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A preparation method of sacubitril valsartan complex and/or co-crystal key intermediate sacubitril calcium

A sacubitril and compound technology, which is applied to the preparation of pharmaceutical intermediates, the preparation field of sacubitril-valsartan complex and/or co-crystal key intermediate sacubitril calcium, can solve the problem of low efficiency, Problems such as long steps and unfavorable amplification

Active Publication Date: 2020-10-23
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] This route has long reaction steps and requires the use of expensive rhodium or ruthenium-based chiral catalysts and special ligands. The conventional palladium-carbon hydrogenation scheme disclosed in this patent has poor stereoselectivity and requires multiple refinements, which is not conducive to scale-up.
[0012] Chinese patents CN201610247438.9, CN201510317119.6, and CN201510890026.2 all report the preparation of Shakubitra calcium, but they all adopt the scheme of first making sodium salt and then converting it to calcium salt, which has long steps and low efficiency, which is not conducive to industrialization Production

Method used

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  • A preparation method of sacubitril valsartan complex and/or co-crystal key intermediate sacubitril calcium
  • A preparation method of sacubitril valsartan complex and/or co-crystal key intermediate sacubitril calcium
  • A preparation method of sacubitril valsartan complex and/or co-crystal key intermediate sacubitril calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Compound II ((2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-pentanoic acid ) preparation

[0037] Add (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-pentane to the hydrogenation vessel under stirring -2-enoic acid (compound III) (75g, 0.20mol), 10% palladium on carbon (Pd / C) (3.0g) and 750ml of ethanol, hydrogen was passed through and kept under pressure (1.0MPa, 25°C) for 20 hours. Filtrate, concentrate to dryness, add an appropriate proportion of isopropyl acetate / petroleum ether for recrystallization, and obtain a white solid (compound II) after drying, the specific data is shown in the table below. 1 H NMR (DMSO-d 6 )δ12.01(s,1H),7.63(d,2H,J=7.6Hz),7.56(d,2H,J=8.0Hz),7.47-7.43(m,2H),7.35(d,1H,J =7.2Hz),7.24(d,2H,J=8.0Hz),6.73(d,1H,J=8.8Hz),3.67-3.66(m,1H),2.68(d,2H,J=6.8Hz), 2.45-2.42(m,1H),1.78-1.71(m,1H),1.32(s,9H),1.40-1.32(m,1H),1.06(d,3H,J=6.8Hz).

[0038] Isopropyl acetate: petroleum eth...

Embodiment 2

[0040] Example 2 Preparation of Compound I ((2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl-pentanoic hydrochloride)

[0041] Add (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-pentane to the reaction flask under stirring Acid (compound II) (45g, 0.12mol), ethanol 225ml, thionyl chloride (69.3g, 0.58mol) was added dropwise at 5°C, after the addition was completed, the temperature was raised to 40°C to react for 4 hours. Concentrate to dryness, beat with petroleum ether, filter, and dry to obtain 39.5 g of off-white solid (Compound I), with a mass yield of 87.8%. 1 H NMR (DMSO-d 6 )δ8.33(s,3H),7.68-7.64(m,4H),7.49-7.45(m,2H),7.38-7.36(m,3H),4.01-3.96(m,2H),3.38-3.36( m,1H),3.12-3.08(m,1H),2.85-2.74(m,2H),1.89-1.83(m,1H),1.66-1.60(m,1H),1.09(t,3H,J=12.4 Hz), 1.07 (d, 3H, J=5.2Hz). HPLC 99.8%, isomer≤0.2%.

[0042]

Embodiment 3

[0043] Example 3 Shakubitra calcium (4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5 Preparation of -oxopent-2-yl)amino)-4-oxobutyrate calcium)

[0044] Add (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl-pentane hydrochloride (compound I) into the reaction flask under stirring (36g, 0.10mol), succinic anhydride (9.7g, 0.10mol) and DMF 90ml, add an appropriate amount of calcium-containing alkali (mixture of one or more kinds) in batches at 0-10°C, after adding, heat up to 25°C for reaction 4 hours. Add water, beat, filter, and get crude product. Add an appropriate proportion of organic solvent and water to the mixed system for recrystallization, filter, and dry to obtain an off-white solid (Sacubitronic Calcium), with all isomers ≤ 0.1%, and other data are shown in the table below.

[0045]

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Abstract

The invention relates to a preparation method of sacubitril-valsartan complex and / or co-crystal key intermediate sacubitril calcium. The preparation method of sacubitril calcium provided by the present invention adopts (R, E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino) -2-methyl-pent-2-enoic acid undergoes hydrogenation, esterification, and acylation reactions to obtain sacubitronic calcium. The preparation method provided by the invention is easy to operate, low in cost, and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a method for preparing a drug intermediate, in particular to a method for preparing a sacubitril-valsartan complex and / or a co-crystal key intermediate, sacubitril calcium. Background technique [0002] The chemical name of sacubitril valsartan calcium sodium is: Hexa-[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylaminomethyl Acyl)propanoic acid-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-yl anion)biphenyl-4'-ylmethyl}amino)butyric acid]deca Hexasodium Monocalcium Pentahydrate Complex is a structural analogue of Novartis's marketed drug Sacubitril-Valsartan Sodium (LCZ696) developed by our company. [0003] [0004] Sacubitril valsartan sodium (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNi) developed by Novartis, which was approved by the FDA on July 08, 2015, for chronic heart failure patients with reduced ejection fraction, May reduce the risk of cardi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/10C07C231/24C07C231/12C07C233/47C07D257/04
CPCC07B2200/13C07C227/04C07C231/10C07C231/12C07C231/24C07C269/06C07D257/04C07C233/47
Inventor 王颖乔智涛李泽林
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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