Preparation method of LCZ696 intermediate

A technology of intermediates and ligands, which is applied in the field of preparation of aromatic ring compounds, can solve the problems of unsuitability for industrial scale-up production, expensive starting raw materials, and large amount of solvents used, so as to avoid the use of heavy metal catalysts and reduce heavy metals The effect of the use of catalyst and the convenience of obtaining materials

Active Publication Date: 2016-08-24
CANGZHOU SENARY CHEM SCI TEC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The starting material price of this method is relatively expensive, the supplier is limited, the overall raw material consumption is high, the yield is relatively low, the amount of solvent used is large, the cost is high, the chiral selectivity is poor, the post-treatment is cumbersome, the process operation is complicated, and it is not suitable for industrial scale-up. Production

Method used

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  • Preparation method of LCZ696 intermediate
  • Preparation method of LCZ696 intermediate
  • Preparation method of LCZ696 intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Put 2g of monomethyl oxalyl chloride and 8ml of tetrahydrofuran into the reaction flask, cool down to -10~0°C, add 15.94g of 20% benzylmagnesium bromide tetrahydrofuran solution dropwise, add dropwise for 1h, keep stirring for 2h after dropping, add 8ml of 1N hydrochloric acid, continued to stir, added 12ml of ethyl acetate to extract three times, combined the organic phases, washed with 4ml of saturated sodium chloride, and concentrated to no fraction to obtain 2.33g of the compound of formula I, with a yield of 80%.

Embodiment 2

[0038] Put 10g of monomethyl oxalyl chloride and 40ml of tetrahydrofuran into the reaction bottle, cool down to -10~0°C, add 53.1g of 20% benzylmagnesium bromide tetrahydrofuran solution dropwise, add dropwise for 1h, keep stirring for 2h after dropping, add 40ml of 1N hydrochloric acid, continued to stir, added 60ml of ethyl acetate to extract three times, combined the organic phases, washed with 20ml of saturated sodium chloride, and concentrated to no fraction to obtain 7.56g of the compound of formula I with a yield of 78%.

Embodiment 3

[0040] Put 50g of monomethyl oxalyl chloride and 200ml of tetrahydrofuran into the reaction bottle, cool down to -10~0°C, add 199.3g of 20% benzylmagnesium bromide tetrahydrofuran solution dropwise, add dropwise for 2h, keep stirring for 2h after dropping, add 200ml of 1N hydrochloric acid, continued to stir, added 300ml of ethyl acetate to extract three times, combined the organic phases, washed with 100ml of saturated sodium chloride, and concentrated to no fraction to obtain 30.15g of the compound of formula I, with a yield of 78%.

[0041]

[0042] Using the compound of formula I as the substrate, a series of bromination reagents were compared and screened. The chemical equation is as follows. The bromination reaction was carried out at 10-35°C for 4-10 hours. The results are shown in Table 1: sodium bromide, tetra-tert-butyl Ammonium tribromide, N-bromosuccinimide and bromine can be used as bromination reagents to perform bromination well.

[0043]

[0044]

[00...

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Abstract

The invention discloses a preparation method of LCZ696 intermediate and relates to the technical field of preparation of an aromatic nucleus compound containing 2 benzene rings and 1 chiral center. The preparation method includes the steps of S1, allowing benzyl magnesium bromide to react with methyl oxalyl chloride to obtain a compound as shown in formula I; S2, allowing the compound as shown in formula I to have a bromination reaction with a bromination reagent to generate a compound as shown in formula II; S3, coupling the compound as shown in formula II with phenylboronic acid to obtain a compound as shown in formula III; S4, performing reductive ammoniation on the compound as shown in formula III to obtain a compound as shown in formula IV; S5, applying Boc to the compound as shown in formula IV to obtain a compound as shown in formula V; S6, performing ester group reduction on the compound as shown in formula V to obtain a compound as shown in formula VI. The preparation method has the advantages that overall raw material consumption is lowered, and product productivity and market competiveness are increased; by the overall process optimization, the reaction of each step can be performed and controlled easily, the use of heavy metal catalysts is reduced and avoided, and accordingly the quality index of the final product is increased, and an economic and environment-friendly process route is developed.

Description

technical field [0001] The invention relates to the technical field of preparation of aromatic ring compounds containing two benzene rings and one chiral center. Background technique [0002] LCZ696 is a dual inhibitor of angiotensin II (AT2) receptors and neprilysin receptors, and its antihypertensive effect is better than standard antihypertensive drugs. Two components of valsartan and AHU-377 were selected. At present, the efficacy and safety of the drug milestone III surpasses the clinical standard drug enalapril. LCZ696 is the first "breakthrough" drug that may rewrite the guidelines for the treatment of heart failure. Its unique chemical structure and the superiority of the results of the PARADIGM-HF trial make it have far-reaching clinical significance. [0003] tert-butyl N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate is an important intermediate for the synthesis of LCZ696. The existing preparation methods are mainly chemical synthesis methods, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/16C07C269/06
CPCC07C67/307C07C67/343C07C269/04C07C269/06C12P13/00C07C69/738C07C271/22C07C271/16
Inventor 张少平黄培晨王平于淑玲
Owner CANGZHOU SENARY CHEM SCI TEC
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