A kind of lzc696 intermediate and its synthetic method

A compound and reaction system technology, which is applied in the field of intermediates for the synthesis of NEP inhibitors, can solve the problems of sensitivity, high production costs, and unrecoverable palladium heavy metal catalysts, etc., and achieve the effect of low process costs and simple purification procedures

Active Publication Date: 2018-07-06
SHANGHAI BOC CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This patent uses very expensive raw materials D-tyrosine and trifluoromethanesulfonic anhydride as raw materials, and also uses Suzuki coupling reaction, which is extremely sensitive to oxygen, palladium heavy metal catalysts cannot be recovered, and post-treatment wastewater needs to be strictly Discharge can only be done after treatment, and the entire process requires column chromatography to purify intermediates and final products. These three factors lead to very high production costs for this process

Method used

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  • A kind of lzc696 intermediate and its synthetic method
  • A kind of lzc696 intermediate and its synthetic method
  • A kind of lzc696 intermediate and its synthetic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] This embodiment discloses a method for producing a compound of formula A

[0064]

[0065] Include the following steps:

[0066] a) Take the compound D-serine methyl ester hydrochloride (1000g, 6.45mol, 1eq) and dissolve it in 5L of dichloromethane, add triethylamine (1955g, 19.35mol, 3eq), keep the temperature at -5~5℃, divide Add triphenylchloromethane (2152g, 7.74mol, 1.2eq) in batches, stir at room temperature until the reaction is complete, add water to quench, separate the layers, wash the organic phase with hydrochloric acid, and use anhydrous sodium sulfate when TLC detection confirms that there is no triethylamine After drying and concentrating the solvent, a white solid was obtained which was N-trityl-D-serine methyl ester. Yield 92%. The nuclear magnetic and mass spectrum data of product in this step are as follows:

[0067] 1H NMR (300MHz, CDCl3) 7.34(s, 6H), 7.23(d, 6H), 7.21(m, 3H), 5.23(s, 1H), 4.23(m, 1H), 3.87(m, 1H), 3.72 (m,1H)3.62(m,3H),3.52(m...

Embodiment 2

[0081] The compound A obtained by the method in Example 1 is used to prepare compound B, specifically:

[0082] (R)-tert-butyl(1-((1,1'biphenyl)-4-yl)3-((tert-butyldimethylsilyl)oxy)propan-2-yl)carbamate (1000g, 2.26mol, 1eq) was dissolved in 6L of dichloromethane, cooled to -10°C and slowly added tetrabutylammonium fluoride (540g, 2.06mol, 0.9eq), after the reaction, sodium bicarbonate solution was added, and the liquid was separated , the organic phase was washed with salt water, separated, the organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated to obtain a white powder which was LZC696 intermediate (R)-tert-butyl (1-([1,1'-biphenyl ]-4-yl)-3-hydroxypropan-2-yl)carbamate. Yield 90%, purity 99%, EE>99%. The nuclear magnetic data and mass spectrum data of product in this step are as follows:

[0083]1HNMR (300MHz, DMSO) 7.65(m,1H),7.63(m,1H),7.58(m,1H),7.56(m,1H),7.47(s,1H),7.45(s,1H),7.28( s,1H),7.43(s,1H),7.36(s,1H),7.34(s,1H),6....

Embodiment 3

[0089] This embodiment discloses a method for producing a compound of formula A, comprising the following steps:

[0090] a) Dissolve the compound D-serine methyl ester hydrochloride (10g, 64.5mmol, 1eq) in 100mL of dichloromethane, add triethylamine (19.6g, 193.5mmol, 3eq), keep the temperature at 45-50°C, divide Add triphenylchloromethane (21.5g, 77.4mmol, 1.2eq) in batches, stir at room temperature until the reaction is complete, add water to quench, separate the layers, wash the organic phase with hydrochloric acid, and use anhydrous sulfuric acid when it is confirmed by TLC that there is no triethylamine Drying over sodium and concentrating the solvent gave a white solid which was N-trityl-D-serine methyl ester. Yield 89%. The nuclear magnetic and mass spectrum data of product in this step are as follows:

[0091] 1H NMR (300MHz, CDCl3) 7.35(s, 6H), 7.23(d, 6H), 7.21(m, 3H), 5.24(s, 1H), 4.23(m, 1H), 3.87(m, 1H), 3.72 (m,1H)3.62(m,3H),3.52(m,1H)MS: m / z=362.2(M+H)+;

...

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Abstract

The invention discloses a compound, which is (R)-tert-butyl(1-((1,1'biphenyl)-4-yl)3-((tert-butyldimethylsilyl)oxy ) propane-2-yl) carbamate, its structural formula is as shown in formula A: A. Using this compound to synthesize the LZC696 intermediate, there are no expensive reagents and raw materials in the whole process, no oxygen-sensitive reaction, and the purification procedure is simple. It only needs to recrystallize and purify the compound 3 and the final product to achieve commercial purity. The synthesis process of the invention has low cost, is simple and environment-friendly, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, in particular to a method for synthesizing an intermediate of an NEP inhibitor. Background technique [0002] Mammalian endogenous atrial natriuretic peptide (ANP), also known as atrial natriuretic peptide (ANF), has diuretic, natriuretic and vasodilation functions. Native ANF peptides are metabolized and inactivated, in particular by the action of a degradative enzyme thought to be equivalent to neutral endopeptidase (NEP, EC 3.4.24.11), which is also responsible for enkephalin Metabolic inactivation. Biaryl-substituted phosphonic acid derivatives are recognized in the art as useful neutral endopeptidase (NEP) inhibitors, such as inhibitors of mammalian ANF-degrading enzymes, by inhibiting ANF from being degraded to active Poor metabolites to prolong and enhance the diuretic, natriuretic and vasodilatory effects of ANF in mammals. NEP inhibitors are therefore particularly useful in the treatme...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18C07C271/16C07C269/06
Inventor 李尚立董玉军丁杨
Owner SHANGHAI BOC CHEM CO LTD
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