A method for synthesizing deuterium-labeled docetaxel

Abstract

The invention discloses a preparation method of deuterium-labeled docetaxel, comprising the following steps: (1) under the action of an organic base, deuterium or tritiated tert-butyl alcohol and p-nitrophenyl chloroformate are subjected to an esterification reaction to obtain deuterium or tritiated (4-nitrophenyl) tert-butyl carbonate; (2) the deuterium or tritiated (4-nitrophenyl) tert-butyl carbonate obtained in step (1) is subjected to an amidation reaction with a compound IM-1, and after the reaction is completed, the docetaxel is obtained through post-treatment. The synthesis method is convenient for synthesizing intermediates, has stable chemical properties, and has high utilization rate of deuterated reagents and high product yield.

Description

Technical Field

[0001] The invention belongs to the field of preparation of deuterated or tritium-substituted drugs, and particularly relates to a method for synthesizing deuterium- or tritium-labeled docetaxel. Background Art

[0002] Docetaxel is a taxane anticancer drug that promotes the assembly of microtubule dimers into microtubules and stabilizes microtubules by preventing the depolymerization process, thereby blocking cells in the G2 and M phases and inhibiting the mitosis and proliferation of cancer cells. The pharmacological effect of docetaxel is stronger than that of paclitaxel, with an intracellular concentration three times higher than that of paclitaxel and a longer intracellular retention time. Its affinity for microtubules is twice that of paclitaxel; as a microtubule stabilizer and assembly promoter, its activity is twice that of paclitaxel; as a microtubule depolymerization inhibitor, its activity is twice that of paclitaxel. In in vitro antitumor activity tests, it has been confirmed that the antitumor activity of docetaxel is 1.3 to 12 times that of paclitaxel. Clinical studies have shown that docetaxel has a higher efficacy than paclitaxel for anthracycline-resistant breast cancer. Docetaxel is the most effective drug for the second-line treatment of anthracycline-resistant breast cancer so far; in monotherapy and combination chemotherapy for non-small cell lung cancer, docetaxel is one of the most effective drugs.

[0003] Docetaxel and other traditional taxane therapeutic drugs may not distribute to the desired areas in the body. In this regard, these traditional molecules may be relatively evenly distributed throughout the patient's body, thereby exerting effects on both normal and cancerous tissues. However, it would be desirable if docetaxel and other traditional taxanes could be modified so that they accumulate in tumor tissue while still maintaining their potent anticancer effects. To support the study of docetaxel metabolism, the present invention will deuterate the tert-butyl group in docetaxel (such as Formula 1)

[0004]

[0005] Previous studies have referred to the method for synthesizing di-tert-butyl dicarbonate (as shown in Scheme 2) with D 10 -tert-butyl alcohol is used as raw material, carbon dioxide is used as another reactant and solvent, and the product deuterated ditert-butyl dicarbonate is reacted under supercritical carbon dioxide to form the product, and finally D9-docetaxel is synthesized. The method is complicated to operate and is not conducive to a small amount of laboratory operation; and deuterated ditert-butyl dicarbonate is synthesized by reacting phosgene or triphosgene with reference to the reaction route, and the reaction is dangerous and has poor reliability in laboratory operation. Moreover, the synthesized deuterated ditert-butyl dicarbonate is used for the next step of reaction, and the utilization rate of the deuterated reagent is poor (half of the deuterated markers cannot participate in the reaction).

[0006]

[0007] There are also reports (Scheme 3) using bis(1-benzo[d]triimidazole) carbonate and D 10 -tert-butyl alcohol is used as a raw material to first synthesize D9-tert-butylbenzotriazole carbonate, and then synthesize D9-docetaxel. The D9-tert-butylbenzotriazole carbonate synthesized by this method has poor stability, is not conducive to separation and purification, and the reaction cannot be effectively monitored.

[0008] Summary of the invention

[0009] The invention provides a method for synthesizing deuterium- or tritium-labeled docetaxel. The method has convenient intermediate synthesis, stable chemical properties, and high utilization rate of deuterium- or tritium-substituted reagents and product yield.

[0010] The technical solution of the present invention is as follows:

[0011] A method for preparing deuterium or tritium-labeled docetaxel, comprising the following steps:

[0012] (1) Under the action of an organic base, deuterated or tritiated tert-butyl alcohol and p-nitrophenyl chloroformate undergo an esterification reaction to obtain deuterated or tritiated (4-nitrophenyl) tert-butyl carbonate;

[0013] (2) subjecting the deuterium- or tritiated-(4-nitrophenyl)carbonate obtained in step (1) to an amidation reaction with compound IM-1, and after completion of the reaction, subjecting the compound to post-treatment to obtain the deuterium- or tritium-labeled docetaxel;

[0014] The deuterium or tritium-substituted-docetaxel is D9-docetaxel or T9-docetaxel;

[0015] The reaction formula for synthesizing D9-docetaxel is as follows:

[0016]

[0017] The method of the invention can synthesize the deuterated intermediate deuterium or tritiated (4-nitrophenyl) carbonate tert-butyl ester with a high yield, the intermediate is easy to synthesize and has stable chemical properties, and the utilization rate of elemental deuterium is also relatively high. Deuterium or tritiated (4-nitrophenyl) carbonate tert-butyl ester can be used to efficiently synthesize D9-docetaxel.

[0018] In step (1), the type of organic base, the type of solvent and the reaction temperature will have a significant impact on the reaction yield.

[0019] The organic base in step (1) has a greater influence on the reaction. Preferably, in step (1), the organic base is pyridine.

[0020] Preferably, in step (1), the esterification reaction is carried out in a halogenated hydrocarbon solvent, and the halogenated hydrocarbon solvent is dichloromethane or chloroform.

[0021] Preferably, in step (1), the p-nitrophenyl chloroformate is dissolved in the halogenated hydrocarbon solvent and then added dropwise to the mixture of deuterated or tritiated tert-butyl alcohol and the organic base to react.

[0022] Preferably, in step (1), the reaction temperature is -20 to 0°C and the reaction time is 10 to 30 hours.

[0023] Preferably, in step (2), the amidation reaction is carried out under the action of DMAP.

[0024] Preferably, in step (2), the amidation reaction is carried out in a mixed solvent of an ether solvent and water;

[0025] The ether solvent is THF or dioxane.

[0026] Preferably, in step (2), the temperature of the amidation reaction is 10 to 30° C., and the reaction time is 10 to 20 hours.

[0027] Preferably, in step (2), the post-processing process after the reaction is completed is as follows:

[0028] Water and saturated aqueous ammonium chloride solution are added to the reaction solution in sequence, and then the solution is extracted with ethyl acetate, dried, concentrated, and subjected to column chromatography to obtain the deuterium or tritiated docetaxel.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0030] (1) The intermediate deuterated or tritiated (4-nitrophenyl) carbonate tert-butyl ester obtained by the synthesis method of the present invention has stable properties, is easy to synthesize, and is easy to implement during operation;

[0031] (2) The synthesis method of the present invention has a high utilization rate of the deuterated reagent, and the yield and purity of the obtained product are higher. DETAILED DESCRIPTION

[0032] Example 1

[0033] Synthesis of D9-(4-nitrophenyl) tert-butyl carbonate: In a 25 mL single-mouth bottle, 10-tert-Butanol (1g, 11.8mmol, 1eq) was mixed with pyridine (1.148mL, 14.2mmol, 1.2eq), and protected with a nitrogen balloon. A solution of p-nitrophenyl chloroformate (2.394g, 11.88mmol, 1eq) in DCM (13mL) was added dropwise under a CaCl2 ice-salt bath (-15°C), and stirred for 22h under a normal temperature water bath. After the reaction was completed, the reaction solution was directly concentrated (below 35°C), and column chromatography (Hex:EA=50:1-20:1) was performed to obtain a white solid D9-(4-nitrophenyl) tert-butyl carbonate: 2.238g, yield: 75.8%.

[0034] Synthesis of D9-docetaxel: THF (75 mL) was added to IM-1 (5.739 g, 8.1 mmol, 0.9 eq), and H2O (12 mL) and DMAP (2.2 g, 18 mmol, 2 eq) were added under stirring, and finally D9-(4-nitrophenyl) tert-butyl carbonate (2.238 g, 9.01 mmol, 1 eq) was added, and the mixture was stirred at room temperature for 14 h. After the reaction was completed, 50 mL of water and 35 mL of saturated ammonium chloride were added under stirring, and EA was extracted (100 mL*4), dried over anhydrous MgSO4, concentrated (below 35 °C), and column chromatographed (Hex:EA=5:1~1:2) to obtain white solid D9-docetaxel: 1.996 g, yield: 30.2%. Purity: 99.45%, isotopic abundance: 98 Atom% D

[0035] The reaction formula is as follows:

[0036]

[0037] Comparative Example 1

[0038] In a 25 mL single-mouth bottle, D 10 -tert-Butanol (1 g, 11.8 mmol, 1 eq) was mixed with triethylamine (1.44 g, 14.2 mmol, 1.2 eq) and protected by a nitrogen balloon. A solution of p-nitrophenyl chloroformate (2.394 g, 11.88 mmol, 1 eq) in DCM (13 mL) was added dropwise with stirring in a CaCl2 ice-salt bath (-15 ° C). After the addition, the mixture was stirred and reacted in a water bath at room temperature for 22 h. Sampling and detection showed that basically no tert-butyl D9-(4-nitrophenyl) carbonate was generated.

[0039] Example 2

[0040] Synthesis of D9-(4-nitrophenyl) tert-butyl carbonate: In a 25 mL single-mouth bottle, 10-tert-Butanol (1g, 11.8mmol, 1eq) was placed in a 25mL round-bottom flask and pyridine (4.8mL) was added as a solvent. p-Nitrophenyl chloroformate (2.394g, 11.8mmol, 1eq) was added at room temperature and stirred for 4 hours under nitrogen. MTBE (5mL) was added and the suspension was filtered to remove the solid. The solid was washed with MTBE (5mL). The organic phase was washed with water (5ml) and the aqueous phase was extracted with MTBE (5mL). Washed with 1N hydrochloric acid (5mL*3), NaHCO3 (10%, 5mL*2), NaCO3 (5mL), NaHCO3 (5mL*2), water (5mL) and brine (5mL) respectively. The organic layer was dried over Na2SO4. The solvent was removed and the residue was dissolved in ethanol (8mL). Water (10mL) was slowly added to the precipitated solid. The suspension was cooled in a refrigerator overnight. The suspension was filtered, the solid was collected and washed with ethanol (8 mL) / water (10 mL) solution. The washed solid was placed in vacuum at room temperature for two days to obtain white solid D9-(4-nitrophenyl) carbonate tert-butyl ester: 34 mg, yield: 1.16%.

[0041] Synthesis of D9-docetaxel: THF (1 mL) was added to IM-1 (88 mg, 0.12 mmol, 0.9 eq), and H2O (0.5 mL) and DMAP (31 mg, 0.27 mmol, 2 eq) were added under stirring, and finally D9-(4-nitrophenyl) tert-butyl carbonate (34 mg, 0.13 mmol, 1 eq) was added, and the mixture was stirred at room temperature for 10 h. After the reaction was completed, 3 mL of water and 1 mL of saturated ammonium chloride were added under stirring, and EA was extracted (10 mL*4), dried over anhydrous MgSO4, concentrated (below 35°C), and column chromatographed (Hex:EA=5:1-1:2) to obtain white solid D9-docetaxel: 31 mg, yield: 30%. Purity: 95.50%, isotopic abundance: 98 Atom%D.

Claims

1. A method for preparing deuterium-labeled docetaxel, characterized in that: The following steps are involved: (1) In a 25 mL single-necked bottle, 1 g D 10 - tert-Butanol was mixed with 1.148 mL of pyridine, protected by a nitrogen balloon, and a solution of 2.394 g of p-nitrophenyl chloroformate in 13 mL of DCM was added dropwise under stirring in a -15°C CaCl2 ice salt bath. After the addition, the mixture was stirred and reacted in a normal temperature water bath for 22 h. After the reaction was completed, the reaction solution was directly concentrated below 35°C, and column chromatography was performed to obtain 2.238 g of white solid D9-(4-nitrophenyl) tert-butyl carbonate, with a yield of 75.8%. The eluent for column chromatography was Hex:EA=50:1-20:1; (2) subjecting the deuterated tert-butyl (4-nitrophenyl) carbonate obtained in step (1) to an amidation reaction with compound IM-1, and after completion of the reaction, subjecting the compound to post-treatment to obtain the deuterium-labeled docetaxel; The deuterated-docetaxel is D9-docetaxel; The reaction formula for synthesizing D9-docetaxel is as follows:

2. The method for preparing deuterium-labeled docetaxel according to claim 1, characterized in that: In step (2), the amidation reaction is carried out under the action of DMAP.

3. The method for preparing deuterium-labeled docetaxel according to claim 1, characterized in that: In step (2), the amidation reaction is carried out in a mixed solvent of an ether solvent and water; The ether solvent is THF or dioxane.

4. The method for preparing deuterium-labeled docetaxel according to claim 1, characterized in that: In step (2), the temperature of the amidation reaction is 10 to 30° C., and the reaction time is 10 to 20 hours.

5. The method for preparing deuterium-labeled docetaxel according to claim 1, characterized in that: In step (2), the post-processing process after the reaction is completed is as follows: Water and saturated aqueous ammonium chloride solution are added to the reaction solution in sequence, and then extracted with ethyl acetate, dried, concentrated, and subjected to column chromatography to obtain the deuterated docetaxel.

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