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Preparation method of 4-cyano-5-bromopyrimidine

A technology of trimethylbromosilane and cuprous cyanide, applied in organic chemistry and other fields, can solve problems such as expensive raw materials, poisoning death, and unsuitability for large-scale production

Pending Publication Date: 2021-07-09
PHARMABLOCK SCIENCES (NANJING) INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This method uses highly poisonous potassium cyanide as a reaction reagent, which requires high reaction operating conditions. Once improper operation, a small amount of potassium cyanide can cause personnel poisoning and death; in addition, this method has a low yield (32%) and is not suitable for mass production
[0010] In addition, the 4-position halogen atom of the pyrimidine ring passes through zinc cyanide, and a coupling reaction occurs under the action of a palladium catalyst to generate a 4-position cyano-substituted pyrimidine derivative. Zinc cyanide also belongs to a highly toxic drug, and this method uses For palladium catalysts, the price of raw materials is relatively expensive. Under these conditions, dehalogenation by-products will be generated in the reaction, which is difficult to separate and purify, and is not suitable for large-scale production.

Method used

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  • Preparation method of 4-cyano-5-bromopyrimidine
  • Preparation method of 4-cyano-5-bromopyrimidine
  • Preparation method of 4-cyano-5-bromopyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] Preparation of Compound III:

[0038] Compound II (87.50 g, 452.36 mmol, 1 eq.), Trimethyl bromide (346.3 g, 2.26 mol, 5.00 meq.) Were mixed into acetonitrile (800 mL), heated to reflux mixing reaction for 5 h, GC detection raw material disappeared ( HP-5 columns, general-12min, TF = 3.66 min), concentrated the reaction solution to remove acetonitrile. In the residual liquid, 200 ml of acetonitrile was added, and the residual TMSBR was removed under reduced pressure was removed. After repeating the compound III, the compound III was 110.1 g of the brown solid, and directly put into the next reaction.

[0039] Preparation of Compound I:

[0040] Compound III (40.05 g, 168.1 mmol, 1 eq), CuCn (18.88 g, 201.7 mmol, 1.20 eq.) Were mixed into DMAC (260 mL), heated to 90 ° C for stirring, 7h, TLC showed the reaction. The reaction solution was poured until 700 ml of water, MTBE 200ml * 2 extraction, combined with organic phase, dried, concentrated sand column chromatogr...

Embodiment 2

[0042]

[0043] Preparation of Compound III:

[0044] Compound II (50.01 g, 258.49 mmol, 1 eq.), Trimethyl bromide (79.14 g, 516.98 mmol, 2.00 meq.) Were mixed into toluene (500 mL), heated to reflux mixing reaction for 5 h, GC detection raw material disappeared ( HP-5 column, general-12min, TF = 3.66 min), in pouring the reaction solution into a saturated aqueous solution of sodium bicarbonate, stirred, separation, and then concentrated under reduced pressure, then concentrate, 200 ml of toluene is added to the residue , The removal of the remaining TMSBR in the reduced pressure was concentrated, and the compound III was repeated twice, and the compound III had a brown solid 65.01g, directly input into the next reaction.

[0045] Preparation of Compound I:

[0046] Compound III (65.01 g, 258.49 mmol, 1 eq.), Cucn (24.19 g, 258.49 mmol, 1.0 eq.) Were mixed in DMF (300 mL), and the reaction was heated to 95 ° C for 6 h, and the TLC showed the reaction. The reaction fluid was pour...

Embodiment 3

[0048]

[0049] Preparation of Compound III:

[0050] Compound II (50.01 g, 258.49 mmol, 1 eq.), Trimethyl bromide (118.72 g, 775.47 mmol, 3.00 meq.) Were mixed in THF (500 mL), heated to reflux mixing reaction for 5 h, GC detection raw material disappeared ( HP-5 column, general-12min, TF = 3.66 min), in pouring the reaction solution into a saturated aqueous solution of sodium hydrogencarbonate, stirred, separation, and then concentrated under reduced pressure, and then add 200 ml of THF to the residue , The reduced pressure concentrated removal of the remaining TMSBR in the system, and the compound III was repeated twice, and the compound III crude product was 69.12g of brown solid and directly input the next reaction.

[0051] Preparation of Compound I:

[0052] Compound III (69.12 g, 258.49 mmol, 1 eq.), CuCn (36.29 g, 387.73 mmol, 1.5 eq.) Were mixed in NMP (300 mL), and the reaction was heated to 85 ° C for 8 h, and the TLC showed the reaction. The reaction liquid was pour...

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Abstract

The invention discloses a preparation method of 4-cyano-5-bromopyrimidine, the preparation method comprises the following steps: taking 4-chloro-5-bromopyrimidine (compound II) as a raw material, and carrying out bromine chlorine substitution reaction on the 4-chloro-5-bromopyrimidine (compound II) and trimethylbromosilane to generate 4, 5-dibromopyrimidine (compound III); the compound III and cuprous cyanide are subjected to a nucleophilic substitution reaction to generate 4-cyano-5-bromopyrimidine (compound I), and the yield of the two-step reaction can reach 70% or above.

Description

Technical field [0001] The present invention relates to the synthesis of the pharmaceutical intermediate, and in particular, to the preparation method of 4-cyano-5-bromidine. Background technique [0002] Pyrimidine loop derivatives are a very important six-dimensional heterocyclic compound, which has important applications in the pharmaceutical field, and widely used in research and development and clinical study of anticancer drugs. Among them, 4-cyano-5-pyrimidine can be synthesized as a key intermediate to synthesize a series of active compounds containing pyrimidine fragments. [0003] The synthesis method of 4-cyano-5-pyrimidine is less preparation method. Among them, patented US 20070037820A1 reported a synthetic method of 4-cyano-5-bromidine: [0004] [0005] Reagents and conditions: (1) M-CPBA, CHCl 3 , REFLUX, 8H, 23%; (2) TEA, MECN, R.T., 2H, 20%. [0006] The route is synthesized by two steps to synthesize the target compound 4-cyano-5-bromridine. The first step is...

Claims

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Application Information

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IPC IPC(8): C07D239/30
CPCC07D239/30
Inventor 杨广超张洪飞余善宝
Owner PHARMABLOCK SCIENCES (NANJING) INC
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