CN1521161A - Preparation of Oxaliplatin - Google Patents

Abstract

The present invention is the preparation process of antitumor medicine Oxaliplatin C8H14N2O4Pt. In the technological process, cis-dichloro cyclohexanediamine-platinum (II) or cis-diidio cyclohexanediamine-platinum (II) as initiator is made to react with silver oxalate in lucifugous condition at 40-75 deg.c to obtain water solution of Oxaliplatin; and the water solution is further decompression concentrated to obtain solid Oxaliplatin product. The said Oxaliplatin preparation process is short, high in production efficiency and easy in operation.

Description

Preparation of Oxaliplatin

technical field

The invention relates to the synthesis and preparation of antitumor drug oxaliplatin.

Background technique

Oxaliplatin is a platinum group metal complex and is a new generation of platinum-based antineoplastic drugs after cisplatin and carboplatin. Oxaliplatin, also known as oxaliplatin, English name Oxaliplatin, abbreviated as L-OHP, full name cis-oxalic acid (trans-(-)-1,2-cyclohexanediamine) platinum(II)[cis- oxalato(trans-(1R,2R)-(-)-1,2-diaminocyclohexane)platinum(II)], molecular weight is 397.33, chemical structural formula:

Oxaliplatin was first developed by Debiopharm in Switzerland and was approved for clinical use in France in 1997, mainly for the treatment of metastatic colorectal cancer. At present, it has been approved for clinical application in many countries or regions. The US FDA also approves the treatment of colorectal cancer. Oxaliplatin is a complex formed with oxalate and trans-(-)-1,2 cyclohexylamine (DACH) as ligands and divalent metal platinum. In the article "Synthesis and Structural Characterization of Platinum Oxalate" published in No. 1, Volume 21, 2000 of "Precious Metals", the synthesis method of oxaliplatin is reported, and the synthesis route is as follows:

"Drugs of the future" also reported the synthesis method of Oxaliplatin in the article "Oxaliplatin" published in Volume 14, Issue 6, 1989. The process route is:

The synthesis of oxaliplatin disclosed in the above two documents is to use cis-dichlorocyclohexanediamine platinum (II) or cis-diiodocyclohexanediamine platinum (II) as an intermediate, and add silver nitrate Hydrolysis reaction, and then filter to remove silver chloride or silver iodide precipitation, add potassium oxalate or sodium oxalate to the mother liquor, generate oxaliplatin aqueous solution after reaction, and concentrate under reduced pressure to obtain oxaliplatin product. Due to the use of multi-step chemical reactions in this preparation technology, the process flow is lengthy and complicated, and the product yield is low.

Contents of the invention

The object of the present invention is to provide a kind of preparation method of oxaliplatin with simple and convenient technological process.

The preparation method of oxaliplatin of the present invention adopts cis-dichloro (trans-(-)-1,2-cyclohexanediamine) platinum (II), its molecular formula Pt(DACH)Cl ₂ , its structural formula for:

Or cis-diiodo(trans-(-)-1,2-cyclohexanediamine) platinum(II), its molecular formula is Pt(DACH)I ₂ , and its structural formula is:

React with silver oxalate Ag ₂ C ₂ O ₄ under the condition of 40°C to 75°C protected from light, and the reaction molar ratio of the two is 1:1 to obtain an aqueous solution of oxaliplatin.

The oxaliplatin aqueous solution prepared by the above reaction is placed in an evaporation container, the pressure in the evaporation container is reduced, and the oxaliplatin aqueous solution is heated and concentrated in a water bath at 40° C. to 75° C. to obtain a solid oxaliplatin product.

The corresponding chemical reaction formula is:

        

or

Compared with the method reported in the above literature, the preparation method of oxaliplatin of the present invention shortens the production cycle, simplifies the production process, is easy to operate, and increases the production efficiency by nearly 10 percentage points.

1. Reagents and materials

1. Pt(DACH)I ₂ , molecular weight: 563.08. Dissolve K ₂ PtCl ₄ in an appropriate amount of water, add excess analytically pure KI, add DACH equivalently after 30 minutes, filter the precipitated yellow precipitate after 2 hours, wash with water, ethanol and acetone respectively, and dry at 70°C to obtain Pt( DACH) I ₂ product, purity ≥ 98%.

2. Pt(DACH)Cl ₂ , molecular weight: 380.17. Dissolve K ₂ PtCl ₄ in an appropriate amount of water, add DACH in an equivalent amount, react for 2 hours, filter the precipitated yellow precipitate, wash with water, ethanol and acetone, and dry at 70°C to obtain Pt(DACH)Cl ₂ product with a purity of ≥98 %.

3.Ag ₂ C ₂ O ₄ (commercially available, analytically pure)

4. KI (analytical pure), ethanol (analytical pure), acetone (analytical pure).

Detailed ways

Example 1

Dissolve 5 grams of Pt(DACH)Cl ₂ in an appropriate amount of deionized water, control the temperature at about 40°C, add Ag ₂ C ₂ O ₄ in an equivalent amount, and stir for 6 hours in the dark, then filter to remove the AgCl precipitate, and concentrate the mother liquor under reduced pressure. A 4.2 g sample of white crystals was obtained with a yield of 81%. The structure was consistent with the target compound by elemental analysis and infrared analysis.

Elemental analysis: measured values are C: 24.21%, H: 3.57%, N: 7.01%, Pt: 49.04%. Theoretical values are C: 24.19%, H: 3.55%, N: 7.05%, Pt: 49.09%. The composition agrees with the theory.

Infrared absorption spectrum: IR spectrum (KBr pellet cm ^-1 ): NH (3212, 3171, 1610); CH (3095, 2932, 2863, 1447); C=O (1702, 1664); CO (1379); CC (916,909); Pt-N (480); Pt-O (310).

Mass Spectrometry (MS): The fast atom bombardment method was adopted, and the measurement results are shown in Table 1.

Table 1 m/e relative abundance Corresponding Fragment 398 100 molecular ion peak 353 3 [Pt(DACH)CO ₂ ] ⁺ 309 15 [Pt(DACH)] ²⁺ 115 5 [C ₆ H ₁₅ N ₂ ] ⁺ 98 17 [C ₆ H ₁₂ N] ⁺ 81 10 [C ₆ H ₉ ] ⁺

Example 2

Dissolve 5 grams of Pt(DACH)Cl ₂ in an appropriate amount of deionized water, control the temperature at about 75°C, add Ag ₂ C ₂ O ₄ in an equivalent amount, and stir for 4 hours in the dark, then filter to remove the AgCl precipitate, and concentrate the mother liquor under reduced pressure. A 4.12 g sample of white crystals was obtained with a yield of 79%. The structure is consistent with the target compound by elemental analysis, infrared, mass spectrometry and other analysis.

Elemental analysis: measured values are C: 24.23%, H: 3.56%, N: 7.04%, Pt: 49.12%. Theoretical values are C: 24.19%, H: 3.55%, N: 7.05%, Pt: 49.09%. The composition agrees with the theory.

Infrared absorption spectrum: IR spectrum (KBr pellet cm ^-1 ): NH (3217, 3176, 1613); CH (3099, 2936, 2867, 1450); C=O (1710, 1669); CO (1382); CC (917,912); Pt-N(480):Pt-O(310).

Mass Spectrometry (MS): The fast atom bombardment method was adopted, and the measurement results are shown in Table 2.

Table 2 m/e relative abundance Corresponding Fragment 398 100 molecular ion peak 309 17 [Pt(DACH)] ²⁺ 115 4 [C ₆ H ₁₅ N ₂ ] ⁺ 98 25 [C ₆ H ₁₂ N] ⁺ 81 12 [C ₆ H ₉ ] ⁺

Example 3

Dissolve 5 grams of Pt(DACH)Cl ₂ in an appropriate amount of deionized water, control the temperature at about 55°C, add an equivalent amount of Ag ₂ C ₂ O ₄ , and stir for 5 hours in the dark. The subsequent operations are the same as in Example 1, and sample 4.21 is obtained. gram, the structure is consistent with the target compound, and the yield is 81%.

Example 4

Dissolve 9 grams of Pt(DACH)I ₂ in an appropriate amount of deionized water, control the temperature at about 40°C, add Ag ₂ C ₂ O ₄ in an equivalent amount, and stir for 5 hours in the dark. The subsequent operations are the same as in Example 1, and sample 5.12 is obtained. gram, the structure is consistent with the target compound, and the yield is 82%.

Example 5

Dissolve 9 grams of Pt(DACH)I ₂ in an appropriate amount of deionized water, control the temperature at about 75°C, add Ag ₂ C ₂ O ₄ in an equivalent amount, and stir for 5 hours in the dark. The subsequent operations are the same as in Example 1 to obtain sample 5.02 gram, the structure is consistent with the target compound, and the yield is 80.5%.

Example 6

Dissolve 9 grams of Pt(DACH)I ₂ in an appropriate amount of deionized water, control the temperature at about 55°C, add Ag ₂ C ₂ O ₄ in an equivalent amount, and stir for 5 hours in the dark. The subsequent operations are the same as in Example 1, and sample 5.19 is obtained. gram, the structure is consistent with the target compound, and the yield is 83.1%.

Claims (2)

1. the preparation method of antitumor drug oxaliplatin, its structural formula is as follows:

It is characterized in that it adopts cis-dichloro (trans-(-)-1,2-cyclohexanediamine) platinum (II), its molecular formula is Pt(DACH)Cl ₂ , and its structural formula is:

Or cis-diiodo(trans-(-)-1,2-cyclohexanediamine) platinum(II), its molecular formula is Pt(DACH)I ₂ , and its structural formula is:

React with silver oxalate Ag ₂ C ₂ O ₄ at 40°C to 75°C under dark conditions, and the molar ratio of the two is 1:1. 2. The preparation method of oxaliplatin according to claim 1, characterized in that the aqueous solution of oxaliplatin is placed in an evaporation vessel and the pressure in the evaporation vessel is reduced, and concentrated oxaliplatin is heated in a water bath at 40° C. to 75° C. Platinum aqueous solution to obtain oxaliplatin solid product.