- An enantioselective approach to 4-substituted proline scaffolds: Synthesis of (s)-5-(tert-butoxy carbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid
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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.
- Ariza, Xavier,Bartra, Martí,Berenguer, Ramon,Gómez, Roberto,Garcia, Jordi,López, Blanca,Torralvo, Hèctor
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- Development and Scale-Up of the Electrochemical Dehalogenation for the Synthesis of a Key Intermediate for NS5A Inhibitors
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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.
- Gütz, Christoph,B?nziger, Markus,Bucher, Christoph,Galv?o, Tomás R.,Waldvogel, Siegfried R.
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Read Online
- Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy
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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.
- 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
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- Preparation method of (S)-5-(tert-butyloxycarbonyl)-5-azaspiro [2, 4] heptane-6-carboxylic acid
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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.
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Paragraph 0066-0068
(2020/07/13)
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- MASP INHIBITORY COMPOUNDS AND USES THEREOF
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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.
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- Ledipasvir preparation method
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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.
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Paragraph 0088; 0090; 0091; 0161; 0230
(2018/05/16)
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- Improved method for preparing ledipasvir optical intermediate
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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.
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Paragraph 0054; 0055; 0056
(2017/10/13)
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- 5 - azaspiro [2.4] heptane - 6 - carboxylic acid derivatives of the synthesis method (by machine translation)
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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)
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Paragraph 0074-0076
(2017/08/25)
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- (S)- 5 - R - 5 - azaspiro [2, 4] heptane -6 - carboxylic acid
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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.
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Paragraph 0063; 0064; 0065; 0066; 0067; 0068
(2017/04/12)
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- HEPATITIS C VIRUS INHIBITORS AND USES THEREOF IN PREPARATION OF DRUGS
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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.
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Paragraph 0320; 0324
(2017/12/17)
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- A Novel Cathode Material for Cathodic Dehalogenation of 1,1-Dibromo Cyclopropane Derivatives
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Leaded bronze turned out to be an excellent cathode material for the dehalogenation reaction of cyclopropanes without affecting the strained molecular entity. With this particular alloy, beneficial properties of lead cathodes are conserved, whereas the corrosion of cathode is efficiently suppressed. The solvent in the electrolyte determines whether a complete debromination reaction is achieved or if the process can be selectively stopped at the monobromo cyclopropane intermediate. The electroorganic conversion tolerates a variety of functional groups and can be conducted at rather complex substrates like cyclosporine A. This approach allows the sustainable preparation of cyclopropane derivatives.
- Gütz, Christoph,Selt, Maximilian,B?nziger, Markus,Bucher, Christoph,R?melt, Christina,Hecken, Nadine,Gallou, Fabrice,Galv?o, Tomás R.,Waldvogel, Siegfried R.
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supporting information
p. 13878 - 13882
(2015/09/28)
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- THROMBIN INHIBITORS
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The compounds of the invention may be useful in inhibiting thrombin and associated thrombotic occlusions.
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- SYNTHESIS OF ANTIVIRAL COMPOUND
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The present disclosure provides processes for the preparation of a compound of formula I: which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates to compounds of formula I.
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Paragraph 0176
(2014/01/07)
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- SOLID FORMS OF AN ANTIVIRAL COMPOUND
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Amorphous and crystalline solid forms of the anti-HCV compound (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Compound I) were prepared and characterized in the solid state: Also provided are processes of manufacture and methods of using the amorphous and crystalline forms.
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Paragraph 0233-0235
(2014/01/07)
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- PROCESSES FOR THE PREPARATION OF NOVEL BENZIMIDAZOLE DERIVATIVES
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The present invention relates to processes and intermediates for the preparation of novel benzimidazole derivatives, especially in the synthesis of hepatits C virus NS5A inhibitors. In particular, the present invention relates to processes and intermediates for the preparation of compounds of formulae (I-a):
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- PROCESSES FOR THE PREPARATION OF 5-AZASPIRO[2.4]HEPTANE-6-CARBOXYLIC ACID AND ITS DERIVATIVES
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The present invention relates generally to an improved process for the preparation of 5-azaspiro[2.4]heptane-6-carboxylic acid and its derivatives which are useful intermediates in the synthesis of biologically active molecules, especially in the synthesis of hepatits C virus NS5A inhibitors. In particular, the present invention relates to processes and intermediates for the preparation of compounds of formulae (la), (lb) and (Ic):
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Page/Page column 22
(2012/12/13)
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- Synthesis of a novel Boc-protected cyclopropane-modified proline analogue
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The synthesis of the Boc derivative of a novel member of the cyclopropane-modified proline library, Boc-protected 5-azaspiro[2.4]heptane-6- carboxylic acid, is reported. The synthesis was performed in six steps starting from (2S,4R)-4-hydroxyproline using a modified Simmons-Smith reaction as the key step. The reaction conditions for all the steps were carefully selected to avoid racemization at the chiral centers in the intermediates and the final product.
- Tymtsunik, Andriy V.,Bilenko, Vitaliy A.,Ivon, Yevhen M.,Grygorenko, Oleksandr O.,Komarov, Igor V.
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p. 3847 - 3849
(2012/08/27)
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