1129634-44-1Relevant articles and documents
An enantioselective approach to 4-substituted proline scaffolds: Synthesis of (s)-5-(tert-butoxy carbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid
Ariza, Xavier,Bartra, Martí,Berenguer, Ramon,Gómez, Roberto,Garcia, Jordi,López, Blanca,Torralvo, Hèctor
, (2020)
A catalytic and enantioselective preparation of the (S)-4-methyleneproline scaffold is described. The key reaction is a one-pot double allylic alkylation of an imine analogue of glycine in the presence of a chinchonidine-derived catalyst under phase transfer conditions. These 4-methylene substituted proline derivatives are versatile starting materials often used in medicinal chemistry. In particular, we have transformed tert-butyl (S)-4-methyleneprolinate (12) into the N-Boc-protected 5-azaspiro[2.4]heptane-6-carboxylic acid (1), a key element in the industrial synthesis of antiviral ledipasvir.
Development and Scale-Up of the Electrochemical Dehalogenation for the Synthesis of a Key Intermediate for NS5A Inhibitors
Gütz, Christoph,B?nziger, Markus,Bucher, Christoph,Galv?o, Tomás R.,Waldvogel, Siegfried R.
, p. 1428 - 1433 (2015)
The electrochemical 2-fold dehalogenation of a spirocyclopropane-proline derivative at leaded bronze was scaled-up in a divided batch-type electrolysis cell in good yield and excellent selectivity. The upscaling via a flow electrolysis cell was also successful. Conditions were elaborated employing a single cell passage for complete conversion. The keys here are the direct cooling of the cathode and ensuring a good laminar flow.
Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy
Banerjee, Abhisek,Behera, Dayanidhi B.,Chakraborti, Samitabh,Das, Sanjib,Gharat, Laxmikant A.,Iyer, Pravin S.,Kadam, Pradip,Karanjai, Keya,Patil, Sandip,Pawar, Mahesh,Qadri, Mohammad Mohsin,Saini, Jagmohan S.,Velagaleti, Ranganadh,Yadav, Pravin
, (2021/06/25)
Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.
Preparation method of (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2, 4] heptane-6-carboxylic acid
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Paragraph 0066-0068, (2020/07/13)
The invention relates to the technical field of organic synthesis. The invention specifically relates to a preparation method of an antiviral drug ledipasvir chiral intermediate (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2, 4] heptane-6-carboxylic acid. The preparation method comprises the following steps: condensing 5-(tert-butyloxycarbonyl)-5-azaspiro [2.4] heptane-6-carboxylic acid racemate anda chiral amine resolution reagent to obtain amides (I) and (II); hydrolyzing the compound (I) to obtain a target compound (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2.4] heptane-6-carboxylic acid (III), hydrolyzing the compound (II) to obtain an enantiomer (IV), removing Boc from the compound (IV), performing configuration conversion to obtain a compound (VII), and performing amino protection on the compound (VII) to obtain the target compound (III). The invention provides a simple and convenient cost-reducing industrial production route for the chiral intermediate of the antiviral drug ledipasvir, and has the advantages of simple reaction operation, high chiral resolution yield and lower cost.
MASP INHIBITORY COMPOUNDS AND USES THEREOF
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, (2020/11/23)
The present invention relates to novel Mannose-binding lectin (MBL)-associated serine protease (MASP) inhibitory compounds, as well as analogues and derivatives thereof, to processes for the preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of renal and cardiovascular disorders and of ischemia reperfusion injuries.
Ledipasvir preparation method
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Paragraph 0088; 0090; 0091; 0161; 0230, (2018/05/16)
The invention discloses a Ledipasvir preparation method. The Ledipasvir preparation method includes steps: (1) Ledipasvir intermediate product 1-LD-B preparation; (2) Ledipasvir intermediate product 2-LD-E preparation; (3) Ledipasvir intermediate product 3-LD-F preparation; (4) Ledipasvir intermediate product 4-LD-J preparation; (5) Ledipasvir intermediate product 5-LD-L preparation; (6) Ledipasvir-LD-Q preparation. The Ledipasvir preparation method has advantages of technical maturity and stability, product quality stability, safety and reliability in production process and suitableness for industrial production.
Improved method for preparing ledipasvir optical intermediate
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Paragraph 0054; 0055; 0056, (2017/10/13)
The invention relates to an improved method for preparing a ledipasvir optical intermediate, and belongs to the field of pharmaceutical chemical engineering. The method adopts 5-azaspiro[2,4]heptane-6-carboxylic acid, a crystallization induced asymmetric conversion method is used to conduct chiral separation, so that an (S)-5-azaspiro[2,4]heptane-6-carboxylic acid or a salt thereof is obtained; and the (S)-5-azaspiro[2,4]heptane-6-carboxylic acid or the salt thereof is transformed into the ledipasvir optical intermediate which is (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid. The method has a low price, is simple and convenient, improves the utilization rate of the raw materials, and is suitable for large industrialized production.
5 - azaspiro [2.4] heptane - 6 - carboxylic acid derivatives of the synthesis method (by machine translation)
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Paragraph 0074-0076, (2017/08/25)
The present invention provides a (5S) - 5 - azaspiro [2.4] heptane - 6 - carboxylic acid derivatives of the synthetic method, in order to 1, 1 - cyclopropane dicarboxylic alcohol as the starting material, the reaction with thionyl chloride, is oxidized and get sulfonic acid ester compound, then with glycine methyl ester imine under the action of the tertiary butyl alcohol potassium condensation, again through the system acidic, alkaline methylsulphonyl complete hydrolysis, cyclization, amino protection of the racemic product, finally split to obtain the finished product, the total yield up to 30% or more, the reaction route step is short, reagent used in the security, the operation is simple, of low cost, high yield, suitable for industrial production. (by machine translation)
(S)- 5 - R - 5 - azaspiro [2, 4] heptane -6 - carboxylic acid
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Paragraph 0063; 0064; 0065; 0066; 0067; 0068, (2017/04/12)
The invention relates to a preparation method of (S)-5-R-5-azaspiro (2,4) heptane-6-carboxylic acid which is a compound as shown in a formula (III). The preparation method comprises the following steps: dissolving a compound 5 in an inert solvent and adding alkali to perform reaction (5), wherein LG is a leaving group and R is an amino-protecting group. The reaction provided by the invention can be performed by chiral synthesis, the yield is above 75% and the total yield is about 50%. The high performance liquid chromatography (HPLC) purity of the product is above 99%, the ee is more than 98%, chiral separation is not required, the yield is greatly improved and the cost is reduced.
HEPATITIS C VIRUS INHIBITORS AND USES THEREOF IN PREPARATION OF DRUGS
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Paragraph 0320; 0324, (2017/12/17)
A series of hepatitis C virus (HCV) inhibitors and compositions and applications thereof in the preparation of drugs for treating chronic HCV infection. Especially, a series of compounds that are used as NS5A inhibitors, and compositions and uses thereof in the preparations of drugs.
