CN1629171A - Novel sunplatinum preparation and its preparation process - Google Patents
Novel sunplatinum preparation and its preparation process Download PDFInfo
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- CN1629171A CN1629171A CN 200410838960 CN200410838960A CN1629171A CN 1629171 A CN1629171 A CN 1629171A CN 200410838960 CN200410838960 CN 200410838960 CN 200410838960 A CN200410838960 A CN 200410838960A CN 1629171 A CN1629171 A CN 1629171A
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- heptan
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Abstract
The invention discloses a novel process for preparing sunplatinum preparation, which can be applied for preparing low-cost, high-quality raw material medicament of sunplatinum. The invention also provides a novel sunplatinum preparation, i.e. sunplatinum injection.
Description
Background of invention
Malignant tumour is one of topmost disease that threatens at present the human life.According to statistics, in the whole world 5,800,000,000 populations in 1996, because of tumour dead have 630 surplus ten thousand people, wherein nearly 60% dies from lung cancer, cancer of the stomach, mammary cancer, colorectal carcinoma, oral carcinoma, liver cancer, cervical cancer, die from tumour person and account for more than 12% of total death toll, for being only second to the second largest cause of the death of cardiovascular disorder.In China, cancer also is the second largest cause of the death of population.China's population cause of death of announcing in 1997, the sample survey result shows, China's the nineties population tumor mortality rate is 124.4610 ten thousand, its percentage that accounts for total cause of the death rises to 17.64% from 12.57% of the seventies, wherein the mortality ratio of cancer of the stomach, liver cancer, lung cancer, these four kinds of cancers of the esophageal carcinoma is 92.06/10 ten thousand, accounts for 73.97% of whole cancer mortalities.In recent years, along with the deterioration of environment and a large amount of uses of hormone, cancer morbidity more becomes ascendant trend.Therefore, the exploitation cancer therapy drug, the broad-spectrum anti-cancer drug that especially can treat the high cancer of the stomach of sickness rate (accounting for cancer general mortality rate 21.76%), liver cancer (17.83%), lung cancer (11.19%), the esophageal carcinoma (15.02%) has good society and economic benefit undoubtedly.
Since it is found that cis-platinum had antitumour activity in 1967, the application of platinum metals cancer therapy drug and research have obtained development rapidly.Today, cis-platinum and carboplatin have become indispensable medicine in the cancer chemotherapy.In the cancer therapy choice drug of the U.S. and Canada's recommendation, cis-platinum is proposed as choice drug in 18 kinds of cancers such as esophagus cancer, nonsmall-cell lung cancer.
Heptan platinum (Heptaplatin SKI2053R) is the platinum kind anti-cancer drugs of new generation of pharmaceutical industry Co., Ltd. of Korea S SK (Sunkyong Industries) exploitation.On July 22nd, 1999, Korea S registered first, Korea S's Initial Public Offering on October 20 in 1999, and trade(brand)name SImpla, formulation is 50mg, 100mg freeze-dried powder.At first approval is used for and the treatment of 5 FU 5 fluorouracil (5-FU) combined utilization carrying out property, transitivity and postoperative recurrence adenocarcinoma of stomach.Its anti-tumor activity is strong, and renal toxicity is little, solubleness and good stability in the aqueous solution.A large amount of experimentation on animals and clinical studyes show, compare with cis-platinum and carboplatin, and heptan, platinum had following outstanding advantage: heptan, the platinum antineoplastic effect was strong, and toxic side effect is little, and clinical efficacy is good.
Heptan, the compound patent of platinum was that pharmaceutical industry Co., Ltd. of Korea S SK (SunkyongIndustries) applied on December 30th, 1991, priority date on March 23rd, 1991, patent No. WO9216539A1; And on March 22nd, 1992 at China application patent families CN1065274A (on October 14th, 1992 is open), on June 3rd, 1998 is granted, publication number CN1038590C.According to China before 93 years patent system approval be preparation technology's patent.
We have developed a new preparation were established, and its novelty and practicality all are better than the patent of pharmaceutical industry Co., Ltd. of Korea S SK.Purpose is the medicine with the domestic urgent need of explained hereafter of independent intellectual property right.
Before this heptan platinum preparation be the injection lyophilized powder, its complicated process of preparation is used inconveniently, the low cost of manufacture of injection liquid is easy to use.
Goal of the invention
The invention provides a kind of new platinum preparation technology in heptan, this operational path method novelty, workable, economy is strong, is produced on a large scale, and quality product is high and stable, and the antitumour drug injection platinum in heptan that can be market in urgent need provides the bulk drug of super quality and competitive price.
The invention provides a kind of new platinum preparation in heptan, low cost of manufacture, easy to use.
Innovation part of the present invention is: (1) synthetic heptan platinum reaction in introduce the one kettle way reaction method, simplified schedule of operation; (2) introduce the calculated amount soda solution grouting during synthetic intermediate 4, generate particulate state LiAlO
2Simplify separable programming, reduced production cost.(3) heptan, cisplatin for injection liquid both reduced production cost, had made things convenient for use again.
Detailed Description Of The Invention
Heptan the platinum synthetic route
Heptan platinum
Embodiment
(1) D-diethyl tartrate (intermediate 2) is synthetic:
Add 330ml dehydrated alcohol, D-tartrate 30.0g (0.2mol), the 1ml vitriol oil, reflux 10 hours in the 500ml there-necked flask.Be chilled to room temperature, add about 7ml 28% ammoniacal liquor in the reaction mixture and transfer PH7-8, restir 30 minutes, the elimination white precipitate, evaporate to dryness filtrate, the fraction of 132-134 ℃/6mmHg is collected in underpressure distillation, gets the 34.2g colorless oil.Molar yield: 83%.[α]
D 20=-9.4 ° (C=1, acetone).
Synthesizing of (2) 2,3-O-isobutylidene-D-diethyl tartrate (intermediate 3):
In the 1000ml there-necked flask, add 525ml dry toluene, 33.0g (0.16mol) D-diethyl tartrate, 72.8ml (0.09mol) isobutyric aldehyde, 51g (0.32mol) anhydrous cupric sulfate (II) and 1g methylsulfonic acid, N
2Protection, stirred overnight at room temperature adds the 3g anhydrous K again
2CO
3Stirred 30 minutes, and filtered, the filtrate evaporate to dryness, the oily resistates with quick silica gel column chromatography purifies (eluent: ether/hexane=1/4), must 25.5 yellow oil.Molar yield: 78%.[α]
D 20=+2.0 ° (C=1, acetone).
(3) (4R, 5R)-4,5-two (methylol)-2-sec.-propyl-1,3-dioxolane (intermediate 4) synthetic:
N
2Protection is suspended in 4.5g (0.12mol) lithium aluminium hydride in the 130ml anhydrous diethyl ether down, stirs 15 minutes.Splash into 23.2g (0.09mol) 2, anhydrous diethyl ether (50ml) solution of 3-O-isobutylidene-D-diethyl tartrate, control adding speed makes exothermic heat of reaction only cause weak backflow, and the time spent was above 30 minutes.Finish, back flow reaction is 6 hours again.The frozen water cooling is stirred down and is slowly dripped the 6.0ml ethyl acetate successively, and 4.3ml 4mol/L NaOH solution has the particulate state precipitation to generate, and filters.Filter residue extracts with the 40ml aether backflow, filters, and gets extracting solution.Merge diethyl ether solution, with anhydrous K
2CO
3Drying is filtered, and filtrate concentrating eliminates solvent, gets 12.8g oily matter.Molar yield: 81%.[α]
D 20=+16.9 ° (C=1, methyl alcohol).
(4) (4R, 5R)-2,3-O-isobutylidene-threitol-1,4-'s two (methylsulfonic acid vinegar) (intermediate 5) is synthetic:
With 11.0g (62.4mmol) (4R, 5R)-4,5-two (methylol)-2-sec.-propyl-1,3-dioxolane are dissolved in the 60ml anhydrous pyridine, temperature control (5 ℃ are added dropwise to methylsulfonyl chloride 17.8g (0.155mol) under stirring.The stirring at room reaction is spent the night.In the 100ml frozen water under reaction solution is poured into and stirred, crystallization 2 hours.The filter collection, washed several times with water, a small amount of absolute ethanol washing is drained, and gets native white crude product.With the dehydrated alcohol heating for dissolving, activated carbon decolorizing, heat filtering, filtrate room temperature crystallization spends the night, filter group body, a small amount of normal hexane washing, the dry 17.8g white crystals that gets.Molar yield: 86%.M.P：69-71℃。[α]
D 20=+24.56 ° (C=1, methyl alcohol).
(5) (4R, 5R)-4,5-two (azido-methyl)-2-sec.-propyl-1,3-dioxolane (intermediate 6) synthetic:
(4R, 5R)-2,3-O-isobutylidene-threitol-1,4-two (methylsulfonic acid vinegar) and 13.0g (0.2mol) sodium azide drop in the reaction flask, N with 80ml dry DMF, 16.6g (0.05mol)
2Under the protection, 100 ℃ of stirring reactions were chilled to room temperature after 8 hours, with the dilution of 80ml water, again with 3 * 100ml extracted with diethyl ether.The ether layer is with the water washing of 2 * 100ml salt.Anhydrous MgSO
4Drying is filtered, the filtrate evaporate to dryness, and residuum is purified (ether/hexane=1/4) with quick silica gel column chromatography, gets pale yellow oily matter 10.2g.Molar yield: 90%.[α]
D 20=+110 ~+112 ° (C=0.04, acetone).
(6) (4R, 5R) 4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane (intermediate 7) synthetic:
With 10.2g (45mmol) (4R, 5R)-4,5-two (azido-methyl)-2-sec.-propyl-1, the 3-dioxolane is dissolved in the 100ml ethanolic soln, adds 10% palladium-charcoal 1g, shortening 2 hours (intermittently emitting the nitrogen of generation) under 40 ℃, about 3.5 normal atmosphere.Reaction is finished, and filters through diatomite layer earlier, uses 0.22 μ m filtering with microporous membrane again, and the filtrate decompression evaporate to dryness gets little yellow oily matter 7.3 grams.Molar yield: 93%.[α]
D 20=+42.9 ° (C=1, methyl alcohol).
(7) cis-[(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] diiodo-closes the synthetic of platinum (II) (intermediate 8):
16.6g (40mmol) potassium platinochloride is dissolved in 780ml water, filters, filtrate joins in the 125ml aqueous solution of 41.3g (0.25mol) KI under stirring, N
2Protection lucifuge was down reacted 30 minutes, got the sour potassium solution of black tetraiodo platinum (II).Other gets (4R, 5R) 4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane 7.0g (40mmol) is dissolved in the 900ml water.
620ml water is added flask, N
2Protection, 60 ℃ and stir fast down simultaneously that constant speed adds above-mentioned two kinds of solution, the time spent is about more than 60 minutes.Finish, continue to stir 1 hour, solid collected by filtration is successively with water, ethanol and ether washing.Lucifuge vacuum-drying gets the 18.4g yellow powder.Molar yield: 73%.[α]
D 20＝-34~-37°(C＝1，DMSO)。
(8) synthesizing of platinum in heptan:
In the 2L there-necked flask, drop into 1600ml water, mechanical stirring, N
2Protection, temperature control is heated to 60 ℃.Add 12.5g (0.02mmol) cis-[(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] diiodo-successively and close platinum (II), 4.6g Ag
2O (0.02mmol), 2.1g (0.02mmol) propanedioic acid, lucifuge stirred 40 hours for 60 ± 5 ℃, and reaction mixture removes the brownish black solid with 0.22 μ m filtering with microporous membrane again after the filter just of silica gel algae soil layer, get the colourless aqueous solution.Be evaporated to about 150ml, filter collects to such an extent that be with light brown off-white color solid, a small amount of washing, and lucifuge vacuum-drying gets 6.4g platinum in heptan crude product, is band light brown off-white color solid.Mother liquor reclaims.Molar yield: 68%.
(9) making with extra care of platinum in heptan:
Get 6.4g platinum in heptan crude product, add and steam full water 385ml,, insolubles is arranged for mouth thermal backflow dissolving.Cold slightly, add the 0.64g gac, refluxed filtered while hot again 20 minutes.Filtrate is chilled to room temperature, has a small amount of white group to separate out, further in 0-5 ℃ of crystallization 2 hours.Filter collection solid, water, ethanol are washed, and lucifuge vacuum-drying gets 5.2g off-white color crystalline powder.Mother liquor reclaims the refining 0.4g off-white color crystalline powder that gets in addition.Refining yield: 87.5%.[α]
D 20＝-47.11°(C＝1，DMSO).
1HNMR(d
6-DMSO)δ(ppm)0.87(d，J＝7.0Hz，2CH
3)，1.75(m，1H，CH(CH
3)
2)，2.57(m，2H，2CHNH
2)，2.98(m，1H，CHNH
2)，3.09(m1H，CHNH
2)，3.27(s，2H，CH
3)4.31(m1H，CH)，4.55(m，1H，CH)，4.80(d，J＝4.5Hz，1H，CH)，5.28(brs，1H，NH)，5.45(brs，1H，NH)，5.49(brs，2H，NH
2)。Heptan cisplatin for injection liquid production method:
1. write out a prescription:
Heptan platinum 50g
N.F,USP MANNITOL 100g
Glycine 50g
Water for injection 10000ml
Make 1000 bottles
2. technology:
(1) 50g platinum in heptan dissolves in the water for injection of 9000ml heat, is chilled to room temperature.
(2) 100g N.F,USP MANNITOL and 50g glycine dissolve in the 800ml water for injection.
(3) merge above-mentioned two kinds of solution, add water for injection to 10000ml, millipore filtration sterile filtration is distributed into 1000 bottles.
Claims (3)
1. heptan provided by the invention the platinum preparation were established, it is characterized in that: heptan, the final step of platinum was closed platinum (II), Ag to cis-[(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] diiodo-in synthetic
2O and propanedioic acid be directly one kettle way reaction in water, makes platinum in heptan.
2. heptan provided by the invention, the platinum preparation were established is characterized in that (4R, 5R)-4,5-two (methylol)-2-sec.-propyl-1 in the synthesis step of 3-dioxolane (intermediate 4), is metered into alkali lye, generates particulate state LiAlO
2
3. the preparation that the invention is characterized in platinum in heptan is an injection liquid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410838960 CN1629171A (en) | 2004-10-22 | 2004-10-22 | Novel sunplatinum preparation and its preparation process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410838960 CN1629171A (en) | 2004-10-22 | 2004-10-22 | Novel sunplatinum preparation and its preparation process |
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| CN1629171A true CN1629171A (en) | 2005-06-22 |
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|---|---|---|---|
| CN 200410838960 Pending CN1629171A (en) | 2004-10-22 | 2004-10-22 | Novel sunplatinum preparation and its preparation process |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100497359C (en) * | 2006-01-06 | 2009-06-10 | 昆明贵研药业有限公司 | Novel synthesis process of anti-cancer Sunpla |
| CN101245083B (en) * | 2008-03-18 | 2012-11-21 | 南京工业大学 | Platinum complex containing 1,3-dioxolane structure, synthesizing process and uses thereof |
| CN104211734A (en) * | 2014-08-10 | 2014-12-17 | 昆明贵研药业有限公司 | Novel synthetic method of antitumor drug heptyl platinum |
| WO2020042079A1 (en) * | 2018-08-30 | 2020-03-05 | Rhodia Operations | Process for preparing solketal amine via direct amination |
-
2004
- 2004-10-22 CN CN 200410838960 patent/CN1629171A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100497359C (en) * | 2006-01-06 | 2009-06-10 | 昆明贵研药业有限公司 | Novel synthesis process of anti-cancer Sunpla |
| CN101245083B (en) * | 2008-03-18 | 2012-11-21 | 南京工业大学 | Platinum complex containing 1,3-dioxolane structure, synthesizing process and uses thereof |
| CN104211734A (en) * | 2014-08-10 | 2014-12-17 | 昆明贵研药业有限公司 | Novel synthetic method of antitumor drug heptyl platinum |
| WO2020042079A1 (en) * | 2018-08-30 | 2020-03-05 | Rhodia Operations | Process for preparing solketal amine via direct amination |
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