- Method for synthesizing AHU377 calcium salt
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The invention discloses a method for synthesizing an AHU377 calcium salt. The method comprises the following steps: reacting 4-bromo-D-phenylalanine with thionyl chloride, reacting obtained methyl 4-bromo-D-phenylalaninate hydrochloride with BOC acid anhydride, reacting the obtained reaction product with phenylmagnesium bromide to obtain N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methylester, reacting the N-tert-butyloxycarbonyl-amino-4,4-biphenyl-R-alanine methyl ester with sodium borohydride, reacting the obtained reaction product with ethyl 2-(triphenylphosphoranylidene)propionate to obtain ethyl (4R)-5-[1,1'-biphenyl]-4-yl-4-[[tert-butoxycarbonyl]amino]-2-methyl-2-pentenoate, reacting the ethyl (4R)-5-[1,1'-biphenyl]-4-yl-4-[[tert-butoxycarbonyl]amino]-2-methyl-2-pentenoatewith lithium hydroxide, performing catalytic hydrogenation, reacting the obtained catalytic hydrogenation product with thionyl chloride to obtain ethyl (2R, 4S)-5- ([1,1-biphenyl)-4-amino-2-methylpentenoate hydrochloride, and stirring and reacting the ethyl (2R, 4S)-5- ([1,1-biphenyl)-4-amino-2-methylpentenoate hydrochloride, calcium chloride and succinic anhydride to obtain the target product.The method has the advantages of simple steps, mild reaction conditions, high purity and high yield.
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- Method for preparing LCZ-696 key intermediate
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The invention relates to a method for preparing an LCZ-696 key intermediate, and aims to provide a novel method for preparing the LCZ-696 key intermediate. The LCZ-696 key intermediate has high yield, high impurity and low requirement for production equipment and is easy for industrialized production. The method includes the following steps: 1, adding NaHCO3 in water, conducting stirring and dissolving until the obtained aqueous solution is clarified, cooling the NaHCO3 aqueous solution to 10-20 DEG C, maintaining the temperature constant, and dropwise adding a NaClO solution to the NaHCO3 aqueous solution; 2, adding isopropyl acetate, a compound I and NaBr successively into a reaction kettle, conducting stirring at 20-35 DEG C for 20-40min for sufficiently dissolving, and adding TEMPO; 3, rapidly and dropwise adding the NaHCO3-NaClO aqueous solution in the compound I-NaBr-TEMPO isopropyl acetate solution obtained in step 2, purifying a compound II, and then preparing a compound IV. The method has the advantages that the yield of the compound IV is increased to 80% or above from about 50% in the prior art, the content of impurities is reduced, the purity of the prepared product reaches 99.0% or above, and thus the prepared product can be directly used in a following reaction without being purified. Moreover, the reaction temperature can be controlled in the range of 10 to 35 DEG C, the requirements for industrial equipment and operation time are reduced, and industrial production is thus greatly facilitated.
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Paragraph 0039; 0045; 0051; 0057
(2017/03/25)
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- Preparation method of LCZ-696 key intermediate
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The invention relates to a preparation method of an LCZ-696 key intermediate. The preparation method of the LCZ-696 key intermediate provided by the invention comprises the steps that a compound I is added into ethyl alcohol; lithium hydroxide and pure water are added; heat insulation reaction is performed for 1 to 2h at 78 to 82 DEG C; temperature reduction is performed; active carbon is added for decolorization; then, the temperature is raised to 80 to 85 DEG C; heat insulation backflow is performed for 1 to 3h; filtering is performed; filtering liquid is collected; a citric acid monohydrate or citric acid water solution is dripped; reaction stops; heat insulation backflow is performed for 1 to 2h at 80 to 85 DEG C; temperature reduction, stirring, crystallization, filtering and drying are performed to obtain a pure white solid compound II; a catalyst and a ligand are added; hydrogen gas is introduced; the pressure is maintained to be 1.5 to 3.5Mpa; reaction is performed for 20 to 40h at 70 to 80 DEG C to obtain reaction liquid of a compound III. The preparation method has the advantages that the yield of the compound II is improved to 8 to 12 percent from that of the prior art; the refining step is omitted; the operation difficulty is lowered; the industrial production is facilitated; meanwhile, the conversion rate of the compound II is improved by 30 to 40 percent through being compared with that of palladium-carbon hydrogenation, so that the cost of the compound III is greatly reduced; in addition, the optical isomers of the product are reduced; the reaction conversion rate is greatly improved.
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Paragraph 0031; 0032; 0033
(2017/08/29)
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- Preparation method of sacubitril intermediate having low triphenylphosphine oxide content
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The invention relates to a preparation method of a sacubitril intermediate having low triphenylphosphine oxide content. The preparation method comprises that water, isopropyl acetate, sodium bromide, sodium bicarbonate and tetramethylpiperidine oxide into (R)-tert-butyl(1-([1, 1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, adding a sodium hypochlorite solution into the mixture drop by drop for a reaction, after the reaction, carrying out layering, taking an organic layer, adding ethoxyformylethylidenetriphenyl phosphorane into the organic layer, after a reaction, concentrating the reaction product, removing isopropyl acetate, adding ethanol, water and lithium hydroxide into the mixture, carrying out heating until reflux, carrying out concentration until drying, adding water and activated carclazyte into the product, carrying out stirring at the room temperature, filtering the mixture, adding ethanol and acetic acid into the filtrate, carrying out heating until reflux, and carrying out cooling and stirring to precipitate solids which are the sacubitril intermediate finished products. The preparation method can reduce triphenylphosphine oxide content of the (R)-tert-butyl(1-([1, 1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate.
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Paragraph 0011
(2017/10/12)
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- PROCESS FOR THE PREPARATION OF INTERMEDIATES FOR THE MANUFACTURE OF NEP INHIBITORS
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The invention relates to a new process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone, such as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.
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Paragraph 0147
(2013/06/28)
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- PROCESS FOR THE PREPARATION OF INTERMEDIATES FOR THE MANUFACTURE OF NEP INHIBITORS
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The invention relates to a new process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a y-amino-5-biphenyl-a-methylalkanoic acid, or acid ester, backbone, such as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.
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Page/Page column 16; 17
(2012/03/26)
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- Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors
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The invention relates to a process for producing a compound according to formula (i) wherein R1 and R1' are independently hydrogen or an amine protecting group and R2 is a carboxylic group or derivative thereof, comprising reacting a compound according to formula (ii) wherein R1, R1' and R2 are defined as above, with hydrogen in the presence of a transition metal catalyst and optionally a chiral ligand, wherein the transition metal is selected from group 7, 8 or 9 of the periodic table. Furthermore, the invention relates to products obtainable by said process and to their use in the production of NEP inhibitors. Moreover, the invention relates to the use of transition metal catalyst in the preparation of NEP inhibitors or prodrugs thereof.
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Page/Page column 17
(2008/06/13)
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