- Diastereoselective Synthesis of an Industrially Relevant 4-Aminopentanoic Acid by Asymmetric Catalytic Hydrogenation in a Biphasic System Using Aqueous Sodium Hydroxide as Substrate Phase
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A 'basic solution' for multiphase catalysis: The diastereoselective synthesis of a pharmaceutically relevant 4-aminopentanoic acid derivative has been studied using a chiral homogeneous catalyst in tailored biphasic reaction media. Different polar solvents were investigated as the stationary phase for the well-established Ru-Mandyphos catalyst in combination with aqueous NaOH as the substrate and product phase. Facile product isolation and effective recycling of the catalyst phase were demonstrated at gram-scale. In particular, up to 3200 turnovers have been achieved in seven repetitive batches with a diastereoselectivity of 87-96% using [EMIM][NTf2]/NaOHaq as the biphasic system.
- Piscopo, Calogero G.,Gallou, Fabrice,Leitner, Walter,Franciò, Giancarlo
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- Optimization and process improvement for LCZ696 by employing quality by design (QbD) principles
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Efforts toward optimization and improvement for the synthesis of LCZ696 employing design of experiment (DoE) principles are described. By increasing the purity of intermediates and mitigating impurity risk during each step, a telescoped process was developed via removal of isolation of intermediates with the overall yield increased by 28.5% from 45.3% to 73.8%. And the whole production cycle was also shortened from 12 days to 7 days with simplified operations and restored process greenness. Meanwhile, the corresponding impurity profile was thus studied in detail and well documented.
- Chen, Zhijun,Wang, Hailong,Wu, Shuming,Wang, Jian,Zhang, Chenxia,Yang, Hua,Wang, Zhongqing
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- Synthesis, Isolation, and Analysis of Stereoisomers of Sacubitril
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An efficient industrial synthetic process for sacubitril has been developed. Stereoisomers derived from sacubitril and its crucial intermediate have been synthesized, isolated, and characterized for quality control. These stereoisomers were characterized by spectral data (MS and NMR) and used as reference standards for development of HPLC methods.
- Halama, Ale?,Zapadlo, Michal
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- Method for preparing chiral biaryl substituted 4-amino-butyric acid and derivative thereof
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The invention discloses a method for preparing chiral biaryl substituted 4-amino-butyric acid and a derivative thereof. The method belongs to chiral catalytic hydrogenation reaction, and has the advantages of high conversion rate, good selectivity, simplicity in operation, low catalyst dosage, low production cost, suitability for industrial large-scale production and the like.
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Paragraph 0057-0068
(2021/09/01)
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- Substituted ferrocenyl diphosphine homogeneous catalyst ligand
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The invention provides a substituted ferrocenyl diphosphine homogeneous catalyst ligand formula I compound. Further, the formula I compound is a metal complex ligand of a homogeneous hydrogenation catalyst. The catalyst ligand is easy to synthesize, convenient to post-treat and easy for industrial production, and very high activity, productivity and enantioselectivity can be obtained by using thecatalyst. The compound is shown in the specification.
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Paragraph 0028-0029
(2021/03/13)
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- Preparation method of sacubitril valsartan sodium
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The invention provides a preparation method of sacubitril valsartan sodium, and belongs to the field of medical chemistry. The preparation method comprises the following steps: by using a compound S309A03 as a raw material, carrying out hydrogenation reaction to generate a compound BPA08, reacting the compound BPA08 in ethanol to generate a compound SAC01, reacting the compound SAC01 with succinicanhydride to generate a compound SAC02, optionally reacting the compound SAC02 with sodium hydroxide, and reacting the compound SAC03 with calcium chloride to generate a compound SAC04; and subjecting the compound SAC04 to acid treatment to obtain a compound YJX01, and enabling the compound YJX01 to react with VST in a single solvent in the presence of sodium hydroxide to prepare the compound YJX02. The preparation method disclosed by the invention is simple to operate, the time required by the process is reduced, the total yield of the process route is greatly improved, an unexpected technical effect is obtained, impurities in the process are removed, and a product with higher purity is obtained. The method has mild process conditions and easily available raw materials, and is suitable for industrial amplification.
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Page/Page column 11-14
(2021/03/31)
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- Preparation method of sacubitril intermediate
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The invention relates to a preparation method of a sacubitril intermediate, and belongs to the technical field of drug intermediate synthesis. The problems that existing operation is large in difficulty and not easy to control are solved. In the presence of a nickel salt catalyst and (R,R)-(-)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine, a compound (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid represented by formula II and ammonium formate are mixed in an alcohol solvent and undergo an asymmetric reduction reaction to obtain the corresponding sacubitril intermediate compound represented by formula I. The method does not need to be required to be in an inert atmosphere during production, and is more beneficial to operation. The cost of the raw materials is effectively reduced, and the effect of high yield can still be achieved.
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Paragraph 0033-0061
(2020/07/02)
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- Method for preparing sacubitril and intermediate thereof
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The invention provides a method for preparing sacubitril and an intermediate thereof and belongs to the field of medicine synthesis. The method comprises the following steps: by taking a compound I asa raw material, carrying out an asymmetric reduction reaction under the action of a chiral metallic catalyst so as to obtain an intermediate; finally carrying out a simple synthesis step, thereby obtaining a target product sacubitril. The method is short in synthesis route, easy to implement, high in reaction yield, good in diastereoselectivity, and capable of avoiding relatively tedious aftertreatment steps, and reducing the production cost of the sacubitril while the production efficiency of the sacubitril is improved.
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- Oxa-spiral diphosphine ligand and application thereof in alpha, beta-unsaturated carboxylic acid asymmetric hydrogenation
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The invention provides an oxa-spiral diphosphine ligand. The oxa-spiral diphosphine ligand has a structure shown by a general formula (I) as shown in description, wherein R1, R2, R3 and R4 in the general formula (I) are same and are alkyl, alkoxy, aryl, aroxyl, or hydrogen atoms; R1, R2, R3 and R4 comprise forms of ring formation, non-ring formation, any two ring formation or multiple-ring formation between pairs; R5 and R6 are alkyl, aryl or hydrogen atoms; and R7 and R8 are alkyl or benzyl or aryl. The invention further provides application of the oxa-spiral diphosphine ligand O-SDP in the alpha, beta-unsaturated carboxylic acid asymmetric hydrogenation. A complex of the oxa-spiral diphosphine ligand O-SDP and ruthenium has excellent activity and enantioselectivity in the asymmetric hydrogenation of the alpha, beta-unsaturated carboxylic acid in multiple types, and a chiral carboxylic acid product is obtained with the enantioselectivity being up to 99%. The synthesis method can be applied to the construction of a core skeleton of chemical molecules with important activity, wherein the chemical molecules comprise Paroxetine, Femoxetine, nipecotic acid and Sacubitril.
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Paragraph 0092-0094
(2019/04/04)
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- 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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- Preparation method of sacubitril-valsartan compound and/or eutectic key intermediate sacubitril calcium
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The invention relates to a preparation method of a sacubitril-valsartan compound and/or eutectic key intermediate sacubitril calcium. The provided preparation method of sacubitril calcium adopts (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((t-butyloxycarboryl)amino)-2-methyl-pentyl-2-olfine acid, and hydrogenation, esterification and acylation reactions are carried out, so that sacubitril calcium is obtained. The provided preparation method is simple to operate, low in cost and applicable to industrial production.
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Paragraph 0035-0038
(2018/09/11)
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- AHU - 377 preparation method of the midbody and intermediate and intermediate preparation method
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The invention relates to the field of chemical synthesis of medicines and in particular relates to a preparation method and intermediate of an AHU-377 intermediate and a preparation method of the intermediate. The preparation method of the AHU-377 intermediate shown in a formula (I) in the description comprises the following steps: performing a substitution reaction on a compound shown in a formula (II) in the description and a compound shown in a formula (III) in the description and then carrying out hydrolysis to prepare the AHU-377 intermediate shown in the formula (I), wherein the hydrolysis reaction is carried out in the presence of hydrogen peroxide and lithium hydroxide hydrate. The invention also aims to provide a new compound with a structure shown in the formula (II). In the new route, as a new compound shown in a formula (IV) in the description is prepared through reaction of the compound in the formula (II) and the compound in the formula (III), the selectivity is quite good, and a few diastereoisomers are generated in the reaction process and can be removed only through simple aftertreatment.
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Paragraph 0113; 0114; 0115; 0116
(2017/10/13)
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- Preparation method of LCZ696 midbody
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The invention relates to the technical field of drug midbody synthesis, and particularly discloses a preparation method of the LCZ696 midbody. The method takes N-[(1R)-2-[1, 1'-biphenyl]-4-radical-1-(iodomethyl) ethyl] tert-butyl carbamate as a raw material, and the raw material is reacted with dimethyl methylmalonate; through hydrolytic decarboxylation and chiral resolution, the (2R, 4S)-5-(biphenyl-4-radical)-4-[(t-butyloxycarboryl) amio]-2-methylpentanoic acid. The method is simple in synthetic mode and short in steps; the chiral amine and other low-price resolving agent can be used for replacing the chiral noble metal catalyst; the method is stable in activity, gentle in condition, and low in equipment requirement; moreover, the operation condition of the method is easy to control, and free from pollution, low in energy consumption, and small in risk; therefore, the method is applicable to the industrial production.
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- N - tert-butoxycarbonyl - (4S) - (the phenyl phenyl methyl) - 4 - amino - (2R) - methyl butyric acid chiral preparation method
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The invention relates to a chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid. The chiral preparation method comprises the following step: enabling a compound (1) and hydrogen to react in the presence of Pd/C and (S-phenylethylamine), thereby preparing a compound (2-a) as shown in the specification. The chiral preparation method is simple in reaction condition, easy to operate, easy in obtaining reagents, and applicable to industrial production, the cost can be lowered as an expensive chiral catalyst is not used, and both the reaction efficiency is improved and the product purity is ensured.
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Paragraph 0041
(2017/08/25)
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- Sacubitril and preparation method of midbody of sacubitril
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The invention discloses sacubitril and a preparation method of midbody of the sacubitril, and relates to the field of pharmaceutical synthesis. According to preparation method of the sacubitril midbody, a compound I of a first chiral center is taken as a starting material, and is subjected to acylation reaction prothetic group adding, asymmetric methylation reaction and hydrolysis prothetic group removal, so that the sacubitril midbody is obtained. Asymmetric methylation in the alpha-position of the carbanyl group is effectively and selectively is realized through the adding of chiral prothetic group and the cooperative control of the chiral prothetic group and the first chiral center, so as to construct a second chiral center. The preparation method of the sacubitril midbody has the advantages that the raw materials are easy to get, the method is simple to operate, separation and purification are convenient, the yield and diastereoselectivity are high, and the dose is convenient to magnify to realize industrial production. The obtained sacubitril midbody is high in chiral purity, a tedious step for separating a diastereoisomer is canceled, and the production efficiency is improved.
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- Novel synthesis method of key component Sacubitril of novel anti-heart-failure drug
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The invention discloses a novel synthesis method of key component Sacubitril of a novel anti-heart-failure drug. The method includes transforming a starting material compound 1 to a compound 2; coupling the compound 2 with (1'1)-4-biphenylmagnesium bromide to obtain a compound 3; subjecting the compound 3 to hydrolysis reaction by loading a Boc protecting group, and preparing a compound 5 by means of one-pot reaction; subjecting the compound 5 to Boc group removal and esterification reaction to obtain a compound 6, and reacting the compound 6 with succinic anhydride without separation to obtain a compound 7, namely Sacubitril, wherein the route is as following.
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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; 0034
(2017/08/29)
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- A NEP inhibitor intermediates preparation method
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The invention discloses a preparation method of an NEP (neutral endopeptidase) inhibitor intermediate, further discloses a selective reduction preparation method of the NEP inhibitor intermediate (2R, 4S)-5-([1,1'-biphenyl]-4-yl)-4-((t-butyloxycarboryl)amino)-2-methylpentanoic acid in presence of a chiral ligand, and particularly discloses a diastereoselective hydrogenation synthetic method with hydrogen under the condition of presence of a transition metal catalyst and the chiral ligand. The metal catalyst used in the method is cheap, the chiral ligand is obtained easily, high yield is realized, a high-purity product is produced preferably, and the product with the proportion of diastereoisomers being 90:10 is produced preferably.
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Paragraph 0037; 0038; 0039; 0040; 0041; 0042; 0043; 0044
(2017/08/25)
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- Preparation method and application of biaryl substituted 4-amino-butyric acid or derivative of biaryl substituted 4-amino-butyric acid
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The invention relates to a preparation method of biaryl substituted 4-amino-butyric acid or a derivative of biaryl substituted 4-amino-butyric acid. The preparation method comprises the step as follows: a compound (II) is subjected to a reaction with hydrogen under the condition of presence of a transition metal catalyst and a chiral ligand, and a compound (I) is generated, wherein the transition metal catalyst is a rhodium catalyst, the chiral ligand is a chiral phosphorous ligand with a conformational stiffening ring structure, phosphorus can be in bond linkage with the ring structure or taken as one part of the ring structure, and biaryl substituted 4-amino-butyric acid or the derivative of biaryl substituted 4-amino-butyric acid is prepared from the compound (I) through further processing.
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Paragraph 0025
(2017/06/02)
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- NOVEL PROCESS FOR THE PREPARATION OF SACUBITRIL AND ITS INTERMEDIATES
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A process for the preparation of sacubitril and its intermediates is disclosed. By practicing the methods disclosed herein, a solid form of sacubitril may be generated. A crystalline form of sacubitril is also disclosed.
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- Preparation method of anti-heart-failure drug intermediate
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The invention discloses a preparation method of an anti-heart-failure drug intermediate (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tertbutyloxycarbonyl)amino)-2-methylpentanoic acid. Under catalysis of a transition metal catalyst bis(dicyclopentadiene)rhodium tetrafluoroborate and a ligand (CK004), butoxy carbonyl-D-tyrosine which is used as a raw material undergoes diastereoselective hydrogenation synthesis by the use of hydrogen to obtain chiral center; and a product obtained after recrystallization of the chiral center and hydroxide radical form a leaving group by the use of trifluoromethanesulfonic anhydride; and an intermediate V undergoes a coupling reaction by the use of phenylboronic acid so as to obtain the finished product. The invention provides a brand-new synthesis route of the anti-heart-failure drug intermediate. The reaction steps are easy to control, and stable industrial production preparation can be realized.
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- NEW PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL FOR THE MANUFACTURE 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 -amino- -biphenyl- -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 0459; 0460; 0461; 0462
(2013/06/28)
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- NEW PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL FOR THE MANUFACTURE 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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- 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 17-18
(2008/06/13)
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