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8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-hydroxy-quinolizine-3-carboxylate and synthetic method thereof

A synthesis method and cyclopropyl technology, applied in directions such as organic chemistry, can solve problems such as low yield and low yield, and achieve the effect of improving yield and improving yield

Active Publication Date: 2017-03-29
TENNOR THERAPEUTICS (SUZHOU) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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Examples

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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 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4-hydroxy-quinolizine-3-carboxylate and a synthetic method thereof. The synthetic method comprises the following steps: a compound 6 and tert-butyldimethylsilyl chloride react in a first solvent under the effect of alkali to obtain a compound 12; the compound 12 and 3-ethoxy-2-fluoroacryloyl chloride react in a second solvent in a low-temperature condition under the effect of alkali to obtain a compound 13; the compound 13 and acid react in a third solvent to form a ring to obtain a compound 15; the compound 14 reacts in a chlorine hydride / methanol or chlorine hydride / ethanol liquid to obtain a compound 15; and the compound 15 and phosphorus oxychloride react in a fourth solvent to obtain the end product. The synthetic method provided by the invention carries out ring closing reaction first and hydrolysis of cyano groups second, and can effectively improve the yield of intermediate steps.

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. SUMMARY 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-oxo...

Claims

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Application Information

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