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Preparation method of 5-chloro-6-chloromethyluracil

The technology of chloromethyluracil and methanol is applied in the field of preparation of drug precursor 5-chloro-6-chloromethyluracil, can solve the problems of high price and difficult availability of raw materials, and achieves low production cost and low price , process stable and reliable effect

Inactive Publication Date: 2017-07-11
卡硼瑞(北京)科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

As we all know, selenium dioxide is acutely toxic, highly toxic, and has an irritating effect on the skin and mucous membranes similar to sulfur dioxide. Rats inhale selenium dioxide vapor at 150-600mg / m 3 Animals die immediately. This product is controlled by the public security department according to the Regulations on the Safety Management of Hazardous Chemicals. The raw materials are not easy to obtain and the price is expensive.

Method used

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  • Preparation method of 5-chloro-6-chloromethyluracil
  • Preparation method of 5-chloro-6-chloromethyluracil
  • Preparation method of 5-chloro-6-chloromethyluracil

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Add 86g (0.55mol) orotic acid B to a four-neck flask equipped with mechanical stirring, reflux condenser and thermometer at room temperature 0 (without crystal water), 500ml of thionyl chloride, 20ml of pyridine and 10ml of DMF, heated up to 75-80°C, refluxed for 20h, cooled to room temperature, concentrated and collected excess thionyl chloride liquid, added 500ml of toluene to raise the temperature to 110°C, Continue to reflux for 5 hours, lower the temperature to 50°C, slowly add 200ml of methanol dropwise, and keep the reaction temperature at 50-60°C. 600ml of methanol was recrystallized and dried with hot air to obtain an off-white solid. The melting point was measured: mp: 245°C, and 91 grams (0.53mol) of orotate (B 1 ), molar yield: 96%.

[0051] 1 HNMR (400MHz, DMSO-d 6 )δ H 11.45(1H,s), 11.21(1H,s), 6.01(1H,s), 3.81(3H,s)

Embodiment 2

[0053] At room temperature, 78g (0.5mol) orotic acid B 0 (containing crystal water) and 5ml 98% sulfuric acid were added to 200ml methanol and 200ml dimethyl carbonate mixture solution, refluxed for 30h, detected by TLC until the reaction was complete, concentrated the solid obtained, washed with hot water, filtered to remove water, and then used 300ml of methanol was recrystallized and dried with hot air to obtain an off-white solid. The melting point was measured: mp: 246°C, and 83 grams (0.49mol) of orotate (B 1 ), the molar yield is 98%.

[0054] 1 HNMR (400MHz, DMSO-d 6 )δ H 11.45(1H,s), 11.21(1H,s), 6.01(1H,s), 3.81(3H,s)

[0055] Step 2) Reaction formula:

[0056]

Embodiment 3

[0058] 68g (0.40mol) orotate (B 1 ) into 500ml of acetic acid, 25ml of acetic anhydride and a catalytic amount of ferric trichloride, heated to 90-95°C, and 0.8g (0.80mol) of sulfonyl chloride was added dropwise. Complete chlorination (TLC detection) stopped the reaction, cooled the reaction solution to 10°C, filtered to obtain a solid, washed with acetic acid and water in turn, and dried with hot air to obtain a yellow solid. Melting point: mp: 250°C, 72.0g (0.35 mol) 5-chloro-orotate (B 2 ), a molar yield of 88%.

[0059] 1 HNMR (400MHz, DMSO-d6) δH11.82 (1H, s), 11.61 (1H, s), 3.82 (3H, s)

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Abstract

The invention provides a 5-chloro-6-chloromethyl-uracil and a preparation method thereof. The method comprises the following steps: esterifying the 6-position carboxylic acid of orotic acid used as an initial raw material, chlorinating the 5-position hydrogen, reducing the 6-position ester into a hydroxymethyl group, and carrying out a chlorination substitution reaction to obtain the target product. The preparation method has the advantages of simplicity in operation, stable process, high yield and low cost, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemical synthesis, in particular to a preparation method of drug precursor 5-chloro-6-chloromethyluracil. Background technique [0002] In September 2015, a new anti-metabolite compound drug TAS-102 tablet developed by Tahoe Oncology Company of Japan was approved by the FDA for marketing. It is an anti-tumor nucleoside analog trifluorothymidine (trifluridine, Trifluridine, referred to as FID) and thymidine phosphorylase inhibitor tipiracil (Tipiracil, tipiracil hydrochloride, referred to as TPI) The compound drug composed of it is used for the treatment of patients with refractory metastatic colorectal cancer who no longer respond to chemotherapy and biological therapy. [0003] Colorectal cancer accounts for 9% of the tumor incidence in my country, and 40% of the patients will have K-ras gene mutations. For patients with K-ras mutations, the use of 5-FU treatment has no benefit, and the clinical result...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/553
CPCC07D239/553
Inventor 陈功谢素琼宋雪
Owner 卡硼瑞(北京)科技有限公司