- Radiosynthesis of the 11C-methyl derivative of LBQ657 for PET investigation of the neprilysin inhibitor sacubitril
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Neprilysin, also known as neutral endopeptidase, is a cell surface membrane metalo-endopeptidase that cleaves various peptides. Altered neprilysin expression has been correlated with various cancers and cardiovascular diseases. In this work, we present the radiosynthesis of the novel O-11C-methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [11C]methyl ester ([11C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a 11C-methyl instead of an ethyl. [11C]MeOLBQ was produced in a one-pot two-step synthesis. The O-11C-methylation of the pentanoic acid part was done with [11C]methyl triflate followed by the deprotection of the tert-butyl ester precursor in acidic conditions. [11C]MeOLBQ ([11C]7) was produced in 9.5 ± 2.5% RCY (25 ± 6% decay-corrected from [11C]CO2, n = 3) high molar activity 348 ± 100 GBq/μmol (9425 ± 2720 mCi/μmol) at EOS, in high chemical (>95%) and radiochemical (>99%) purities. The total synthesis time including HPLC purification and reformulation was 29 minutes. To our knowledge, this is the first PET-labeled analog of the clinically used NEP inhibitor sacubitril.
- Teyssier, Valentin R.,Simard, José-Mathieu,Dornan, Mark H.,Tournoux, Fran?ois,DaSilva, Jean N.
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- Multigram scale, chiron-based synthesis of sacubitril
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Based on a chiron approach, sacubitril, a neprilysin inhibitor and API of Entresto, was synthesized in 7 steps with an overall yield of 40%. Two chiral centers of sacubitril are easily obtained from the starting material, one inherited and another inverted. Noteworthy steps are an efficient and mild preparation of epoxide from chiral vicinal diol using C4F9SO2F/DBU, and a one-flask preparation of succinic amide from azide. All the reactions are performed on multigram scales.
- Wang, Yun,Chen, Fen-Er,Shi, Yong,Tian, Wei-Sheng
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- Highly Regio- A nd Enantioselective Hydrogenation of Conjugated α-Substituted Dienoic Acids
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Highly regio- A nd enantioselective hydrogenation of conjugated α-substituted dienoic acids was realized for the first time using Trifer-Rh complex, providing a straightforward method for the synthesis of chiral α-substituted ?,?′-unsaturated acids. DFT calculations revealed N+H-O hydrogen bonding interaction is formed to stabilize the transition state and the coordination of 4,5-double bond to Rh(III) center would facilitate the reductive elimination process. This hydrogenation provided a gram-scale synthesis of the precursor of sacubitril.
- Liu, Xian,Liu, Song,Wang, Quanjun,Zhou, Gang,Yao, Lin,Ouyang, Qin,Jiang, Ru,Lan, Yu,Chen, Weiping
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p. 3149 - 3154
(2020/04/09)
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- Compound for preparing sacubitril and preparation method and applications thereof
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The invention provides a compound for preparing sacubitril and a preparation method and applications thereof. The compound has structures represented by the formula I and the formula II. The compoundhas two chiral centers. When the compound is applied to prepare sacubitril, complicated low-yield-selectivity reactions for introducing chiral groups are avoided completely, the reaction efficiency isgreatly improved; and the reaction steps are shortened. The compound represented by the formula I and the formula II can be used to prepare a sacubitril intermediate namely (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-ethyl methyl valerate. The preparation method only comprises several simple steps, does not contain any reaction for introducing chiral centers, has the advantages of short synthesisroute, low synthesis cost, and convenient operation, and is suitable for industrial production.
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- A biphenyl methyl lactam compound preparation method
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A biphenyl methyl lactam compound preparation method, relates to the field of compound preparation techniques, the method comprising the following steps: (1) compound a in the alcohol organic solvent and in the presence of strongly alkaline inorganic alkali reaction, to the reaction solution, the reaction liquid filter, for adjusting the pH value of the filtrate acetic acid to weak acid, concentrated, to obtain white solid, adding water stirring beating, and fighting slurry, obtain white solid biphenyl methyl lactam compound crude product; (2) in a certain amount of 2nd organic solvent is added in the benzyl group of the connection lactam compound crude product, heated and dissolved and across the membrane, slow cooling crystallization, to obtain purified diphenyl methyl lactam compounds. The method of having high yield, purity of the product and the like.
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Paragraph 0023-0039
(2019/07/04)
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- SACUBITRIL INTERMEDIATE AND PREPARATION METHOD THEREOF
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The present invention relates to a sacubitril intermediate and a preparation method thereof. The sacubitril intermediate disclosed herein can be prepared by a deprotection reaction of a compound. In addition, the intermediate can be used as a raw material to synthesize sacubitril. The method disclosed herein has advantages of easily obtained raw materials, simple preparation process, low cost, environment friendly, and etc., which is very suitable for industrial production.
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- NEW PROCESSES AND INTERMEDIATES FOR NEP INHIBITOR SYNTHESIS
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The present invention relates to a new chemical synthesis, intermediates and catalysts useful for the preparation of the neprilysin (NEP) inhibitor sacubitril, inter alia via nitro 5 compounds. It further relates to new intermediate compounds and their use for said new chemical synthesis route, as well as a new catalyst ligand.
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Page/Page column 69; 70
(2018/03/09)
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- SOLID FORMS OF (2R,4S)-5-(BIPHENYL-4-YL)-4-[(3-CARBOXYPROPIONYL)AMINO]-2- -METHYLPENTANOIC ACID ETHYL ESTER, ITS SALTS AND A PREPARATION METHOD
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The invention relates to solid forms of the free acid of sacubitril of formula 1, especially a crystalline form, incl. a method of removing chemical impurities from the crude free acid of sacubitril that is characterized in the use of well crystallizing salts of sacubitril with the amines of formula 9, where R1, R2, R3 independently stand for hydrogen or a C1-C7 alkyl, preferably the salt with cyclohexylamine, tert-butylamine or iso-propylamine. The invention further relates to a novel solid, crystalline form of sacubitril (8) - hemisolvate of the potassium salt of sacubitril, incl. a direct and highly efficient and industrially usable preparation methods of a solid form of sacubitril free acid and its pharmaceutically applicable salts, especially the crystalline sodium salt of formula 5, calcium salt of sacubitril of formula 6 and hemisolvate of the potassium salt of sacubitril of formula 8.
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Page/Page column 36; 37
(2017/07/06)
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- Method for preparing LCZ696 impurity reference substance
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The invention provides a method for preparing an LCZ696 impurity reference substance. The method comprises the following steps: performing a reaction on (2R, 4S)-5-(biphenyl-4-yl)-4-[(t-butyloxycarboryl) amino]-2-methylpentanoic acid and thionyl chloride in ethanol so as to obtain a compound of formula I; performing a reaction on the compound of the formula I under a weak alkali condition so as to obtain a compound of formula II; performing heating reflux on succinic anhydride in isopropanol so as to obtain a compound of formula III; performing a reaction on the compound of the formula III with thionyl chloride so as to obtain a compound of formula IV; preparing the LCZ696 impurity reference substance of formula V from the compound of the formula II and the compound of the formula IV under catalysis of a strong alkali catalyst. By adopting the method provided by the invention, consumption of raw materials is reduced as a whole, the method is economic and environmental-friendly, different steps of reactions can be relatively easily implemented and controlled, meanwhile the amount of heavy metal catalysts is reduced and avoided, and the quality indexes of final products are improved.
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Paragraph 0029; 0030; 0031; 0060; 0061; 0062-0083
(2017/11/30)
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- Compounding method for LCZ696 midbody
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The invention discloses a compounding method for a LCZ696 midbody. The compounding route is as follows: wherein R1 is Me, Et or i-Pr; X is Cl, Br or I; R2 is Ms, Ts or Tf. According to the compounding method for the LCZ696 midbody disclosed by the invention, the methylating difficulty is reduced, the midbody is configured and overturned through the consequent reaction, the proportion of the required configuration is greatly increased, the product yield, purity and use ratio are increased and the industrial large-scale production is benefited.
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- Method for preparing chiral diphenyl pyrrolidone and intermediate compounds
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The invention relates to the technical field of chiral diphenyl pyrrolidone preparation methods. Compared with the prior art disclosed in the patent WO2008083967, a method for preparing chiral diphenyl pyrrolidone disclosed by the invention avoids the two steps of adding a protection group of the pivaloyl group and removing the protection group of the pivaloyl group and is short in route, and does not need pivaloyl chloride which may cause serious pollution. Meanwhile, the purity of the important intermediate compound chiral diphenyl pyrrolidone obtained by the method is high, and the follow-up reaction is facilitated. The invention further provides a plurality of novel intermediate compounds.
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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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Paragraph 0049; 0050; 0051; 0052
(2017/04/26)
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- Method for preparing sha Kubi tune (by machine translation)
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The present invention discloses a new kind of antihypertensive medicine LCZ696 sha Kubi tune components of (Sacubitril, AHU-377, I) method for the preparation of, its preparation comprises the steps of: using chiral inducing reagent (S) - 1 - (α-aminobenzyl) - 2-naphthol (S-betti? Base) and 2R-methyl-4-oxo-butyric acid after cyclization, addition, debenzylation, open-loop, reaction of esterification and amidation step to make the sha Kubi tune (I). The raw materials of this preparation method is easy to obtain, process is simple, economic and environmental protection, is suitable for industrial production. (by machine translation)
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Paragraph 0030; 0031
(2017/02/28)
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- Preparation method for Sacubitril intermediate
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The invention relates to a preparation method for a Sacubitril intermediate. The preparation method comprises the following steps that (3R,5S)-5-(hydroxymethyl)-3-methyl-2-pyrrolidone is esterified with toluene sulfochloride or methanesulfonyl chloride to obtain (3R,5S)-5-(methyl p-toluenesulfonate)-3-methyl-2-pyrrolidinone or (3R,5S)-5-(methyl methanesulfonate)-3-methyl-2-pyrrolidinone; (3R,5S)-5-(methyl p-toluenesulfonate)-3-methyl-2-pyrrolidinone or (3R,5S)-5-(methyl methanesulfonate)-3-methyl-2-pyrrolidinone is coupled with 4-diphenylmagnesium bromide or 4-diphenylmagnesium chloride to obtain (3R,5S)-3-methyl-5-(1,1'-diphenyl-4-yl-methyl)-2-pyrrolidinone. According to the preparation method, the method is novel, the raw materials are easy to obtain, the technology is simple, and the purity and yield of the product are both very high.
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- NEW PROCESSES
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The invention relates to a new process for producing NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone. In detail, the new processes, according to the present invention, are ultimately related to the synthesis of intermediates to prepare the above NEP inhibitors, namely compounds according to formula (1), or salt thereof, wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, and R3 is a carboxyl group or an ester group, preferably carboxyl group or alkyl ester.
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Page/Page column 300
(2009/08/16)
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