CN100398550C

CN100398550C - Novel process for synthesis of oxaliplatin as anticancer medicine

Info

Publication number: CN100398550C
Application number: CNB2006100108295A
Authority: CN
Inventors: 何键; 刘伟平; 李永年; 侯树谦; 普绍平; 刘祝东
Original assignee: KUNMING GUIYAN PHARMACEUTICAL CO Ltd
Current assignee: KUNMING GUIYAN PHARMACEUTICAL CO Ltd
Priority date: 2006-04-18
Filing date: 2006-04-18
Publication date: 2008-07-02
Anticipated expiration: 2026-04-18
Also published as: CN1837223A

Abstract

The present invention relates to a new process for synthesizing platinum class anticarcinogen oxaliplatin (oxaliplatin), which comprises the processes that tetra-platinate M2PtCl4 and trans-1R, 2R-diamine cyclohexane react to generate dichlor trans-1R, 2R-diamine cyclohexane platinum (II), and then, the dichlor trans-1R, 2R-diamine cyclohexane platinum (II) and oxalate react to obtain a target compound of oxaliplatin. The technology has the advantages of short synthetic line, no introduction of heavy metal Ag and Hg which is harmful to a human body, and simple recovery and a high recovery rate of platiniferous waste materials. Platinum class anticarcinogen oxaliplatin (oxaliplatin) can be produced in a large scale. Raw material medicine with high purity is provided for the production of an oxaliplatin preparation.

Description

A kind of synthesis technique of anticarcinogen oxaliplatin

Technical field

The present invention relates to a kind of new synthesis process of platinum kind anti-cancer drugs oxaliplatin (oxaliplatin), belong to field of biological pharmacy.

Background technology

The chemistry of oxaliplatin is called (anti-form-1 R, 2R-diamines hexanaphthene) the oxalic acid root closes platinum (II), be with anti-form-1 R, 2R-diamines hexanaphthene (being called for short DACH) is a carrier, the oxalic acid root is platinum (II) title complex of dissociation group, develop by Switzerland Debiopharm company, take the lead in ratifying listing in France in October, 1996.At present also in Europe and other country's listing of South America.The global marketing volume reached 800,000,000 Euros in 2003.China is in approval oxaliplatin injection in 1999 import, and 15 tame hospital application import drugses have carried out clinical trial at home, and is respond well.In November, 2000, the homemade oxaliplatin that Nanjing Pharmaceutical Plant develops obtains New Drug Certificate and the production certification that National Drug Administration issues, and commodity are called " platinum difficult to understand ", and product has begun to put on market.In recent years, oxaliplatin market growing way is powerful.Ranked leading preceding 50 the medicine ranks of China's sales volume in continuous four season of this medicine in 2003, and rank is in rising trend, arranges the 30th in the fourth quarter in 2003.The sales volume of oxaliplatins in 2005 in prescription drugs market reached 12 more than hundred million.

At present, the oxaliplatin of patent report synthetic all quote platinum kind anti-cancer drugs such as cis-platinum, carboplatin, etc. classical synthetic method [Ernest Wong, Christen M G.Current Status of Platinum-basedAntitumor Drugs.Chem.Rev.1999,99:2451-2466], promptly with K ₂PtCl ₄Be starting raw material, realize by following three steps: (1) adds KI, changes into K ₂PtI ₄,, prepare (DACH) X of corresponding cis-[Pt (II) with carrier group DACH reaction ₂] intermediate (X=Cl, I); (2) intermediate and AgNO ₃Or Ag ₂SO ₄Or Ag ₂The O reaction, filtering separation AgI or AgCl precipitation obtain (DACH) (H of cis-[Pt (II) ₂O) ₂] ²⁺(3) potassium or the sodium salt with the leavings group oxalic acid reacts, and makes the target compound oxaliplatin.Or intermediate is direct and the silver salt reaction of oxalic acid, filtering separation AgI or AgCl precipitation, and mother liquor concentrates and obtains oxaliplatin.

There is following shortcoming and defect in the synthetic method of the oxaliplatin that patent and document adopt: the first, owing to used silver compound in synthetic, can introduce silver-colored impurity in the final oxaliplatin product, and influence the quality of product.Ag-containing compound injection has high toxicity to human body, thus American Pharmacopeia (USP27) and European Pharmacopoeia (EP4) silver content in the platinum kind anti-cancer drugs is limited, as carboplatin Ag＜10ppm; Oxaliplatin Ag＜5ppm.The second, cis-[Pt (II) is X (DACH) ₂] intermediate and the reaction of corresponding silver compound not exclusively, the unreacted platinic compound of 10-20% enters in AgI or the AgCl precipitation.The separation of platiniferous AgI waste residue and recovery are the difficult problems in the metallurgy always, need wet method and pyrogenic process coupling to use the recovery that just can reach Pt, Ag.Because treating processes is long, causes dispersion and the loss of Pt, with K ₂PtCl ₄For starting raw material calculates, the loss of metal platinum reaches 5%, has increased the production cost of oxaliplatin greatly.

Summary of the invention

The object of the invention provides a kind of novel process of not having the synthetic oxaliplatin of silver, with the shortcoming and defect of the method that overcomes patent and bibliographical information.

The novel process of synthetic oxaliplatin of the present invention is: earlier tetrachloro is closed inferior platinate M ₂PtCl ₄With the DACH reaction, generate (DACH) Cl of cis-[Pt (II) ₂], then with oxalate react the target compound oxaliplatin.Chemical reaction that relates to and route are:

M ₂PtCl ₄+DACH→cis-[Pt(II)(DACH)·Cl ₂]

cis-[Pt(II)(DACH)·Cl ₂]+M ₂C ₂O ₄→cis-[Pt(II)(DACH)·C ₂O ₄]

Oxaliplatin

M=K, Na, Li DACH=anti-form-1 R, 2R-diamines hexanaphthene

Synthetic oxaliplatin technology of the present invention is not appeared in the newspapers as yet; belong to novel process; have synthetic route short, do not introduce harmful heavy metal Ag and the platiniferous waste recovery simple; and the platinum rate of recovery reaches the advantage more than 99.5%; be produced on a large scale, provide highly purified bulk drug for producing oxaliplatin formulations.

Embodiment

(1) preparation of dichloro cyclohexanediamine platinum (II)

Get 10g (24mmol) K ₂PtCl ₄Be dissolved in the water of 100ml, the cyclohexanediamine (15ml water adds the 10ml dehydrated alcohol) that adds 2.8g (24.6mmol) was 30～40 ℃ of reactions 2 hours, cooling, separate out flaxen crystallization, filter and collect, 65 ℃ of following vacuum-dryings 4 hours, obtain 8.7 gram dichloro cyclohexanediamine platinum productive rates 95% after water, the washing with alcohol.

The feature structure parameter is:＜1〉ultimate analysis C 19.01%; H 3.61%; N 7.31%; Pt 51.27%, with theoretical value C 18.95%; H 3.68%; N 7.38%; Pt 51.3 unanimities.

(2) oxaliplatin is synthetic

Get 4g (7.8mmol) dichloro cyclohexanediamine platinum, place the 500ml beaker to add water 320ml, add 11.5 gram potassium oxalates (62.4mmol) again, transfer PH=6-7 with 20%NaOH, 60～70 ℃ of reactions 8 hours, cooling was filtered, filtrate is concentrated into small volume with rotatory evaporator, cooling is filtered, after water, the washing with alcohol 65 ℃ of following vacuum-dryings 4 hours, obtain the 2.92g oxaliplatin, productive rate 70% (deducting responseless).

(3) purification of oxaliplatin

Get the oxaliplatin crude product of 2.92g, be dissolved in the boiling water of 90ml, take advantage of heat to filter fast, filtrate is cooled to 5 ℃, separate out the crystallization of white, filter and collect, 65 ℃ of following vacuum-dryings 4 hours, obtain 1.75g oxaliplatin elaboration after water, the washing with alcohol, productive rate 62%, it is 99.4% that purity is analyzed through HPLC, and silver content is determined as＜1ppm through AAS, specific rotatory power-73 °.

The feature structure parameter is:＜1〉ultimate analysis C 24.31%; H 3.52%; N 7.0%; Pt49.15%.With theoretical value C 24.18%; H 3.53%; N 7.05%; Pt 49.12%.Consistent.<2>FAB ⁺-MS?m/e＝397(M ⁺，100％)。＜3〉IR (cm ^-1, the KBr compressing tablet) and consistent with the oxaliplatin patent of application before us.These parameters meet the chemical structure of oxaliplatin.

(4) recovery of platiniferous waste material

With the first step, the platiniferous waste liquid of second step and the 3rd reaction is concentrated, regulate PH＞11 with ammoniacal liquor, drip hydrazine hydrate reduction platinum to reaction solution colourless till, continued reacting by heating 30 minutes, cooling, filter and collect platinum in filter paper, wash the back with water, obtain metal platinum 1.4g 800 ℃ of following calcinations 4 hours, through emmission spectrometric analysis purity is 99.99%, and the loss of platinum is less than 0.3%.

Claims

1. the technology of a synthetic oxaliplatin is characterized in that being: earlier tetrachloro is closed inferior platinate M ₂PtCl ₄With anti-form-1 R, 2R-diamines hexanaphthene reaction generates dichloro anti-form-1 R, and 2R-diamines hexanaphthene closes platinum (II), then with oxalate react the target compound oxaliplatin, chemical reaction that relates to and route are:

M ₂PtCl ₄+DACH→cis-[Pt(II)(DACH)·Cl ₂]

cis-[Pt(II)(DACH)·Cl ₂]+M ₂C ₂O ₄→cis-[Pt(II)(DACH)·C ₂O ₄]

Oxaliplatin

M=K, Na, Li DACH=anti-form-1 R, 2R-diamines hexanaphthene.

2. the technology of synthetic oxaliplatin according to claim 1, feature is to be described M ₂PtCl ₄Be K ₂PtCl ₄