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8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxygen-4-hydrogen-quinazine-3-carboxylate and its synthetic method

A synthetic method, cyclopropyl technology, applied in the direction of organic chemistry, can solve the problems of low yield and low yield, and achieve the effect of increasing yield and increasing yield

Active Publication Date: 2018-02-23
TENNOR THERAPEUTICS (SUZHOU) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In this synthetic route, due to the low yield of compound 9 prepared from compound 8 and the low yield of compound 10 prepared from compound 9, the total yield of these two steps is only about 25%, resulting in the final product 8-chloro-1 - The yield of cyclopropyl-7-fluoro-9-methyl-4-oxo-4-hydro-quinolazine-3-carboxylate (compound 11) is low

Method used

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  • 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxygen-4-hydrogen-quinazine-3-carboxylate and its synthetic method

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Embodiment

[0034] This example provides a kind of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-hydrogen-quinazine-3-carboxylate, which is synthesized by the following method:

[0035] (1) Synthesis of Compound 2:

[0036] Under the protection of nitrogen, diphenylphosphine (180g), paraformaldehyde (32g), toluene (2L), morpholine (85.3g), concentrated hydrochloric acid (20mL) were added successively, heated to 110°C and separated using a water trap. water. React for 30 minutes. The reaction temperature was slowly lowered to 0 to 5°C and stirring was continued for 1.5 hours. Then filter and dry the filter cake to obtain compound 2 (255 g, yield: 95.2%). The mass spectrum data of compound 2 is: MS (ESI) 302 (M+H).

[0037] (2) Synthesis of compound 3:

[0038] Under nitrogen protection, compound 2 (255 g) and tetrahydrofuran (1.8 L) were added into the reaction flask. At 0 to 5°C, n-butyllithium / n-hexane solution (610 mL, 2.5M) was slowly added dropwise, and stirred at 0 to 5°C fo...

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Abstract

The invention provides a 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxygen-4-hydrogen-quinazine-3-carboxylate and a synthesis method thereof. The synthesis method comprises the following steps: reacting compound 6 and tert-butyldimethylchlorosilane in a first solvent under the action of a base to obtain compound 12; compounding compound 12 and 3-ethoxy-2-fluoropropene The acid chloride is reacted in a second solvent under low temperature conditions and under the action of a base to obtain compound 13; compound 13 and an acid are reacted in a third solvent to form a ring to obtain compound 14; compound 14 is prepared in hydrogen chloride / methanol or hydrogen chloride / ethanol The reaction is carried out in the solution to obtain compound 15; the compound 15 and phosphorus oxychloride are reacted in the fourth solvent to obtain the final product. In the synthesis method of the present invention, the ring-closing reaction is performed first, and then the cyano group is hydrolyzed, which can effectively improve the yield of the intermediate step.

Description

technical field [0001] The invention relates to an 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-hydrogen-quinazine-3-carboxylate and a synthesis method thereof, belonging to the technical field of chemical synthesis . Background technique [0002] In the prior art, the synthetic method of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-hydrogen-quinazine-3-carboxylate is carried out through the following synthetic route: [0003] [0004] In this synthetic route, due to the low yield of compound 9 prepared from compound 8 and the low yield of compound 10 prepared from compound 9, the total yield of these two steps is only about 25%, resulting in the final product 8-chloro-1 The yield of -cyclopropyl-7-fluoro-9-methyl-4-oxo-4-hydro-quinazine-3-carboxylate (compound 11) was low. Contents of the invention [0005] In view of the defects in the above-mentioned prior art, the object of the present invention is to propose a 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-ox...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D455/02
CPCC07D455/02
Inventor 马振坤贺世杰丁俊
Owner TENNOR THERAPEUTICS (SUZHOU) LTD