ChemicalBook CAS DataBase List sacubitril

sacubitril synthesis

13synthesis methods

Product Name:sacubitril
CAS Number:1038924-61-6
Molecular formula:C17H17NO
Molecular Weight:251.32

Several routes to sacubitril, particularly to advanced intermediates, have been published in the primary and patent literature.23 They differ generally in their choice of chiral pool starting material and their approach to introduction of the second stereocenter. The industrial scale synthesis of intermediate 47 has been reported. Accordingly, addition of the cuprate of biaryl bromide 41 to (S)-epichlorohydrin 42 followed by subjection to HCl provided chloropropanol 43 in 92% yield and 99% ee. Next, a Mitsunobu reaction involving succinimide 44 followed by treatment with refluxing HCl and NaOH generated the corresponding aminoalcohol, which was isolated via crystallization as the HCl salt prior to Boc protection to give N-Boc aminoalcohol 45 in >99% ee. Alcohol 45 was then carried through a four-step process to give acid 47 in 75% yield, starting with oxidation of the alcohol to the corresponding aldehyde with TEMPO/NaOCl. The organic phase was carried forward directly into a Wittig reaction with ylide 46, generating an α,β-unsaturated ester which was hydrolyzed to acid 47 with LiOH in an ethanol/water mixture. Interestingly, a separate patent disclosed the stereoselective hydrogenation of the trisubstituted olefin 47, in which subjection of 47 to catalytic [Ru(p-cymene)I2]2 and chiral phosphine ligand Mandyphos SL-M004-1 (48) under 40 bar of hydrogen gas in warm ethanol delivered 49 in 99:1 dr before recrystallization.
Subsequently, activation of the acid as the acid halide through the use of thionyl chloride and ethanol not only reestablished the ethyl ester but removed the Boc group, revealing a primary amine which then reacted with succinic anhydride to ultimately deliver sacubitril (V). The freebase form of sacubitril does not readily crystallize; the isolation of a number of pharmaceutically acceptable salts of sacubitril via crystallization, most preferably the calcium salt 50 or sodium salts, have been reported.
Preparation of the sacubitril/valsartan supramolecular complex (trisodium salt, hemihydrate) has been described on a kilo-scale from sacubitril calcium salt via neutralization to the freebase and subsequent complexation with valsartan in iPrOAc/ acetone. Addition of NaOH and crystallization then provided the desired trisodium salt hemihydrate.

72479-05-1 Synthesis

72479-05-1
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$18.00/250mg

144432-80-4
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$12.00/1g

1038924-61-6
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$435.00/1g

Yield: 95.9%

Reaction Conditions:

with potassium carbonate in water;dimethyl sulfoxide at 80;Temperature;

Steps:

1
Compound III (3.28 g, 20 mmol, X = Br) was dissolved in a mixture of DMSO (50 ml) and water (10 ml)Compound II (7.87 g, 28.1 mmol) and potassium carbonate (11 g, 80 mmol) were sequentially added.After the reaction solution was degassed, the mixture was heated to 80 ° C and stirred overnight (12 to 20 hours).TLC point plate, the raw material completely reacted.The reaction mixture was filtered through celite and the residue was washed with ethyl acetate (500 ml).The filtrate was washed with 10% ammonium chloride solution, saturated brine,The organic phase was dried over anhydrous sodium sulfate, filtered with suction,The filtrate was concentrated under reduced pressure to give 4.82 g of a white solid in a yield of 95.9%.

References:

Jiangsu Furui Bio-pharmaceutical Co., Ltd.;Chen Benshun CN104926707, 2017, B Location in patent:Paragraph 0036; 0038; 0060-0061

92-66-0 Synthesis