A kind of method for synthesizing multi-substituted pyrimidine derivatives by a two-step method

A technology of pyrimidine derivatives and multi-substitution, applied in the fields of organic synthesis and pharmaceutical intermediates, can solve the problems of low reaction yield and increased production cost, and achieve the effects of simple synthetic route, convenient operation and reduced production cost

Active Publication Date: 2022-06-21
安徽诺全药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] But in the second step reaction yield of this route is low, causes production cost to significantly increase

Method used

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  • A kind of method for synthesizing multi-substituted pyrimidine derivatives by a two-step method
  • A kind of method for synthesizing multi-substituted pyrimidine derivatives by a two-step method
  • A kind of method for synthesizing multi-substituted pyrimidine derivatives by a two-step method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] (1) the preparation of (R)-(2-isocyanato-1-phenylethyl) carbamate tert-butyl ester shown in formula V, its route is as follows:

[0044]

[0045] Operation steps: In a reactor, dissolve 2.5 g, 1.0 equiv. of N-Boc-beta-phenylalanine as shown in formula VI in 12 mL of tetrahydrofuran, and add 1.2 equiv. of chloroformic acid to it under ice bath conditions Ethyl ester and 2.4 equiv. triethylamine were kept in an ice bath, and the reaction was stirred for 1 h; then, under the ice bath condition, an aqueous solution of 3.0 equiv. of sodium azide was added to the reactor, and then the reaction was stirred at room temperature for 18 h. After the reaction, the reaction mixture was washed in a mixture of saturated brine and ethyl acetate, the organic phase was separated, dried with sodium sulfate and spin-dried to obtain 0.9 equiv. (R)-(2- tert-butyl isocyanato-1-phenylethyl)carbamate in 90% yield. Using high-resolution mass spectrometry (ESI+) detection, the found value was...

Embodiment 2

[0052] (1) the preparation of (R)-(2-isocyanato-1-phenylethyl) carbamate tert-butyl ester shown in formula V, its route is as follows:

[0053]

[0054] Operation steps: in the reactor, dissolve 2.5 g, 1.0 equiv. of N-Boc-beta-phenylalanine as shown in formula VI in 10 mL of methyl tert-butyl ether, and add to it under ice bath conditions. 0.9 equiv. ethyl chloroformate and 2 equiv. DBU, keep the ice bath, and stir the reaction for 1 h; then still under the ice bath condition, add 3.5 equiv. of sodium azide aqueous solution to the reactor, and then stir the reaction at room temperature for 18 h. After the reaction, the reaction mixture was washed in a mixture of dichloromethane and water, and the organic phase was separated, dried with sodium sulfate and spin-dried to obtain 0.75 equiv. (R)-(2-isocyanide shown in formula V) tert-butyl acid-1-phenylethyl)carbamate in 75% yield. Using high-resolution mass spectrometry (ESI+) detection, the found value was 295.1654.

[0055]...

Embodiment 3

[0061] (1) the preparation of (R)-(2-isocyanato-1-phenylethyl) carbamate tert-butyl ester shown in formula V, its route is as follows:

[0062]

[0063] Operation steps: In a reactor, dissolve 2.5 g, 1.0 equiv. of N-Boc-beta-phenylalanine as shown in formula VI in 15 mL of 2-methyltetrahydrofuran, and add 2.4 equiv. Phenyl chloroformate and 2.5 equiv. triethylamine were stirred and reacted for 1 h; then, an aqueous solution of 2.5 equiv. of sodium azide was added to the reactor, and then the reaction was stirred at room temperature for 18 h. After the reaction, the reaction mixture was washed in a mixture of dichloromethane and water, and the organic phase was separated, dried with sodium sulfate and spin-dried to obtain 0.81 equiv. (R)-(2-isocyanide as shown in formula V) tert-butyl acid-1-phenylethyl)carbamate in 81% yield. Using high-resolution mass spectrometry (ESI+) detection, the found value was 295.1652.

[0064] (2) the synthesis of the polysubstituted pyrimidine...

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Abstract

The invention discloses a method for synthesizing multi-substituted pyrimidine derivatives in a two-step method, comprising the following steps: (1) derivatizing N-Boc-beta-phenylalanine as shown in formula VI into an acyl azide, and then Curtius rearrangement obtains (R)-(2-isocyanato-1-phenylethyl) tert-butyl carbamate as shown in formula V; (2) (R)-( 2-isocyanato-1-phenylethyl) tert-butyl carbamate and (Z)-3-amino-2-(2-fluoro-3-methoxyphenyl)- Ethyl 2-butenoate obtains the polysubstituted pyrimidine derivatives as shown in formula I through cyclization reaction; The present invention has the advantages that the starting compound is simple and easy to get, the synthetic route is simple, easy to operate, and the yield of the reaction is relatively high. High; the method reduces the production cost of the target compound and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and pharmaceutical intermediates, in particular to a method for synthesizing polysubstituted pyrimidine derivatives by a two-step method. Background technique [0002] Endometriosis is a common gynecological disease, and its occurrence is also relatively harmful, especially for pregnancy. [0003] Endometriosis has the following risks: [0004] (1) Infertility: If a woman has ectopic endometrium, the pelvic cavity of the woman will have pelvic adhesions, which will cause the blockage of the fallopian tubes. If the time is too long, it will cause a lump in the pelvic cavity of the patient, making the male sperm unable to Normal fertilization with egg cells or the inability to send the fertilized egg into the uterus, resulting in female infertility. Many female patients are infertile due to endometriosis, and some mild patients with no obvious abnormality can also have secondary infertil...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/54
Inventor 胡志刚许良志何大荣杜小鹏钱祝进何勇
Owner 安徽诺全药业有限公司
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