Synthesizing process of antineoplastic agent clofarabine

The technology of clofarabine and compound is applied in the field of new synthesis process of antitumor drug clofarabine, which can solve the problems of serious environmental pollution and high cost of starting materials, and achieve the effect of mild conditions

Active Publication Date: 2013-09-11
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] All three routes use the intermediate 1-bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinose, the intermediate sugar is 1,3,5-tri -O-benzoyl-α-D-ribofuranose is obtained as a raw material through a five-step reaction. The cost of the starting material is relatively high, and thionyl chloride is used in the reaction. This kind of solvent is serious for environmental pollution and has been listed Ban products for the country

Method used

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  • Synthesizing process of antineoplastic agent clofarabine
  • Synthesizing process of antineoplastic agent clofarabine
  • Synthesizing process of antineoplastic agent clofarabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Preparation of 2′, 3′, 5′-tri-O-acetylguanosine

[0049]

[0050] Add 100 grams of guanosine, 210 milliliters of acetic anhydride, 280 milliliters of DMF and 100 milliliters of pyridine into a three-neck flask, and heat up to 75-80° C. for 1.5 hours under stirring. After the reaction of the raw materials is complete, concentrate under reduced pressure to remove about one-third of the volume of the DMF and pyridine mixture, add 150ml of ether and 150ml of isopropanol, a white solid precipitates out of the solution, cool down to about 0°C, and filter to obtain 113 grams of solid. The yield is about 78%. 【Melting point: 225-232℃】 1 HNMR(DMSO) 2.05(s, 2'-Oac), 2.06(s, 3'-Oac), 2.12(s, 5'-Oac), 4.29(m, 4'-H), 4.38(m, 5' -H), 5.51(m, 3'-H), 5.81(t, 2'-H), 5.81(d, 1'-H), 6.56(s, 2-NH2), 7.94(s, 8-H )

Embodiment 2

[0051] Example 2: Preparation of 6-chloro-2', 3', 5'-tri-O-acetylguanosine

[0052]

[0053]

[0054]Add 113 grams of 2′, 3′, 5′-tri-O-acetylguanosine, 125 grams of benzyltriethylammonium chloride, 35ml of N, N-dimethylaniline, and 600ml of acetonitrile in a 1-liter three-necked flask , 150ml of phosphorus oxychloride, heat up to 77-83°C under mechanical stirring, reflux for 30 minutes, then cool to about 50°C and concentrate under reduced pressure to a small volume, add the residue to ice water, use 1L, 500ml, 500ml of Extract with dichloromethane, wash the dichloromethane phase with 5% sodium bicarbonate solution to neutrality, dry over anhydrous sodium sulfate, filter, concentrate dichloromethane under reduced pressure to a small volume, add 600ml of isopropanol to separate out a large amount of solids, A light yellow solid was obtained by filtration, and vacuum-dried to obtain 90 g of 6-chlorotriacetylguanosine with a yield of about 76%. 【Melting point: 143-146℃】 1...

Embodiment 3

[0055] Example 3: Preparation of 2,6-dichloro-2', 3', 5'-tri-O-acetyladenosine

[0056]

[0057] Add 90 grams of 6-chloro-2', 3', 5'-tri-O-acetylguanosine and 1.4 liters of dichloromethane into a 2-liter three-necked flask, stir and dissolve, then add 48 grams of antimony trichloride, and wait After the antimony trichloride was dissolved, tert-butyl nitrite was added dropwise, and the solution became cloudy with solid precipitation after the dropwise addition. After tert-butyl nitrite was dripped, reacted for 30 minutes. TLC showed that the raw material had reacted completely. Concentrate under reduced pressure to a small volume to take away tert-butyl nitrite. Add 1.5 L of dichloromethane again, filter to remove salt, dichloromethane phase Wash twice with 5% sodium bicarbonate, then wash twice with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure and add 200ml of ethanol to continue concentrating until solids...

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Abstract

The invention belongs to a chemical synthesis drug process, particularly relating to a new synthesizing process of antineoplastic agent clofarabine, which has cheap, easily obtained original raw materials, moderate condition in the reaction and no device specially required, and can be applied to industrial production. In the method, a new synthesizing intermediate is adopted to carry out systemization, therefore, the invention also relates to a novel intermediate in use of the method.

Description

technical field [0001] The invention belongs to a process for chemically synthesizing medicines, in particular to a new process for synthesizing antitumor drug clofarabine. Background technique [0002] Clofarabine (formerly known as Clofarex), chemically named 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinosyl)-adenine, is a second-generation purine nucleoside similar to It can inhibit tumor by inhibiting the activity of DNA polymerase and RNA reductase. It was approved for the treatment of refractory or relapsed acute lymphoblastic leukemia in children on December 28, 2004. This product has been granted rare drug status by the FDA for the treatment of acute lymphoblastic leukemia in children. This product was approved in January 2005. US debut. Clofarabine, currently the only chemotherapy drug that can be specifically used for childhood leukemia, has a high overall response rate in the treatment of leukemia, is well tolerated, and has no unpredictable adverse reactions. It can...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/173C07H1/00A61P35/00
Inventor 陈云华杨伟强
Owner ZHEJIANG HISUN PHARMA CO LTD
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