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Method for synthesizing trifluridine process impurity

A technology for trifluridine and process impurities, which is applied in the field of chemical pharmacy to achieve the effects of cheap raw materials, improved accurate positioning and characterization, and easy availability of raw materials

Inactive Publication Date: 2018-12-18
江苏悦兴医药技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After retrieval, there is no bibliographical report about the synthesis of this impurity, therefore, it has important practical significance to provide the synthetic method of trifluridine impurity for the preparation of impurity standard

Method used

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  • Method for synthesizing trifluridine process impurity
  • Method for synthesizing trifluridine process impurity
  • Method for synthesizing trifluridine process impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1: Preparation of 3',5'-bis(p-chlorobenzoyl)-2'-deoxy-α-D-ribose-5-trifluoromethyluracil (4)

[0017]

[0018] Add 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)uracil (15.76g, 0.048mol), 100ml of chloroform, 1-chloro-2-deoxy-3,5 -Di-p-chlorobenzoyl-D-ribose (10.5g, 0.024mol) was stirred at room temperature, reacted for 4h, and detected by TLC, raw material 1-chloro-2-deoxy-3,5-di-p-chlorobenzoyl- D-ribose disappears, and the reaction ends. Rotary evaporate to dryness, add ethanol and anisole, stir, filter and dry with suction. β / α=75:25 was detected by HPLC. The sample was prepared, put on the column, and eluted with dichloromethane-methanol (80:1) to obtain 2.48 g of white solid with a yield of 18.51%.

Embodiment 2

[0019] Example 2: Preparation of 3',5'-bis(p-chlorobenzoyl)-2'-deoxy-α-D-ribose-5-trifluoromethyluracil (4)

[0020] Add 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)uracil (15.76g, 0.048mol), anisole 100ml, 1-chloro-2-deoxy-3 , 5-di-p-chlorobenzoyl-D-ribose (10.5g, 0.024mol) was stirred at 60°C, reacted for 12h, and detected by TLC, raw material 1-chloro-2-deoxy-3,5-di-chlorobenzene Formyl-D-ribose disappears and the reaction ends. Add ethanol and stir, filter and dry with suction. β / α=45:55 was detected by HPLC. The sample was prepared, loaded on the column, and eluted with dichloromethane-methanol (80:1) to obtain 6.91 g of white solid with a yield of 50.27%.

[0021] 1 HNMR (600MHz, DMSO-d6, δppm): 2.33(t, 2H), 3.62(m, 2H), 3.73(t, 1H), 5.31(t, 2H), 7.60(d, 4H), 7.89(m, 4H), 8.57(s, 1H), 11.82(s, 1H).

Embodiment 3

[0022] Example 3: 1-((2S,4S,5R)-4-hydroxyl-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H )-diketone (1) preparation

[0023]

[0024] Add 3',5'-bis(p-chlorobenzoyl)-2'-deoxy-α-D-ribose-5-trifluoromethyluracil (10.3g, 0.018mol) and 130ml methanol to a 200ml three-necked flask Stir in an ice bath, add sodium methoxide (1.94 g, 0.036 mol), react for 4 h, and TLC detects that the reaction is complete. HCl gas was introduced to adjust the pH to 5-6, filtered with suction, and the solvent was rotary evaporated to dryness to obtain 4.82 g of a white solid with a yield of 90.42%. HPLC detection 98.27%.

[0025] 1 HNMR (600MHz, DMSO-d6, δppm): 2.31(t, 2H), 3.64(m, 2H), 3.78(t, 1H), 4.25(s, 1H), 5.29(t, 2H), 6.06(t, 1H), 8.62(s, 1H), 11.84(s, 1H).

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Abstract

The invention discloses a method for synthesizing a trifluridine impurity 1-((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione, and belongs tothe technical field of chemical pharmacy. The method comprises the following steps: condensing starting raw materials 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)uracil (2) and 1-chloro-2-deoxy-3,5-di-4-chlorobenzoyl-D-ribose (3) to prepare 3',5'-di(4-chlorobenzoyl)-2'-deoxy-alpha-D-ribose-5-trifluoromethyluracil (4); and hydrolyzing the compound (4) to generate 1-((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (1). The highly-pure trifluridine impurity synthesized in the invention can be used as an impurity standard product in the detection and analysis of finished trifluridine, so the accurate localization and qualitative diagnosis of the impurity in the detection and analysis of the finished trifluridine are improved, and theenhancement of the control of the impurity is benefited, thereby the quality of the finished trifluridine is improved. The method has the advantages of cheap and easily available raw materials, and simplicity in operation, and allows the yield of the obtained product to be (40 + / - 5)% and the HPLC purity of the product to be equal to or more than 98%.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to a trifluridine process impurity 1-((2S,4S,5R)-4-hydroxyl-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-( Synthetic method of trifluoromethyl)pyrimidine-2,4(1H,3H)-dione. Background technique [0002] Trifluridine has the strongest effect on herpes simplex virus (HSV-1 and HSV-2), and also has a certain effect on adenovirus, vaccinia virus, cytomegalovirus, and herpes zoster virus. It is resistant to acyclovir Herpes virus works. Its triphosphate derivatives can be incorporated into DNA and compete with thymidine triphosphate to inhibit DNA polymerase. No selectivity for viral DNA and host cell DNA. It is suitable for herpes simplex keratitis, conjunctivitis and other herpetic eye diseases. At the same time, trifluridine is also one of the raw materials of TAS-102 (Taiho Pharmaceutical). TAS-102 is a compound drug developed by Japanese pharmaceutical company Taiho Pharma...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00
CPCC07B2200/07C07H1/00C07H19/073
Inventor 花海堂翟富民胡玉乾
Owner 江苏悦兴医药技术有限公司
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