CN103232494A - Oxaliplatin preparation method - Google Patents
Oxaliplatin preparation method Download PDFInfo
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- CN103232494A CN103232494A CN2012101601302A CN201210160130A CN103232494A CN 103232494 A CN103232494 A CN 103232494A CN 2012101601302 A CN2012101601302 A CN 2012101601302A CN 201210160130 A CN201210160130 A CN 201210160130A CN 103232494 A CN103232494 A CN 103232494A
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- Prior art keywords
- trans
- cyclohexanediamine
- reaction
- handed
- suction filtration
- Prior art date
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- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 17
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 22
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 8
- 239000011591 potassium Substances 0.000 claims abstract description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 7
- 229910001961 silver nitrate Inorganic materials 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000000967 suction filtration Methods 0.000 claims description 18
- 229960004839 potassium iodide Drugs 0.000 claims description 8
- 235000007715 potassium iodide Nutrition 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 abstract description 7
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 102100028735 Dachshund homolog 1 Human genes 0.000 abstract 1
- 101000915055 Homo sapiens Dachshund homolog 1 Proteins 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 239000013064 chemical raw material Substances 0.000 abstract 1
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 4
- 238000013019 agitation Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 description 2
- 229910021612 Silver iodide Inorganic materials 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940045105 silver iodide Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 101710134784 Agnoprotein Proteins 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000029565 malignant colon neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Substances OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- -1 silver ions Chemical class 0.000 description 1
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 1
- 229940039790 sodium oxalate Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the field of pharmaceutical engineering, and discloses an oxaliplatin preparation method. According to the invention, potassium chloroplatinite is adopted as a raw material, and is subjected to a reaction with trans-L-1,2-cyclohexanediamine and potassium iodide according to a molar ratio of 1:1:6.02, such that cis-diiodo(trans-L-cyclohexanediamine)platinum is produced; under a dark condition, an aqueous solution of silver nitrate is added, and a reaction is carried out for 12-18h; pump filtration is carried out, and active carbon is added into the filtrate for purifying and decolorizing; potassium oxalate is added into the filtrate, and a reaction is carried out for 4h under room temperature; and a filter cake is vacuum-dried to constant weight. A molar ratio is that Pt(DACH)I2: AgNO3: K2C2O4 = 1:2:1.2. The method has the advantages of simple process flow, high synthesis yield, and suitability for industrial productions using chemical raw material reagents.
Description
Technical field
The present invention relates to the synthetic preparation of antitumor drug oxaliplatin.
Background technology
Oxaliplatin has another name called RP-54780, and English name Oxaliplatin is abbreviated as L-OHP, and full name is that cis-oxalic acid (trans-(-)-1,2---hexanaphthene) closes platinum, and molecular weight is C
8H
14N
2O
4Pt, its structural formula is:
Oxaliplatin is the earliest by Switzerland Debiopharm company exploitation, gets permission to be mainly used in treating the transitivity cancer of colon for clinical in France in 1997, is used for clinical in a plurality of countries and address approval at present.
Volume 6 periodicals carried in 1989 the 14th " Oxaliplatin " and " synthesizing and structural characterization of RP-54780 " two pieces of disclosed oxaliplatins of document of 21 first phases phase of " precious metal " end of the year 2000 publication synthetic be that to close platinum with cis-dichloro (trans-left-handed-cyclohexanediamine) be intermediate, add Silver Nitrate, remove by filter silver-colored throw out, add sodium oxalate in the mother liquor, reaction generates the aqueous solution of oxaliplatin, and concentrating under reduced pressure obtains the oxaliplatin product.
Characteristics such as this technology exists yield low, and impurity is many.
Summary of the invention
In view of this, the invention provides the high method for preparing oxaliplatin of a kind of yield.
Step 1. potassium chloroplatinite is raw material, with trans-left-handed-1,2-cyclohexanediamine and potassiumiodide reaction generate cis-diiodo-(trans-left-handed-cyclohexanediamine) and close platinum.
Step 2. cis-diiodo-(trans-left-handed-cyclohexanediamine) closes platinum adds Silver Nitrate under the lucifuge condition reactant aqueous solution 12-18h, adds excessive activated carbon purification decolouring behind the suction filtration.
Reaction raw materials mol ratio potassium chloroplatinite in the step 1 of the present invention: trans-left-handed-1,2-cyclohexanediamine: potassiumiodide=1: 1: 6.02, adding excessive potassiumiodide can make reaction more complete, productive rate is higher, simultaneously can with step 2 in the money market ionic reaction, remove silver ions residual in the solution.
In the step 2 of the present invention the growth in reaction times can intermediate reaction more complete, improve productive rate, suction filtration can be removed the Silver iodide of precipitation, adds gac simultaneously and can remove the Silver iodide that suspend in the solution and excessive I
-Ion.Add potassium oxalate in the suction filtration rear filtrate, the reaction back suction filtration that finishes with small amount of ethanol and the washing of a small amount of frozen water, is drained final vacuum and is dried to constant weight and namely gets oxaliplatin.
Embodiment
Reagent and material that invention is adopted
1.K
2PtCl
4, molecular weight is 415.09, specification 46.51%, sealing, drying, room temperature preservation
Trans-left-handed-1,2-cyclohexanediamine, molecular weight are 114.19, specification 99.4%, low-temperature dark is preserved.
3.KI, commercially available, analytical pure.
4.AgNO
3, commercially available, analytical pure.
5.K
2C
2O
4, commercially available, analytical pure.
Embodiment 1:
Take by weighing the inferior potassium platinate of 53.5g tetrachloro, pour in the 2L four-hole bottle, measure the 516ml deionized water again and add in the four-hole bottle, feed nitrogen protection, open and stir.Take by weighing the 129.4g potassiumiodide and put into beaker and add the 258ml deionized water, add in the four-hole bottle room temperature reaction 30min after the dissolving fully.Take by weighing 14.7g trans-left-handed-1, the 2-cyclohexanediamine, with adding after the 64.5ml water dissolution in the four-hole bottle, room temperature reaction 5h, reaction finishes, suction filtration, 50 ℃ of vacuum-dryings are to constant weight behind deionized water and the absolute ethanol washing filter cake.
Gained 70.9g cis-diiodo-(trans-left-handed-cyclohexanediamine) is closed platinum and 42.8g Silver Nitrate lucifuge reaction 12-18h, add 0.71g gac magnetic agitation 15min behind the cooling suction filtration, add the 27.7g potassium oxalate behind the suction filtration again, stirring at room 4h, suction filtration after reaction finishes, 35 ℃ of vacuum-dryings of filter cake are to constant weight.Get oxaliplatin 38.0g, productive rate 76%.
Embodiment 2:
Take by weighing the inferior potassium platinate of 80.25g tetrachloro, pour in the 3L four-hole bottle, measure the 760ml deionized water again and add in the four-hole bottle, feed nitrogen protection, open and stir.Take by weighing the 193.5g potassiumiodide and put into beaker and add the 380ml deionized water, add in the four-hole bottle room temperature reaction 30min after the dissolving fully.Take by weighing 22.05g trans-left-handed-1, the 2-cyclohexanediamine, with adding after the 95ml water dissolution in the four-hole bottle, room temperature reaction 5h, reaction finishes, suction filtration, 50 ℃ of vacuum-dryings are to constant weight behind deionized water and the absolute ethanol washing filter cake.
Gained 106.7g cis-diiodo-(trans-left-handed-cyclohexanediamine) is closed platinum and 64.4g Silver Nitrate lucifuge reaction 12-18h, add 1.1g gac magnetic agitation 15min behind the cooling suction filtration, add the 41.6g potassium oxalate behind the suction filtration again, stirring at room 4h, suction filtration after reaction finishes, 35 ℃ of vacuum-dryings of filter cake are to constant weight.Get oxaliplatin 54.8g, productive rate 73%.
Embodiment 3:
Take by weighing the inferior potassium platinate of 133.75g tetrachloro, pour in the 5L four-hole bottle, measure the 1280ml deionized water again and add in the four-hole bottle, feed nitrogen protection, open and stir.Take by weighing the 322.5g potassiumiodide and put into beaker and add the 640ml deionized water, add in the four-hole bottle room temperature reaction 30min after the dissolving fully.Take by weighing 36.75g trans-left-handed-1, the 2-cyclohexanediamine, with adding after the 160ml water dissolution in the four-hole bottle, room temperature reaction 5h, reaction finishes, suction filtration, 50 ℃ of vacuum-dryings are to constant weight behind deionized water and the absolute ethanol washing filter cake.
Gained 176.8g cis-diiodo-(trans-left-handed-cyclohexanediamine) is closed platinum and 106.7g Silver Nitrate lucifuge reaction 12-18h, add 1.8g gac magnetic agitation 15min behind the cooling suction filtration, add the 69.0g potassium oxalate behind the suction filtration again, stirring at room 4h, suction filtration after reaction finishes, 35 ℃ of vacuum-dryings of filter cake are to constant weight.Get oxaliplatin 92.0g, productive rate 74%.
Prove by experiment: it is simple that the inventive method prepares the oxaliplatin technical process, and the synthetic yield height has overcome the existing great drawback of prior preparation method.
If the content that is not described in detail is arranged, should be those skilled in the art's technique known in this specification sheets, repeat no more herein.
Claims (3)
1. method for preparing oxaliplatin
Step 1. is raw material with the potassium chloroplatinite, with trans-left-handed-1,2-cyclohexanediamine and potassiumiodide reaction generate cis-diiodo-(trans-left-handed-cyclohexanediamine) and close platinum.
Step 2. cis-diiodo-(trans-left-handed-cyclohexanediamine) closes platinum adds Silver Nitrate under the lucifuge condition reactant aqueous solution 12-18h, adds excessive activated carbon purification decolouring behind the suction filtration.
2. preparation method according to claim 1 is characterized in that mol ratio potassium chloroplatinite in the step 1: trans-left-handed-1, and 2-cyclohexanediamine: potassiumiodide=1: 1: 6.02.
3. preparation method according to claim 1 is characterized in that in the step 2, adds the activated carbon purification removal of impurities in the suction filtration rear filtrate several times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101601302A CN103232494A (en) | 2012-05-22 | 2012-05-22 | Oxaliplatin preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101601302A CN103232494A (en) | 2012-05-22 | 2012-05-22 | Oxaliplatin preparation method |
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| Publication Number | Publication Date |
|---|---|
| CN103232494A true CN103232494A (en) | 2013-08-07 |
Family
ID=48880573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101601302A Pending CN103232494A (en) | 2012-05-22 | 2012-05-22 | Oxaliplatin preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103232494A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634945A (en) * | 2004-11-08 | 2005-07-06 | 昆明贵金属研究所 | Synthesis of Oxaliplatin |
| CN1680411A (en) * | 2004-02-05 | 2005-10-12 | W.C.贺利氏有限公司 | Process for the preparation of 1,2-diaminocyclohexane-platinum(ii) complexes |
| CN101054396A (en) * | 2007-05-28 | 2007-10-17 | 江苏恒瑞医药股份有限公司 | Method of preparing oxaliplatin |
| CN101612146A (en) * | 2009-07-22 | 2009-12-30 | 山东罗欣药业股份有限公司 | A kind of oxaliplatin medicament composition and preparation method thereof, and the synthetic method of crude drug oxaliplatin |
| WO2010081924A1 (en) * | 2009-01-13 | 2010-07-22 | Capital, Business Y Gestión De Finanzas, S.L. | Process for preparing pharmaceutical-grade neutral platinum (ii) antineoplastic derivatives having low silver content |
-
2012
- 2012-05-22 CN CN2012101601302A patent/CN103232494A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680411A (en) * | 2004-02-05 | 2005-10-12 | W.C.贺利氏有限公司 | Process for the preparation of 1,2-diaminocyclohexane-platinum(ii) complexes |
| CN1634945A (en) * | 2004-11-08 | 2005-07-06 | 昆明贵金属研究所 | Synthesis of Oxaliplatin |
| CN101054396A (en) * | 2007-05-28 | 2007-10-17 | 江苏恒瑞医药股份有限公司 | Method of preparing oxaliplatin |
| WO2010081924A1 (en) * | 2009-01-13 | 2010-07-22 | Capital, Business Y Gestión De Finanzas, S.L. | Process for preparing pharmaceutical-grade neutral platinum (ii) antineoplastic derivatives having low silver content |
| CN101612146A (en) * | 2009-07-22 | 2009-12-30 | 山东罗欣药业股份有限公司 | A kind of oxaliplatin medicament composition and preparation method thereof, and the synthetic method of crude drug oxaliplatin |
Non-Patent Citations (1)
| Title |
|---|
| 刘霞等: "制备奥沙利铂的一种新工艺", 《中国药学杂志》, vol. 42, no. 20, 31 October 2007 (2007-10-31), pages 1558 - 1560 * |
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Application publication date: 20130807 |