A sacubitril intermediate, a preparation method therefor, and use thereof. A key intermediate N-Boc amino alcohol represented by formula (10) or formula (10-a) can be efficiently prepared. The intermediate can be used to prepare a neutral endopeptidase (NEP) inhibitor or a prodrug thereof, particularly a NEP inhibitor comprising a skeleton of γ-amino-δ-biphenyl-α-methylalkanoic acid or ester, such as sacubitril. Also provided are intermediates for preparing formula (10) or formula (10-a). Raw materials of the process route are cheap, the operation is simple and convenient, the production cost is low, and the method is suitable for industrial production
A sacubitril intermediate, a preparation method therefor, and use thereof. A key intermediate N-Boc amino alcohol represented by formula (10) or formula (10-a) can be efficiently prepared. The intermediate can be used to prepare a neutral endopeptidase (NEP) inhibitor or a prodrug thereof, particularly a NEP inhibitor comprising a skeleton of γ-amino-δ-biphenyl-α-methylalkanoic acid or ester, such as sacubitril. Also provided are intermediates for preparing formula (10) or formula (10-a). Raw materials of the process route are cheap, the operation is simple and convenient, the production cost is low, and the method is suitable for industrial production
C07C 269/06 - Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
C07C 213/00 - Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
C07D 263/22 - Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
2.
METHOD FOR PREPARING AMINO ALCOHOL BY ASYMMETRIC HYDROGENATION AND APPLICATION THEREOF
The present invention relates to the technical field of chemical catalytic reaction. Disclosed are a method for preparing an amino alcohol by asymmetric hydrogenation and an application thereof. A starting raw material of the chemical reaction is an amino ketone compound (I); the amino ketone compound (I) is subjected to asymmetric catalytic hydrogenation reduction to obtain a chiral amino alcohol intermediate (II), the yield of the intermediate (II) being almost quantitative, and the enantioselectivity being up to 99%ee; the intermediate (II) undergoes intramolecular cyclization under suitable conditions to obtain chiral pyrrolidine or piperidine having high optical activity. By utilizing the present method, a series of chiral pyrrolidine and piperidine compounds can be efficiently and highly selectively prepared, and the method has an important practical value and industrial prospect.
C07C 213/00 - Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
C07D 207/08 - Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
A chiral multidentate ligand and the use thereof in asymmetric hydrogenation. The ligand is flexible and variable, and has a three-dimensional structure, high electrical adjustability and higher universality; the synthesis for the ligand can be carried out from cheap and easily available raw materials, and the steps are simple and convenient; and the ligand is relatively stable in an air atmosphere. Particularly, in the use thereof in an asymmetric hydrogenation reaction, a catalyst formed by the chiral multidentate ligand disclosed in the present invention and a metal has high catalytic activity and high stereoselectivity. Specifically, the ligand has the important use in the synthesis of the intermediates of some drugs, such as henylephdrine, mirabegron, ticagrelor and benazepril, which shows wide industrial production prospects and has an extremely high commercial value.
Disclosed are a chiral multidentate ligand (I), a preparation, and an application thereof. In this method, compound (M1) is subjected to condensation with compound (M2) followed by amine deprotection in the presence of a deprotection reagent to obtain compound (M4). Compound (1) is subjected to deprotonation by butyl lithium and phosphorization followed by dimethylamino group substitution to produce compound (3). The compound (3) and the compound (M4) are reacted in the presence of triethylamine to produce chiral multidentate ligands.
Disclosed are a chiral multidentate ligand (I), a preparation, and an application thereof. In this method, compound (M1) is subjected to condensation with compound (M2) followed by amine deprotection in the presence of a deprotection reagent to obtain compound (M4). Compound (1) is subjected to deprotonation by butyl lithium and phosphorization followed by dimethylamino group substitution to produce compound (3). The compound (3) and the compound (M4) are reacted in the presence of triethylamine to produce chiral multidentate ligands.
C07C 37/00 - Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
C07C 237/08 - Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
C07C 29/145 - Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen-containing functional group of C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
C07C 41/18 - Preparation of ethers by reactions not forming ether-oxygen bonds
22-(R)-OSPD to synthesize chiral carboxylic acid II-a, the chiral carboxylic acid II-a can form a salt together with tert-butylamine, and IV-a having high optical purity can be obtained after recrystallization. According to the method provided in the present application, an asymmetric hydrogenation catalyst has high catalytic efficiency and high enantioselectivity, and the operation is simple and convenient, thus facilitating industrial production.
The present invention belongs to the technical field of chemical synthesis and discloses a method for preparing a sacubitril intermediate. A key aza-tricyclic compound 5 is generated by using starting materials, chloramine-T trihydrate (formula 1) and an epoxypropane compound as shown in formula 2 which are simply and easily obtained, by means of a three-step reaction, then biphenyl is introduced by means of a Grignard reaction, then Ts on nitrogen is converted into a Boc group, and the preparation of the N-Boc amino alcohol compound of formula I can be completed. The whole method is simple to operate, safe and pollution-free, has no special requirements for equipment, has a low production cost, is suitable for industrial production, and has notable progress in comparison with the prior art.
C07C 269/04 - Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
7.
METHOD FOR ASYMMETRIC CATALYTIC SYNTHESIS OF NICOTINE
The present invention relates to a method for asymmetric catalytic synthesis of nicotine, specifically to a method for preparing nicotine by five-step reaction by using 3-bromopyridine as a starting material, specifically comprising: 1) carrying out a nucleophilic reaction of 3-bromopyridine and N-Boc-2-pyrrolidone under suitable conditions to obtain a hydrogenated precursor compound (2); 2) obtaining a chiral alcohol intermediate compound (3) having high optical activity by means of asymmetric catalysis of a chiral catalyst; 3) carrying out activation to cause a chiral alcohol to become a leaving group to obtain a compound (4); 4) under suitable conditions, removing protecting groups on nitrogen and causing intramolecular ring closure to obtain a compound (5); and 5) finally, carrying out an N-methylation reaction to purify the product to obtain nicotine. The preparation of the chiral alcohol intermediate compound (3) having high optical activity by asymmetric catalytic reduction is the key step of the method. The present method is easy to operate, low in cost, and applicable to industrial preparation.
C07D 401/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring- member bond
C07C 215/30 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
C07C 213/00 - Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
C07D 213/38 - Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
The present invention relates to the technical field of organic chemical engineering, and in particular to a key intermediate for synthesizing prostaglandin compounds and a preparation method therefor. When applied to the synthesis of prostaglandin compounds, the process flow is simplified, the yield and product purity are improved, the production costs are reduced, and the industrial application is easy.
The present invention relates to the technical field of organic chemical engineering, and in particular to a key intermediate for synthesizing prostaglandin compounds and a preparation method therefor. When applied to the synthesis of prostaglandin compounds, the process flow is simplified, the yield and product purity are improved, the production costs are reduced, and the industrial application is easy.
C07C 59/48 - Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
C07D 317/12 - Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
C07F 7/18 - Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
C07D 307/935 - Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
C07C 49/757 - Unsaturated compounds containing a keto group being part of a ring containing —CHO groups
C07C 33/025 - Acyclic alcohols with carbon-to-carbon double bonds with only one double bond
C07C 33/20 - Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part monocyclic
C07C 43/23 - Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
C07C 59/46 - Unsaturated compounds containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
The present invention relates to the technical field of chiral synthesis, and specifically provides the synthesis and use of a new type of oxa-spirodiphosphine ligands. The bisphosphine ligand is prepared with oxa-spirobisphenol as a starting material after triflation, palladium catalyzed coupling with diaryl phosphine oxide, reduction of trichlorosilane, further palladium catalyzed coupling with diaryl phosphine oxide, and further reduction of trichlorosilane. The oxa-spiro compound has central chirality, and thus includes L-oxa-spirodiphosphine ligand and R-oxa-spirodiphosphine ligand. The racemic spirodiphosphine ligand is capable of being synthesized from racemic oxa-spirobisphenol as a raw material. The present invention can be used as a chiral ligand in the asymmetric hydrogenation of unsaturated carboxylic acids. The complex of the ligand with ruthenium can achieve an enantioselectivity of greater than 99% in the asymmetric hydrogenation of methyl-cinnamic acid.
C07C 51/36 - Preparation of carboxylic acids or their salts, halides, or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
C07F 9/6561 - Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
10.
KEY INTERMEDIATE FOR SYNTHESIZING PROSTAGLANDIN COMPOUNDS AND PREPARATION METHOD THEREFOR
The present invention relates to the technical field of organic chemical engineering, and in particular to a key intermediate for synthesizing prostaglandin compounds and a preparation method therefor. When applied to the synthesis of prostaglandin compounds, the process flow is simplified, the yield and product purity are improved, the production costs are reduced, and the industrial application is easy.
C07C 405/00 - Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins
C07D 307/93 - Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
C07D 307/937 - Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
C07D 311/94 - Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
C07D 317/06 - Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2 condensed with carbocyclic rings or ring systems
A method for preparing nicotine. (1) The nicotinic acid alkyl ester and N-methylpyrrolidone are subjected to a condensation reaction, and then added with a strong acid to obtain 4-methylamino-1-(3-pyridine)-butanone hydrochloride. (2) The 4-methylamino-1-(3-pyridine)-butanone hydrochloride is reacted with an amino-protecting reagent to obtain an intermediate (4). (3) A chiral alcohol (5) is obtained through an asymmetric reduction. (4) The chiral alcohol (5) is converted into the nicotine through a two-step reaction.
C07D 401/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring- member bond
12.
Preparation of chiral primary amine from asymmetric reductive amination of simple ketone catalyzed by ruthenium-diphosphine catalyst
Shenzhen Innovation Center of Small Molecule Drug Discovery Co., Ltd. (China)
Inventor
Lang, Qiwei
Ding, Xiaobing
Yan, Shaobai
Abstract
4 have reductive amination by adding hydrogen and then are heated and hydrolyzed by adding acid. The present invention has the advantages of good substrate universality, high reaction efficiency and the like
C07C 209/26 - Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
C07C 213/02 - Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
C07C 269/06 - Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
Disclosed is a method for preparing nicotine, in particular, a method for preparing nicotine by using nicotinate as a starting material to undergo a five-step reaction. The specific synthetic steps comprise: (1) performing a condensation reaction between nicotinate and N-methyl pyrrolidinone in a suitable reaction vessel; after the reaction finishes, adding a strong acid to react and obtain 4-methylamino-1-(3-pyridine)-butanone hydrochloride; (2) using a suitable amino protective reagent to protect amino and obtain an intermediate (4); (3) obtaining a chiral alcohol intermediate (5) by means of an asymmetric reduction reaction; and (4) obtaining nicotine by means of two-step transformation of the chiral alcohol intermediate. In particular, the asymmetric reduction reaction catalyzed by metals is the key step of the method and the chiral alcohol intermediate with highly optical activity obtained by the reaction can be prepared into nicotine by means of two-step transformation. The disclosed method for preparing nicotine is simple and easy to operate, is low in cost, has mild reaction conditions and is suitable for industrial production.
C07D 401/04 - Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring- member bond
C07C 213/00 - Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
C07C 215/30 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
14.
METHOD FOR SYNTHESIZING TRANYLCYPROMINE INTERMEDIATE
The present invention is applicable to the technical field of pharmaceutical synthesis, and provides a method for synthesizing a tranylcypromine intermediate. The method comprises subjecting a substituted aromatic ketone or a polysubstituted aromatic ketone to a substitution reaction under the action of sodium nitrite, sodium iodide and a reaction solvent to synthesize compound I; subjecting compound I to a copper hydrogen catalysis reaction under the action of a metal precursor, a ligand and a catalyst to produce compound II; causing compound II to produce compound III under the action of DIAD and triphenylphosphine; and causing compound III to produce a tranylcypromine intermediate under the action of zinc powder or iron powder. In the synthesis method, the raw materials used are safe and low in cost, and the yield and selectivity are extremely high, while the reaction cost is reduced; and in the process of synthesizing a chiral alcohol, only low-cost metal precursors and ligands are needed, without it being necessary to use expensive chiral oxazaborolidine and a toxic borane dimethyl sulfide compound; and catalysis is completed with a small equivalent of the catalyst. The invention has an extremely high industrialization value, and meets market demands.
The present application is suitable for use in the technical field of drug synthesis, and provides a method for synthesizing an HIV protease inhibitor intermediate compounds. The method comprises subjecting compound 1a to an asymmetric transfer hydrogenation reaction by adding a catalyst mixture and a hydrogen source in a reaction solvent under argon protection to obtain intermediate compounds 2a and 2a' for an HIV protease inhibitor, wherein the synthesis route thereof is as shown in (I), in which the R group is one of tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, acetyl, or a benzoyl group. The asymmetric transfer hydrogenation technique adopted in the present application provides the synthesized HIV protease inhibitor intermediate compounds having significantly increased stereoselectivity and yield in comparison to similar existing intermediates, with a diastereoselectivity ratio of the product reaching 94:6. Moreover, the catalyst is used in a small amount but has a high catalytic efficiency, reaction activity is improved, raw material wastage is reduced, the whole process is fast and convenient, and the cost is low.
C07C 271/16 - Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
C07C 269/06 - Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
C07C 311/16 - Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
C07C 315/04 - Preparation of sulfonesPreparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
C07C 233/04 - Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic saturated carbon skeleton
C07C 231/18 - Preparation of optical isomers by stereospecific synthesis
C07C 231/12 - Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
C07C 33/46 - Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic part
C07C 27/04 - Processes involving the simultaneous production of more than one class of oxygen-containing compounds by reduction of oxygen-containing compounds
C07C 27/06 - Processes involving the simultaneous production of more than one class of oxygen-containing compounds by reduction of oxygen-containing compounds by hydrogenation of oxides of carbon
C07C 29/143 - Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen-containing functional group of C=O containing groups, e.g. —COOH of ketones
The present invention relates to the technical field of chiral synthesis, and specifically provides a new type of oxa-spirodiphosphine ligands. The bisphosphine ligand is prepared with oxa-spirobisphenol as a starting material after triflation, palladium catalyzed coupling with diaryl phosphine oxide, reduction of trichlorosilane, further palladium catalyzed coupling with diaryl phosphine oxide, and further reduction of trichlorosilane. The oxa-spiro compound has central chirality, and thus includes L-oxa-spirodiphosphine ligand and R-oxa-spirodiphosphine ligand. The racemic spirodiphosphine ligand is capable of being synthesized from racemic oxa-spirobisphenol as a raw material. The present invention can be used as a chiral ligand in the asymmetric hydrogenation of unsaturated carboxylic acids. The complex of the ligand with ruthenium can achieve an enantioselectivity of greater than 99% in the asymmetric hydrogenation of methyl-cinnamic acid.
C07C 51/36 - Preparation of carboxylic acids or their salts, halides, or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
C07F 9/6561 - Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
17.
PREPARATION OF CHIRAL PRIMARY AMINE FROM ASYMMETRIC REDUCTIVE AMINATION OF SIMPLE KETONE UNDER CATALYSIS OF RUTHENIUM-DOUBLE PHOSPHINE CATALYST
44 to a reductive amination under the action of a ruthenium-chiral double phosphine catalyst with the addition of hydrogen, then adding an acid for hydrolyzing same under heating to prepare the chiral primary amine by means of an one-pot method. The present invention has the advantages of a good substrate universality, and a high reaction efficiency, etc.
C07C 209/26 - Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
patents
