEG C react after be filtrated to get it is cis-[dinitric acid-(1R,
2R) -1,2- cyclohexanediamine] platinum solution is closed, myristic acid sodium solution is then added, 60 DEG C of post-reaction treatments obtain Miboplatin.The party
The difficulty of method control Ag+ ions is big, and the Miboplatin prepared has a small amount of silver ion residual.
Chinese pharmaceutical chemistry magazine, 2011,20 (17)：1715-1717 report synthetic method, be in water by it is cis-
[(1R, 2R) -1,2- cyclohexanediamine-diiodo-] close platinum (Cycloplatin) with sulfuric acid silver reaction after be filtrated to get sulfuric acid it is cis-[two water (1R,
2R)-(-) 1,2- cyclohexanediamine] platinum (II) solution is closed, then add Ba (OH)2·8H2O suspension, be filtrated to get it is cis-
[dihydroxy-(1R, 2R) -1,2- cyclohexanediamine] closes platinum (II) solution, is eventually adding positive ten tetra-carbonics solution reaction, post-processes
To Miboplatin.
Use silver complex more the above method, easily cause silver ion excess, and silver ion is influence platinum antineoplastic medicine
The one of the main reasons of produce quality.And also use chloroform in the preparation method having, to the injury of human body and environment compared with
Greatly.Therefore, effective refined purification is carried out to crude product, to meet the purity requirement of medicinal raw material, as urgent problem.
Miboplatin is insoluble in water, if making solvent with water, it is impossible to the purification to Miboplatin is realized, accordingly, it would be desirable to molten from other
Agent or means purify Miboplatin.
The document purified at present on Miboplatin is rarely reported, and only Chinese patent CN102225954 has been reported.The patent
In the mixed solution that Miboplatin is dissolved in n-butanol and absolute ethyl alcohol, appropriate amount of deionized water is added in the solution after filtering insoluble matter,
Obtain Miboplatin fine work.But its solubility is smaller, recrystallization yield is relatively low, and products obtained therefrom yield is below 70%.
The content of the invention
It is an object of the invention to provide a kind of simple to operate, high income, the good Miboplatin method of purification of purity.
In the synthesis and method of purification of the Miboplatin now reported, Miboplatin yield is not high, and impurity is not removed effectively, it is impossible to full
The requirement of sufficient pharmaceutical preparation.
The present invention solves the above problems by the following technical programs：
A kind of preparation method of Miboplatin, takes the mode of gradient cooling, and specifically, this method comprises the following steps：
1) mixed solution of dimethylformamide and n-butanol is prepared, heating adds Miboplatin crude product, insulated and stirred is to complete
Dissolving, obtains Miboplatin crude product solution；
2) after solution clarification, add activated carbon and continue insulated and stirred, filtrate is collected in filtering；
3) filtrate cools, and adds toluene, insulated and stirred；
4) after reaction terminates, cool again, separate out crystal, growing the grain；
5) growing the grain terminates to continue slow cooling, and growing the grain, suction filtration washs, dries, obtain Miboplatin fine work.
Wherein：Step 1) described in dimethylformamide and n-butanol mixed solution in, dimethylformamide and positive fourth
The volume ratio of alcohol is 1~3 ﹕ 1.
Step 1) described in heating refer to mixed solution being warming up to 130~160 DEG C.
Step 1) described in Miboplatin crude product and mixed solution solid-to-liquid ratio be 1g:7~15ml.
Step 2) in add activated carbon quality be Miboplatin crude product 1~3%；Insulated and stirred speed is 20~30 revs/min
Clock；Mixing time is 20~40 minutes.
Step 3) described in toluene and step 1) in the volume ratio of n-butanol be 0.5~1.5 ﹕ 1；Described addition toluene is
Refer to control rate of addition, the completion of dropping in 20~40 minutes.
Step 3) described in cooling refer to that control time was cooled to 70~90 DEG C in 1~2 hour；Insulated and stirred speed is
10~20 revs/min；Mixing time is 0.5~2 hour.
Step 4) described in the described temperature that cools again be 20~30 DEG C, rearing crystal time is 1~4 hour.
Step 5) described in slow cooling refer to that control time was cooled to -5~5 DEG C in 1~2 hour, rearing crystal time is 1
~4 hours.
The present invention can effectively go the removal of impurity, and reaction condition is gentle, and simple to operate, yield is higher (80~90%),
HPLC purity height (more than 99.9%), single impurity can be controlled below 0.1%, always miscellaneous to control within 0.2%.
According to the Miboplatin obtained by the refined purification of the present invention, the quality of the pharmaceutical preparations being made is high, and production cost is low, can be largely
The adverse reaction of upper reduction tumor patient and medical expense, with certain Social benefit and economic benefit.
Embodiment
The present invention and its advantage are illustrated by the following examples, and those of ordinary skill in the art are to institute of the present invention
The obvious change and modification made are also contained within the present invention.
Embodiment 1：Miboplatin it is refined
Miboplatin crude product used in the present embodiment is prepared using Japan Patent JP11-315088 preparation method, purity 97.18%
(HPLC detections), maximum single miscellaneous 1.86%, total miscellaneous 3.71%.
Process for refining：
1) the mixed solution 60ml (DMF ﹕ n-butanols=2 ﹕ 1) of dimethylformamide and n-butanol is prepared, 145 are warming up to
DEG C, Miboplatin crude product 5.00g is added, insulated and stirred obtains Miboplatin crude product solution to being completely dissolved；
2) after solution clarification, activated carbon 0.10g is added, insulated and stirred is continued 30 minutes with 25 revs/min of speed, mistake
Filter, collects filtrate；
3) filtrate was cooled to 80 DEG C in 1.5 hours, toluene 20ml was added dropwise in 30 minutes, then with 15 revs/min of clock rates
Spend insulated and stirred 1 hour；
4) after reaction terminates, 25 DEG C are cooled to again, separate out crystal, growing the grain 3 hours；
5) after growing the grain terminates, 5 DEG C were cooled in 1 hour, again growing the grain 3 hours, suction filtration is washed, and is dried, is obtained solid
4.40g, yield 88%, purity 99.97% (HPLC detections), maximum single miscellaneous 0.05%, it is always miscellaneous to be less than 0.05%.
Embodiment 2：Miboplatin it is refined
Prepared by preparation method disclosed in Miboplatin crude product international monopoly WO 94/14470 used in the present embodiment, purity 95.89%
(HPLC detections), maximum single miscellaneous 1.71%, total miscellaneous 3.35%.
Process for refining：
1) the mixed solution 60ml (DMF ﹕ n-butanols=3 ﹕ 1) of dimethylformamide and n-butanol is prepared, 140 are warming up to
DEG C, Miboplatin crude product 5.00g is added, insulated and stirred obtains Miboplatin crude product solution to being completely dissolved；
2) after solution clarification, activated carbon 0.05g is added, insulated and stirred is continued 40 minutes with 20 revs/min of speed, mistake
Filter, collects filtrate；
3) filtrate was cooled to 90 DEG C in 1 hour, toluene 15ml was added dropwise in 20 minutes, then with 10 revs/min of speed
Insulated and stirred 2 hours；
4) after reaction terminates, 30 DEG C are cooled to again, separate out crystal, growing the grain 2 hours；
5) after growing the grain terminates, -5 DEG C were cooled in 2 hours, again growing the grain 4 hours, suction filtration is washed, and is dried, is obtained solid
4.30g, yield 86%, purity 99.96% (HPLC detections), maximum single miscellaneous 0.07%, it is always miscellaneous to be less than 0.07%.
Embodiment 3：Miboplatin it is refined
Prepared by preparation method disclosed in Miboplatin crude product European patent 0193936A1 used in the present embodiment, purity 96.76%
(HPLC detections), maximum single miscellaneous 1.58%, total miscellaneous 2.96%.
Process for refining：
1) the mixed solution 50ml (DMF ﹕ n-butanols=1 ﹕ 1) of dimethylformamide and n-butanol is prepared, 150 are warming up to
DEG C, Miboplatin crude product 5.00g is added, insulated and stirred obtains Miboplatin crude product solution to being completely dissolved；
2) after solution clarification, activated carbon 0.15g is added, insulated and stirred is continued 20 minutes with 30 revs/min of speed, mistake
Filter, collects filtrate；
3) filtrate was cooled to 70 DEG C in 2 hours, toluene 25ml was added dropwise in 40 minutes, then with 20 revs/min of speed
Insulated and stirred 0.5 hour；
4) after reaction terminates, 20 DEG C are cooled to again, separate out crystal, growing the grain 4 hours；
5) after growing the grain terminates, 0 DEG C was cooled in 1.5 hours, again growing the grain 2 hours, suction filtration is washed, and is dried, is obtained solid
4.50g, yield 90%, purity 99.98% (HPLC detections), maximum single miscellaneous 0.06%, it is always miscellaneous to be less than 0.08%.
Embodiment 4：Miboplatin it is refined
Miboplatin crude product used in the present embodiment is prepared using the preparation method of Chinese patent 201010185779.0, purity
93.61% (HPLC detections), maximum single miscellaneous 1.23%, total miscellaneous 2.41%.
Process for refining：
1) the mixed solution 75ml (DMF ﹕ n-butanols=1.5 ﹕ 1) of dimethylformamide and n-butanol is prepared, 135 are warming up to
DEG C, Miboplatin crude product 5.00g is added, insulated and stirred obtains Miboplatin crude product solution to being completely dissolved；
2) after solution clarification, activated carbon 0.05g is added, insulated and stirred is continued 25 minutes with 25 revs/min of speed, mistake
Filter, collects filtrate；
3) filtrate was cooled to 85 DEG C in 1.5 hours, toluene 15ml was added dropwise in 25 minutes, then with 18 revs/min of clock rates
Spend insulated and stirred 1.5 hours；
4) after reaction terminates, 23 DEG C are cooled to again, separate out crystal, growing the grain 1 hour；
5) after growing the grain terminates, 5 DEG C were cooled in 2 hours, again growing the grain 1 hour, suction filtration is washed, and is dried, is obtained solid
4.20g, yield 84%, purity 99.97% (HPLC detections), maximum single miscellaneous 0.07%, it is always miscellaneous to be less than 0.09%.
Embodiment 5：Miboplatin it is refined
Miboplatin crude product used in the present embodiment be purchased from Shandong Boyuan Pharmaceutical Co., Ltd., purity 89.55% (HPLC detections), most
It is big by single miscellaneous 1.09%, total miscellaneous 2.21%.
Process for refining：
1) the mixed solution 35ml (DMF ﹕ n-butanols=2.5 ﹕ 1) of dimethylformamide and n-butanol is prepared, 130 are warming up to
DEG C, Miboplatin crude product 5.00g is added, insulated and stirred obtains Miboplatin crude product solution to being completely dissolved；
2) after solution clarification, activated carbon 0.10g is added, insulated and stirred is continued 35 minutes with 28 revs/min of speed, mistake
Filter, collects filtrate；
3) filtrate was cooled to 75 DEG C in 2 hours, toluene 15ml was added dropwise in 35 minutes, then with 13 revs/min of speed
Insulated and stirred 2 hours；
4) after reaction terminates, 28 DEG C are cooled to again, separate out crystal, growing the grain 4 hours；
5) after growing the grain terminates, 0 DEG C was cooled in 1 hour, again growing the grain 1 hour, suction filtration is washed, and is dried, is obtained solid
4.15g, yield 83%, purity 99.96% (HPLC detections), maximum single miscellaneous 0.06%, it is always miscellaneous to be less than 0.09%.
Embodiment 6：Miboplatin it is refined
Miboplatin crude product used in the present embodiment is purchased from Wuhu Nowe chemical technology Co., Ltd, and (HPLC is examined purity 95.12%
Survey), maximum single miscellaneous 0.97%, total miscellaneous 1.89%.
Process for refining：
1) the mixed solution 45ml (DMF ﹕ n-butanols=2 ﹕ 1) of dimethylformamide and n-butanol is prepared, 155 are warming up to
DEG C, Miboplatin crude product 5.00g is added, insulated and stirred obtains Miboplatin crude product solution to being completely dissolved；
2) after solution clarification, activated carbon 0.15g is added, insulated and stirred is continued 30 minutes with 22 revs/min of speed, mistake
Filter, collects filtrate；
3) filtrate was cooled to 70 DEG C in 1.5 hours, toluene 15ml was added dropwise in 30 minutes, then with 10 revs/min of clock rates
Spend insulated and stirred 2 hours；
4) after reaction terminates, 25 DEG C are cooled to again, separate out crystal, growing the grain 4 hours；
5) after growing the grain terminates, 5 DEG C were cooled in 1 hour, again growing the grain 4 hours, suction filtration is washed, and is dried, is obtained solid
4.35g, yield 87%, purity 99.98% (HPLC detections), maximum single miscellaneous 0.05%, it is always miscellaneous to be less than 0.08%.
Embodiment 7：Miboplatin it is refined
Miboplatin crude product used in the present embodiment is purchased from Nanjing Cavan Dixu Biologicgal Enginnering Technology Co., Ltd, purity 96.23%
(HPLC detections), maximum single miscellaneous 1.31%, total miscellaneous 2.35%.
Process for refining：
1) the mixed solution 70ml (DMF ﹕ n-butanols=2.5 ﹕ 1) of dimethylformamide and n-butanol is prepared, 160 are warming up to
DEG C, Miboplatin crude product 5.00g is added, insulated and stirred obtains Miboplatin crude product solution to being completely dissolved；
2) after solution clarification, activated carbon 0.15g is added, insulated and stirred is continued 30 minutes with 25 revs/min of speed, mistake
Filter, collects filtrate；
3) filtrate was cooled to 90 DEG C in 2 hours, toluene 30ml was added dropwise in 35 minutes, then with 20 revs/min of speed
Insulated and stirred 1.5 hours；
4) after reaction terminates, 30 DEG C are cooled to again, separate out crystal, growing the grain 1 hour；
5) after growing the grain terminates, -5 DEG C were cooled in 1.5 hours, again growing the grain 4 hours, suction filtration is washed, and is dried, must be consolidated
Body 4.25g, yield 85%, purity 99.99% (HPLC detections), maximum single miscellaneous 0.07%, it is always miscellaneous to be less than 0.08%.
The Miboplatin crude product that embodiment 8-14 is used is same as Example 1, and the ratio of Miboplatin crude product and mixed solution is strictly according to the facts
Apply described in example, difference is that the solvent burden ratio used is different, the obtained relevant material result of product and yield, as shown in table 1.
Table 1：The refined Miboplatin of different solvents proportioning
Test example：Stability test
1-3 products obtained therefroms of the embodiment of the present invention are taken, are placed under the conditions of 6 ± 2 DEG C, stability is investigated, to long-term 12 months,
Impurity A, C, D, E, F, S in three batches of products, S- isomers and cis- isomers are not detected, maximum in relevant material other impurities
List is miscellaneous, and significant change does not occur with always miscellaneous.Concrete outcome is shown in Table 2：
Listed impurity title and structural formula are as follows in table 2：
Claims (9)
1. a kind of preparation method of Miboplatin, it is characterised in that this method comprises the following steps：
1) mixed solution of dimethylformamide and n-butanol is prepared, heating adds Miboplatin crude product, insulated and stirred is to completely molten
Solution, obtains Miboplatin crude product solution；
2) after solution clarification, add activated carbon and continue insulated and stirred, filtrate is collected in filtering；
3) filtrate cools, and adds toluene, insulated and stirred；
4) after reaction terminates, cool again, separate out crystal, growing the grain；
5) growing the grain terminates to continue slow cooling, and growing the grain, suction filtration washs, dries, obtain Miboplatin fine work.
2. the method as described in claim 1, it is characterised in that：Step 1) described in dimethylformamide and n-butanol mixing
In solution, the volume ratio of dimethylformamide and n-butanol is 1~3 ﹕ 1.
3. the method as described in claim 1, it is characterised in that：Step 1) described in heating refer to mixed solution being warming up to
130~160 DEG C.
4. the method as described in claim 1, it is characterised in that：Step 1) described in Miboplatin crude product and mixed solution solid-to-liquid ratio
For 1g:7~15ml.
5. the method as described in claim 1, it is characterised in that：Step 2) in add activated carbon quality be Miboplatin crude product 1
~3%；Insulated and stirred speed is 20~30 revs/min；Mixing time is 20~40 minutes.
6. the method as described in claim 1, it is characterised in that：Step 3) described in toluene and step 1) in n-butanol volume
Than for 0.5~1.5 ﹕ 1；Described addition toluene refers to control rate of addition, the completion of dropping in 20~40 minutes.
7. the method as described in claim 1, it is characterised in that：Step 3) described in cooling refer to control time at 1~2 hour
Inside it is cooled to 70~90 DEG C；Insulated and stirred speed is 10~20 revs/min；Mixing time is 0.5~2 hour.
8. the method as described in claim 1, it is characterised in that：Step 4) described in the described temperature that cools again be 20~30
DEG C, rearing crystal time is 1~4 hour.
9. the method as described in claim 1, it is characterised in that：Step 5) described in slow cooling refer to control time 1~2
- 5~5 DEG C are cooled in hour, rearing crystal time is 1~4 hour.
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| CN101469004A (en) * | 2007-12-26 | 2009-07-01 | 南京圣和药业有限公司 | Platinum complexes |
| CN102225954A (en) * | 2011-05-05 | 2011-10-26 | 昆明贵研药业有限公司 | Method for purifying platinum |
| CN104119387A (en) * | 2013-04-24 | 2014-10-29 | 正大天晴药业集团股份有限公司 | Preparation method for miriplatin |
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| WO2006023154A1 (en) * | 2004-07-12 | 2006-03-02 | Sicor, Inc. | Cis-diiodo- (trans-l-1,2-cyclohexanediamine) platinum (ii) complex and processes for preparing high purity oxaliplatin |
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| EP0193936A1 (en) * | 1985-03-06 | 1986-09-10 | Sumitomo Pharmaceuticals Company, Limited | Liposoluble platinum (II) complex and preparation thereof |
| CN101469004A (en) * | 2007-12-26 | 2009-07-01 | 南京圣和药业有限公司 | Platinum complexes |
| CN102225954A (en) * | 2011-05-05 | 2011-10-26 | 昆明贵研药业有限公司 | Method for purifying platinum |
| CN104119387A (en) * | 2013-04-24 | 2014-10-29 | 正大天晴药业集团股份有限公司 | Preparation method for miriplatin |
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