- Direct separation of pregabalin enantiomers using a zwitterionic chiral selector by high performance liquid chromatography coupled to mass spectrometry and ultraviolet detection
-
The chromatographic resolution of pregabalin enantiomers has been often achieved by derivatization of the molecule, in order to reach enough sensitivity at low concentrations of the minor enantiomer present in the active principle. In the present article, the development and optimization of two liquid chromatographic methods are presented for the direct resolution of pregabalin enantiomers on a chiral stationary phase (CSP) containing a zwitterionic selector derived from cinchona alkaloid and sulfonic acid (CHIRALPAK ZWIX). The key parameters for the separation as well as the compatibility of chromatographic conditions with different detection modes (ultraviolet and mass spectrometry) were investigated. The resulting methods were found to be selective, of high performance and low limits of detection (2 μg/mL by UV and 1 ng/mL by MS, respectively) and quantification (6 μg/mL by UV and 5 ng/mL by MS, respectively) for the minor enantiomer which is considered as a chiral impurity.
- Chennuru, Lakshmi Narayana,Choppari, Thirupathi,Nandula, Ramakrishna Prasad,Zhang, Tong,Franco, Pilar
-
-
Read Online
- An efficient process of racemization of 3-(Carbamoylmethyl)-5- methylhexanoic acid: A pregabalin intermediate
-
A simple and cost-effective process for racemization of undesired (S)-3-(carbamoylmethyl)-5-methylhexanoic acid (9), produced during the resolution step, is described. The literature procedure is fraught with many difficulties including number of steps and hazardous reagents. We have developed a one pot process for the above-mentioned racemization of S-enantiomer. The basic objective is to convert S-enantiomer into the symmetrical glutarimide derivative followed by hydrolysis with an alkali. The transformation of 9 into glutarimide derivative (10) has been achieved with piperidine in refluxing toluene.
- Chavan, Anil B.,Maikap, Golak C.,Gurjar, Mukund K.
-
-
Read Online
- Efficient Chemoenzymatic Synthesis of Optically Active Pregabalin from Racemic Isobutylsuccinonitrile
-
An efficient chemoenzymatic route has been developed for the synthesis of optically active pregabalin (PGB) from isobutylsuccinonitrile (IBSN). (S)-3-cyano-5-methylhexanoic acid ((S)-CMHA), a critical chiral intermediate of PGB, was synthesized using regio- and enantioselective hydrolysis of IBSN by immobilized Escherichia coli cells harboring nitrilase BrNIT from Brassica rapa. The catalytic performances of immobilized cells were investigated, and high enantioselectivity (E > 150) and substrate conversion (>41.1%) were obtained at a substrate loading of 100 g/L by immobilized cells after 12 batches of reaction. The unreacted (R)-IBSN was recycled by racemization with a high yield of 94.5%, and the resultant (S)-CMHA was hydrogenated directly to the desired PGB with a high purity of 99.6% and optical purity of 99.4%. The input of raw materials and E factor of this chemoenzymatic route were demonstrated to be much lower than those of the first- and second-generation routes for PGB synthesis.
- Zhang, Qin,Wu, Zhe-Ming,Liu, Shuang,Tang, Xiao-Ling,Zheng, Ren-Chao,Zheng, Yu-Guo
-
-
Read Online
- Nitrile as activating group in the asymmetric bioreduction of β-cyanoacrylic acids catalyzed by ene-reductases
-
Asymmetric bioreduction of an (E)-β-cyano-2,4-dienoic acid derivative by ene-reductases allowed a shortened access to a precursor of pregabalin [(S)-3-(aminomethyl)-5-methylhexanoic acid] possessing the desired configuration in up to 94% conversion and >99% ee. Deuterium labelling studies showed that the nitrile moiety was the preferred activating/anchor group in the active site of the enzyme over the carboxylic acid or the corresponding methyl ester.
- Winkler, Christoph K.,Clay, Dorina,Turrini, Nikolaus G.,Lechner, Horst,Kroutil, Wolfgang,Davies, Simon,Debarge, Sebastien,O'Neill, Pat,Steflik, Jeremy,Karmilowicz, Mike,Wong, John W.,Faber, Kurt
-
-
Read Online
- A new synthetic route for the preparation of pregabalin
-
We reported the synthesis of (S)-pregabalin in a five-step sequence with 20% overall yield. As a modification of the previously developed route, a Michael addition between CH3NO2 and chiral oxaoxazolidinone was employed as a key operation for introducing the methyleneamino group, which allowed avoiding the use of toxic cyanide reagent and led to enantiomerically pure product (>99% ee) after the recrystallization in appropriate solvent.
- He, Chasheng,Zhai, Ziran,Zhou, Yang,Li, Jianqi,Wang, Guan
-
-
Read Online
- Biocatalytic desymmetrization of 3-substituted glutaronitriles by nitrilases. A convenient chemoenzymatic access to optically active (S)-Pregabalin and (R)-Baclofen
-
Desymmetrization of prochiral 3-substituted glutaronitriles offers a new approach to access (S)-Pregabalin and (R)-Baclofen. A number of nitrilases from diverse sources were screened with 3-isobutylglutaronitriles (1a) or 3-(4′-chlorophenyl)glutaronitriles (1b) as the substrate. Some nitrilases were found to catalyze the desymmetric hydrolysis of 1a and 1b to form optically active 3-(cyanomethyl)-5-methylhexanoic acid (2a) and 3-(4′-chlorophenyl) -4-cyanobutanoic acid (2b) with high enantiomeric excesse (ee), respectively. This cannot be achieved using traditional chemical hydrolysis. Among them, AtNIT3 generated (R)-2b, whereas BjNIT6402 and HsNIT produced the opposite (S)-enantiomer with high conversions and ee values. Not only the nitrilases showed different activities and stereoselectivities toward these 3-substituted glutaronitriles, the 3-substituent of the substrates also exerted great effect on the enzyme activity and stereoselectivity. (S)-2a and (S)-2b were prepared with high yields and ee values using BjNIT6402 and HsNIT as the biocatalysts, respectively. A straightforward Curtius rearrangement of (S)-2a and (S)-2b, followed by the acidic hydrolysis, afforded (S)-Pregabalin and (R)-Baclofen. This offers a new platform methodology for the synthesis of optically active β-substituted γ-amino acids of pharmaceutical importance.
- Duan, Yitao,Yao, Peiyuan,Ren, Jie,Han, Chao,Li, Qian,Yuan, Jing,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
-
-
Read Online
- Enantiomerically pure synthesis of β-substituted γ- butyrolactones: A key intermediate to concise synthesis of pregabalin
-
(Chemical Equation Presented) Chiral β-substituted γ-butyrolactones are known to be important intermediates for many biologically active compounds such as γ-aminobutyric acid (GABA) derivatives and lignans. We have developed a general, convenient, and scalable synthetic method for enantiomerically pure β-substituted γ-butyrolactones, with either configuration, via nucleophilic cyclopropane ring opening of (1S,5R)- or (1R,5S)-bicyclic lactone followed by decarbethoxylation. The utility of our method was demonstrated by streamlined synthesis of pregabalin ((S)-3-isobutyl-γ-aminobutyric acid), an anticonvulsant drug for the treatment of peripheral neuropathic pain.
- Ok, Taedong,Jeon, Aram,Lee, Joohee,Jung, Hak Lim,Chang, Seop Hong,Lee, Hee-Seung
-
-
Read Online
- Development of a chemoenzymatic manufacturing process for Pregabalin
-
A new manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac-2-earboxyethyl-3-cyano-5- methylhexanoic acid ethyl ester (1) can be resolved to form 2-carboxyethyl-3- cyano-5-methylhexanoic acid (2). A heat-promoted decarboxylation of 2 efficiently generates (S)-3-cyano-5-rnethylhexanoic acid ethyl ester (3), a known precursor of Pregabalin. This new route dramatically improved process efficiency compared to the first-generation process by setting the stereocenter early in the synthesis and enabling the facile racemization and reuse of (R)-l. The chemoenzymatic process also reduced organic solvent usage resulting in a mostly aqueous process. Compared to the first-generation manufacturing process, the new process resulted in higher yields of pregabalin (40-45% after one recycle of (R)-l), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17.
- Martinez, Carlos A.,Hu, Shanghui,Dumond, Yves,Tao, Junhua,Kelleher, Patrick,Tully, Liam
-
-
Read Online
- An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation
-
A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin I in excellent overall yield and purity.
- Burk, Mark J.,De Koning, Pieter D.,Grote, Todd M.,Hoekstra, Marvin S.,Hoge, Garrett,Jennings, Rex A.,Kissel, William S.,Le, Tung V.,Lennon, Ian C.,Mulhern, Thomas A.,Ramsden, James A.,Wade, Robert A.
-
-
Read Online
- Stereoselective and efficient synthesis of (S)-pregabalin from d-mannitol
-
A straightforward synthesis of (S)-pregabalin in 28% overall yield starting from d-mannitol acetonide, as a primary source of chirality, is presented. The process is suitable for large-scale synthesis and involves simple and high-yielding chemical transformations as well as low-cost commercially available reagents.
- Izquierdo, Sandra,Aguilera, Jordi,Buschmann, Helmut H.,Garcia, Monica,Torrens, Antoni,Ortuno, Rosa M.
-
-
Read Online
- AN IMPROVED PROCESS FOR THE PREPARATION OF PREGABALIN
-
The present invention relates to an improved process for the preparation of Pregabalin (I), which is simple, economical, efficient, and environment friendly, commercially viable with chemical and chiral purity at least 99.95%.
- -
-
-
- PROCESS FOR THE PREPARATION OF GAMMA AMINO BUTYRIC ACIDS AND ANALOGS THEREOF
-
The present invention relates to a process for the preparation of gamma aminobutyric acid derivatives of formula I, in particular pregabalin, baclofen and analogs thereof. Further, this process is comprised of preparation protocol for compounds of formula I, involving Michael addition and Beckmann rearrangement strategy.
- -
-
Page/Page column 14-15
(2021/08/20)
-
- METHODS FOR TREATING CHRONIC FATIGUE SYNDROME AND MYALGIC ENCEPHALOMYELITIS
-
In one aspect the invention relates to a method of treatment selected from the group consisting of: (a) treating a symptom such as pain in a subject identified or diagnosed as having Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); (b) treating a symptom such as pain in a subject having dysfunctional TRPM3 ion channel activity; (c) restoring NK cell function in a subject having dysfunctional TRPM3 ion channel activity; and (d) restoring calcium homeostasis in a subject having dysfunctional TRPM3 ion channel activity. The method comprises the step of administering to the subject a therapeutically effective amount of at least one therapeutic compound selected from the group consisting of: (i) an opioid receptor antagonist; (ii) an opioid antagonist; and (iii) a therapeutic compound that restores TRPM3 ion channel activity. In some embodiments the therapeutic compound is naltrexone hydrochloride.
- -
-
-
- METHOD FOR PREPARING PREGABALIN
-
The present invention relates to a method for preparing pregabalin by a biological enzyme method. In particular, the method comprises producing pregabalin B and an R-configuration compound C by using a compound A as a raw material under the action of a biological enzyme; performing configuration inversion of the separated and recovered R-configuration compound C under the action of an isomerase to produce an S-configuration compound D; and producing pregabalin B from the compound D under the action of a biological enzyme
- -
-
Paragraph 0045; 0048; 0051; 0054; 0057
(2021/04/23)
-
- Method for preparing 3-aminomethyl-5-methylcaproic acid
-
The invention relates to a method for preparing 3-aminomethyl-5-methylcaproic acid, belonging to the technical field of chemistry. According to the preparation method, 3-methyl formate-5-methylhexanoic acid is used as a raw material, and the target product 3-aminomethyl-5-methylcaproic acid can be prepared through two steps of reactions including ammonia ester exchange and reduction. The method has the beneficial effects of simple process route, high product purity of 99.0% or above, less three wastes, no toxic agent, mild reaction conditions and low cost, and is suitable for industrial production.
- -
-
Paragraph 0023; 0028-0029; 0031-0032; 0035-0036; 0039
(2020/07/13)
-
- Preparation method of pregabalin
-
The invention discloses a preparation method of pregabalin, and particularly discloses a synthesis method of pregabalin, and relates to a compound shown as a formula I shown in the specification.
- -
-
Paragraph 0014-0015; 0019
(2020/07/12)
-
- Synthesis of (+/-)-Pregabalin and its novel lipophilic β-alkyl-substituted analogues from fatty chains
-
In this work, were synthesized for the first time a series of new lipophilic β-alkyl substituted GABA derivatives from fatty alkyl chains. The synthesis of these GABA analogues was investigated by two different bicomponent approaches as a key step. The results showed low yields in the path from aliphatic nitroolefins and Meldrum's acid, whereas the Knoevenagel condensation between aliphatic aldehydes and Meldrum's acid afforded fatty alkylidenes in good yields (75-97%). These compounds were subsequently subjected to a conjugate addition reaction with nitromethane, resulting in the fatty Michael adducts (in 87-97% yields) which were in turn submitted to a one pot domino hydrolysis-decarboxylation, leading to the isolation of β-alkyl-substituted γ-nitro acids in good yields (78-92%). Finally, the reduction of the fatty γ-nitro acids allowed for the access to new lipophilic β-alkyl substituted GABA analogues, which were isolated in high yields (90-98%). The new methodology was also applied to the synthesis of antiepileptic drug (+/-)-Pregabalin, which was obtained after four steps in high overall yield. This journal is
- D'Oca, Caroline Da Ros Montes,Mass, Eduardo Bustos,Ongaratto, Renata Fontes,De Andrade, Arthur Motta,D'Oca, Marcelo G. Montes,Russowsky, Dennis
-
p. 13230 - 13239
(2020/08/28)
-
- Method for preparing 4-isobutyl pyrrolidone by solvent-free method
-
The invention discloses a method for preparing 4-isobutyl pyrrolidone by a solvent-free method. The method is characterized in that R-type, S-type or racemic 3-(carbamylmethyl)-5-methylhexanoic acid is used as an initial raw material, 3-aminomethyl-5-methylhexanoic acid is prepared through a Hofmann degradation reaction, and an R-type, S-type or racemic 4-isobutyl pyrrolidone product is prepared through a solvent-free reaction. According to the method, currently prepared sodium hypobromite is used for carrying out the Huffman degradation reaction, so that the defects that sodium hypochlorite is easy to decompose and low in reaction activity can be avoided. The generated 3-aminomethyl-5-methylhexanoic acid is subjected to a melting reaction under the solvent-free condition, pulping and purification are carried out, a small amount of oxidation impurities can be removed, meanwhile, the solid form is improved, finally, suction filtration and drying are carried out, and the 4-isobutyl pyrrolidone product with the purity being 98.5% or above is obtained. In the whole reaction process, less solvent is used, the operation is simple and easy, and the method is clean and environment-friendly.
- -
-
Paragraph 0013
(2020/04/02)
-
- Method for preparing pregabalin by photocatalysis (by machine translation)
-
The preparation method is characterized by comprising the 3S following -3 - steps:5 - 1) dissolving the compound I and a certain amount of alkali in an organic solvent, adding the compound II, heating the reaction, obtaining the compound III, 2) preparing the compound V; 3) preparing the compound V through deprotection, ring opening, chiral resolution, and recrystallization to obtain pregabalin. The preparation method comprises the following steps: 1) dissolving compound III, compound IV and photocatalyst in an organic solvent. The raw materials used in the invention are cheap and easily available, the reaction conditions of the photocatalytic oxidation method are mild, reagents are environmentally friendly, green and environment-friendly, and the method is an ideal industrial production process. (by machine translation)
- -
-
-
- GREENER AND ECONOMIC PROCESS FOR PREPARATION OF PREGABALIN
-
The present invention relates to an economical, enzyme catalyzed and commercially viable greener process for manufacturing Pregabalin of formula (I) in high yield with highchemical and chiral purity.
- -
-
-
- Preparation method of (S)-3-aminomethyl-5-methylhexanoic acid
-
The invention discloses a preparation method of pregabalin, comprising the following steps: (1) dropwisely adding bromine into a sodium hydroxide aqueous solution to generate a reaction solution I; dissolving (R)-(-)-3-carbamylmethyl-5-methylhexanoic acid with a sodium hydroxide aqueous solution to obtain a reaction solution II; (2) dropwise adding the reaction solution II into the reaction solution I to carry out a Hofmann degradation reaction to obtain a reaction solution III; (3) filtering the reaction solution III to obtain a filtrate I; (4) adding concentrated hydrochloric acid into the filtrate I, and stirring and filtering to obtain a solid wet product; and (5) adding the solid wet product into a solvent I, heating, stirring, dissolving, filtering, cooling the filtrate, stirring, filtering, and drying a filter cake to obtain the pregabalin. The preparation method is simple in technological process, good in impurity control effect and suitable for industrial production.
- -
-
Paragraph 0011-0015
(2020/06/09)
-
- Development of a new synthesis approach for S-pregabalin by optimizing the preparation stages
-
In the present study, we aimed to optimize the synthesis stages of S-pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid), a well-known anticonvulsant drug. We used appropriate solvents and compounds to reach a straightforward and applicable method. The advantages of this research were avoiding use of expensive and environment pollutant reagents and solvents, and also using a recoverable reagent. Discarding prevention of the intermediates and reagents besides attaining a higher yield of the obtained product were the additional achievements. All structures were characterized by FT-IR, 1H NMR, and the purity of S-pregabalin was evaluated using the HPLC assay.
- Mansoori, Arsalan,Zahednezhad, Fahimeh,Bavili Tabrizi, Ahad,Shahbazi Mojarrad, Javid
-
-
- Method for synthesizing and refining (S)- pregabalin (by machine translation)
-
The reaction conditions of the method disclosed by the invention are mild, and the method disclosed by the invention is mild in reaction conditions: (S)- kg of crude,methylhexanoic acid is obtained through: degradation, the reaction conditions of the intermediate (R)- (-) - 3 - (isobutyl - 2 2-pyrrolidinone) - 5 - are more moderate, and the reaction conditions of the preparation method, Hoffman are obtained (S)- times by weight, of the preparation method for, pregabalin concentrate (S)- 4 - obtained by hydrolysis-ring; of the raw material, to obtain a high-purity pregabalin intermediate solution (S)- obtained by carrying out hydrolysis (S)- on a crude product with a high purity,methyl.methylhexanoic acid after re-crystallization, to, obtain a high,purity pregabalin product. (by machine translation)
- -
-
Paragraph 0041; 0045-0050; 0054-0059; 0063-0073
(2020/04/17)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF PREGABALIN
-
The present invention relates to an improved process for the preparation of 3-isobutyl glutaric acid compound of formula-1 which is used as the key intermediate in the preparation of Pregabalin compound of formula-A. The present invention also relates to an improved process for the preparation of (S)-3-(aminomethyl)-5-methylhexanoic acid compound of formula-A.
- -
-
-
- Method for preparing pregabalin racemate
-
The invention belongs to the technical field of organic chemistry, and in particular relates to a method for preparing a pregabalin racemate. The method comprises the following steps: uniformly mixing3-carbamoymethyl-5-methylhexanoic acid and NaOBr, conducting heating with a water bath of 40 to 45 DEG C to enable the system to undergo a process of being automatically heated to 81-85 DEG C due toreaction heat release, and then automatically lowering the temperature to 50-60 DEG C for 1 hour; and heating the reaction system to 80 DEG C for 2 hours. The above automatic temperature raising process facilitates Hoffman rearrangement, thereby increasing the reaction conversion rate and the yield of the pregabalin racemate. The preparation method of the invention is high in yield, good in reproducibility and easy for industrial production.
- -
-
Paragraph 0021; 0022; 0023; 0024; 0025; 0026; 0027-0040
(2019/07/11)
-
- Synthetic method of environment-friendly and efficient pregabalin
-
The invention relates to a synthetic method of environment-friendly and efficient pregabalin. The synthetic method comprises the following steps: 1) dehydrating and condensing acetate and isopentyl aldehyde to obtain 5-methyl-2-hexenoate; 2) performing cyano addition on the 5-methyl-2-hexenoate to obtain (S)-5-methyl-3-cyanohexanoate; 3) performing hydrogen reduction cyclization on the (S)-5-methyl-3-cyanohexanoate to obtain (S)-4-isobutylpyrrolidin-2-one; and 4) performing hydrolysis and ring opening on the (S)-4-isobutylpyrrolidin-2-one to obtain the pregabalin. The synthetic route has the advantages of cheap and easily available raw materials, few reaction steps, mild process conditions, simple operation, high reaction yield and less environment pollution, and is more suitable for industrial production of bulk drug pregabalin.
- -
-
-
- Preparation method and application of high-purity dimethyl 3-isobutylglutarate
-
The invention provides a preparation method and application of high-purity dimethyl 3-isobutylglutarate. Specifically, the invention provides the method for preparing dimethyl 3-isobutylglutarate shown as a formula 2, and the method comprises the step of enabling 3-isobutylglutaric acid to react in methanol in the presence of potassium permanganate and concentrated sulfuric acid, so as to obtain the high-purity dimethyl 3-isobutylglutarate. The method is simple, easy to control, high in product conversion rate, mild in reaction condition, convenient for industrial production and low in cost, the product is easy to purify, and the purity is up to 99% or above.
- -
-
Paragraph 0180; 0183
(2019/12/02)
-
- Method for preparing pregabalin by adopting ion exchange method
-
The present invention belongs to the technical field of preparation of compounds, and relates to a method for preparing pregabalin by using an ion exchange method. The method comprises: (1) S,S-salt dissociation: in the presence of a solvent, carrying out dissociation on a S,S salt through an anion exchange resin to obtain a pregabalin solution; and (2) pregabalin preparation: concentrating the obtained pregabalin solution, adding a first organic solvent, and crystallizing to obtain pregabalin. According to the present invention, the method has advantages of high product purity, high yield, low mandelic acid residue, less ash content, environmental protection, easy operation, economy and the like.
- -
-
Paragraph 0033-0035; 0039-0041; 0046-0048; 0053-0062
(2019/08/21)
-
- Preparation method of pregabalin
-
The invention relates to a preparation method of pregabalin. The preparation method comprises the following steps: performing Hoffmann rearrangement reaction under the reaction of (R)-(-)-3-(carbamylmethyl)-5-methylhexanoic acid and sodium hypochlorite in an alkaline solution; after the rearrangement reaction ends, adding a reaction solution into an acid-organic solvent system; extracting and combining organic phases; then adding an alkali for alkali out; performing pulping and washing to prepare the high-purity pregabalin. The preparation method disclosed by the invention has the advantagesof simple process route, high product yield and high product purity, can meet the medicinal quality standard without recrystalization, and is suitable for industrial production.
- -
-
Paragraph 0055-0057; 0063-0078
(2019/05/08)
-
- A preparation method of the pregabalin
-
The invention discloses a method for preparation of pregabalin. In particular, this invention refers to R - 1 - (dibenzyl amino) - 4 - methyl - 2 - chloro-pentane (compound IV) as raw materials for preparing pregabalin (compound I). The invention has a starting raw materials are easy, less reaction steps and the like.
- -
-
-
- Synthesis methods of pregabalin and intermediate thereof
-
The invention discloses synthesis methods of pregabalin and an intermediate thereof. According to the synthesis methods, the intermediate of the pregabalin is synthesized and obtained through simple and easily obtained reaction raw materials and a chiral ligand; the pregabalin is further synthesized. The synthesis method of the pregabalin, which is provided by the invention, is low in cost, simplein step, safe to operate, few in by-product, simple in post treatment, higher in total yield, also higher in purity and easy to realize industrialized production, and an intermediate product and a final product are both easily purified.
- -
-
-
- Rhodium-catalyzed asymmetric hydrogenation of β-cyanocinnamic esters with the assistance of a single hydrogen bond in a precise position
-
With the assistance of hydrogen bonds, the first asymmetric hydrogenation of β-cyanocinnamic esters is developed, affording chiral β-cyano esters with excellent enantioselectivities (up to 99% ee). This novel methodology provides an efficient and concise synthetic route to chiral GABA-derivatives such as (S)-Pregabalin, (R)-Phenibut, (R)-Baclofen. Interestingly, in this system, the catalyst with a single H-bond donor performs better than that with double H-bond donors, which is a novel discovery in the metalorganocatalysis area.
- Li, Xiuxiu,You, Cai,Yang, Yusheng,Yang, Yuhong,Li, Pan,Gu, Guoxian,Chung, Lung Wa,Lv, Hui,Zhang, Xumu
-
p. 1919 - 1924
(2018/02/23)
-
- Asymmetrical synthesis method of lyrica
-
The invention discloses an asymmetrical synthesis method of lyrica, wherein the synthesis steps comprise: carrying out a cyclic anhydridization reaction by using 3-isobutylglutaric acid as a raw material, carrying out an asymmetric ring-opening reaction with (R)-(+)-1-phenylethylamine, and sequentially carrying out a hydrogenation reaction and Huffman rearrangement to obtain lyrica. Compared to the synthesis method in the prior art, the synthesis method of the present invention has advantages of inexpensive and easily-available raw materials and less reaction steps, has the total yield of up to 60%, the purity of the product lyrica of more than 99% and the ee value of more than 99%, and has good application prospect in industrial scale up production.
- -
-
-
- Method for asymmetric preparation of (S)-3-aminomethyl-5-methylcaproic acid
-
The invention discloses a method for asymmetric preparation of (S)-3-aminomethyl-5-methylcaproic acid. The method is characterized by comprising the following four synthesis steps: with 3-isobutylglutaric acid as a raw material, subjecting 3-isobutylglutaric acid and a nitrogen-containing reagent to a ring-closure reaction; subjecting a reaction product and (S)-(+)-1-phenylethylamine to asymmetricring opening; carrying out Huffman rearrangement; and then carrying out amide hydrolysis so as to obtain (S)-3-aminomethyl-5-methylcaproic acid. Compared with the prior art, the method provided by the invention has the advantages of usage of cheap and easily available raw materials, short reaction steps, mild reaction conditions, and no usage of reagents easily leading to poisoning and explosion;the overall yield of method is as high as 72%; the purity of the product pregabalin is greater than 99%, and an ee value is greater than 99%; and the method has good application prospects in industrial large-scale production.
- -
-
-
- A preparation method of the pregabalin (by machine translation)
-
The invention discloses a method for preparation of pregabalin, characterized in that in formula 7 compounds of the formula 8 compound as a raw material, under the illumination condition using the oxidation reducing agent with a chiral organic catalyst joint catalytic asymmetric Michael addition reaction of free radical decarboxylation synthesizing chiral intermediate type 9 compound, then the type 9 compound in acidic or alkaline conditions to hydrolyze [...] 1 compound. Wherein R1 For the Cbz, COOEt, COOMe, COOPr, PhNHCO or Boc, R2 For COOEt, COOMe, COOBu, COOPr, COOBn, COOPh, COOAll or CN, R3 R is H or2 The same. (by machine translation)
- -
-
-
- Preparation method of antiepileptic drug-pregabalin
-
The invention discloses a preparation method of an antiepileptic drug-pregabalin, belonging to the field of drug synthesis. According to the preparation method, a compound 2 is taken as a raw material, and the pregabalin is prepared by the synthesis steps of enabling the raw material and a Grignard reagent to be subjected to an addition reaction, carrying out deprotection, ring-opening and chiralresolution, and the like. Compared with the methods reported in the existing literatures, the preparation method provided by the invention avoids the use of heavy metal reagents, and is fewer in synthesis steps, higher in process stability, simple to operate and mild in reaction conditions, thus being suitable for large-scale production.
- -
-
Paragraph 0009; 0010; 0030; 0033
(2018/04/21)
-
- Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow
-
We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput.
- Lima, Fabio,Grunenberg, Lars,Rahman, Husaini B. A.,Labes, Ricardo,Sedelmeier, Joerg,Ley, Steven V.
-
supporting information
p. 5606 - 5609
(2018/06/04)
-
- PROCESS FOR PRODUCING OPTICALLY ACTIVE 4-NITRO-BUTANOIC ACID ESTER AND PREGABALIN
-
PROBLEM TO BE SOLVED: To provide a process for producing optically active pregabalin with low number of reaction steps and low cost, as well as to provide a process for producing optically active 4-nitro-butanoic acid ester for use in said process. SOLUTION: Provided is a process for producing optically active 5-methyl-3-nitromethyl-2-alkoxycarbonyl-hexanoic acid alkyl ester by reacting dialkyl malonate and 4-methyl-1-nitro-1-pentene in the presence of a chiral catalyst containing a pyridine bisoxazoline derivative and calcium oxide; and a process for producing pregabalin using the present production process. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
- -
-
-
- Method for preparing pregabalin
-
The invention discloses a method for preparing pregabalin, and the method comprises the following steps: (1) in an aqueous solution of sodium hydroxide, performing oxidation reaction of (R)-(-)-3-carbamoyl methyl-5-methyl hexanoic acid with an aqueous solution of sodium hypochlorite to obtain a reaction liquid I; (2) cooling the reaction liquid I, adding a reducing agent, after destruction of sodium hypochlorite, heating for reaction to obtain a reaction liquid II; (3) adding a catalyst into the reaction liquid II, introducing in hydrogen for reduction reaction, and filtering to obtain filtrate I; (4) adding concentrated hydrochloric acid into the filtrate I, stirring, and filtering to obtain a solid wet product; and (5) adding the solid wet product into isopropanol and water, heating, stirring for dissolving clarification, filtering, cooling filtrate, stirring, filtering, and drying the filter cake to obtain pregabalin. The preparation method has simple process and good control effect on impurities, and is suitable for large-scale industrial production.
- -
-
Paragraph 0048-0099
(2017/07/19)
-
- Synthesis of (±)-Pregabalin by Utilizing a Three-Step Sequential-Flow System with Heterogeneous Catalysts
-
(±)-Pregabalin, a γ-amino acid derivative, has been synthesized by utilizing flow methods. A three-step sequential-flow reaction starting from commercial isovaleraldehyde and methyl malonate proceeded smoothly with heterogeneous catalysts to afford the precursor of pregabalin in yields of 75–100 %, and a space-time yield of 52.2 g/L d was reached. In addition, a heterogeneous catalyst for the Knoevenagel reactions of aldehydes with malonates, which is the first step of the synthesis, has been developed. Pregabalin was finally obtained by acid-catalyzed hydrolysis of the precursor followed by neutralization.
- Ishitani, Haruro,Kanai, Kan,Saito, Yuki,Tsubogo, Tetsu,Kobayashi, Shū
-
p. 6491 - 6494
(2017/10/18)
-
- Catalytic Intermolecular Carboamination of Unactivated Alkenes via Directed Aminopalladation
-
An intermolecular 1,2-carboamination of unactivated alkenes proceeding via a Pd(II)/Pd(IV) catalytic cycle has been developed. To realize this transformation, a cleavable bidentate directing group is used to control the regioselectivity of aminopalladation and stabilize the resulting organopalladium(II) intermediate, such that oxidative addition to a carbon electrophile outcompetes potential β-hydride elimination. Under the optimized reaction conditions, a broad range of nitrogen nucleophiles and carbon electrophiles are compatible coupling partners in this reaction, affording moderate to high yields. The products of this reaction can be easily converted to free ?3-amino acids and ?3-lactams, both of which are common structural motifs found in drug molecules and bioactive compounds. Reaction kinetics and DFT calculations shed light on the mechanism of the reaction and explain empirically observed reactivity trends.
- Liu, Zhen,Wang, Yanyan,Wang, Zichen,Zeng, Tian,Liu, Peng,Engle, Keary M.
-
supporting information
p. 11261 - 11270
(2017/08/22)
-
- Method for synthesizing Pregabalin by taking oxopyrrolidine as intermediate
-
The invention discloses a method for synthesizing Pregabalin by taking oxopyrrolidine as an intermediate. The method comprises the steps: carrying out Knoevenagel condensation reaction on isovaleraldehyde and nitromethane in an ethanol solvent by taking piperazine as a catalyst; carrying out Michael addition on the product obtained in the step one and diethyl malonate in an alkaline alcohol solvent; carrying out catalytic hydrogenation on the product obtained in the step two by taking Raney nickel as a catalyst, so as to obtain the oxopyrrolidine intermediate; hydrolyzing the intermediate by taking strong alkali as a catalyst, and then, adding acid into hydrolyzate for acid precipitation; and finally, carrying out chiral resolution by taking (S)-(+)-mandelic acid as a resolving agent. According to the method, isovaleraldehyde and nitromethane, which are cheap and are readily available, serve as raw materials and are subjected to Knoevenagel condensation reaction, Michael addition, hydrogenation reaction, hydrolyzing acid precipitation and chiral resolution, thereby obtaining Pregabalin. The reaction route is simple, and the yield of reaction of each step is relatively high, so that the total yield and purity of final Pregabalin are guaranteed.
- -
-
-
- Method for synthesizing Pregabalin by taking isovaleraldehyde as raw material
-
The invention discloses a method for synthesizing Pregabalin by taking isovaleraldehyde as a raw material. The method comprises the steps: carrying out Knoevenagel condensation on isovaleraldehyde and diethyl malonate in a cyclohexane solvent by taking a mixture of di-n-propylamine and acetic acid as a catalyst; carrying out Michael addition on the product obtained in the step one in an alkaline alcohol solvent; carrying out deacidifying reaction on the product obtained in the step two in a solvent prepared from DMSO and water by taking lithium chloride as a catalyst under the condition of heating; carrying out hydrolytic reaction on the product obtained in the step three under alkaline conditions; carrying out catalytic hydrogenation on the product obtained in the step four by taking Raney nickel as a catalyst; and carrying out chiral resolution on the product obtained in the step five by adopting lipase Lipolase 100T. According to the method, isovaleraldehyde, which is cheap and is readily available, serves as a raw material and is subjected to Knoevenagel condensation reaction, Michael addition, decarboxylation, hydrolysis, hydrogenation reaction and chiral resolution, thereby obtaining Pregabalin. The reaction route is simple, and the yield of reaction of each step is relatively high, so that the total yield and purity of final Pregabalin are guaranteed.
- -
-
Paragraph 0018; 0049; 0055
(2016/10/08)
-
- Method for synthesizing pregabalin from isobutyraldehyde
-
The present invention discloses a method for synthesizing pregabalin from isobutyraldehyde. The method comprises the following steps: performing Baylis-Hillman reaction on isobutyraldehyde and acrylonitrile by using DABCO and 2,6-di-tert-butylphenol as catalysts; performing substitution with 1-ethyl chloroformate in a solvent composed of pyridine and dichloroethane; performing carbonylation reaction on CO and ethanol by using palladium acetate and triphenylphosphine as catalysts; performing catalytic hydrogenation on raney nickel; performing hydrolysis in potassium hydroxide and methanol solvent, and adding acid for acid precipitation; and finally performing chiral resolution by using (S)-mandelic acid as a resolving agent. According to the method disclosed by the present invention, the inexpensive and easily available isobutyraldehyde is used as a raw material, and the pregabalin is obtained through Baylis-Hillman reaction, substitution reaction, carbonylation reaction, hydrogenation reaction, hydrolysis and acid precipitation and chiral resolution. The reaction route is simple, and the yield of the whole reaction is relatively high, so that overall yield and purity of the final pregabalin are ensured.
- -
-
Paragraph 0016; 0053
(2016/10/08)
-
- Method for synthesizing Pregabalin by taking chloroacetonitrile and isobutylaldehyde as raw materials
-
The invention discloses a method for synthesizing Pregabalin by taking chloroacetonitrile and isobutylaldehyde as raw materials. The method comprises the steps: carrying out substitution reaction on chloroacetonitrile and trimethyl phosphite in a methanol solvent by taking sodium methoxide as a catalyst; carrying out substitution reaction on the substitution reaction product and 1-ethyl chloroacetate in an ethanol solvent by taking sodium hydroxide as a catalyst; carrying out Wittig-Horner reaction on the substitution reaction product and isobutylaldehyde in a THF solvent by taking sodium hydride as a catalyst; carrying out catalytic hydrogenation by taking Raney nickel as a catalyst; carrying out hydrolysis in a methanol solvent by taking potassium hydroxide as a catalyst, and then, adding acid into hydrolyzate for acid precipitation; and finally, carrying out chiral resolution by taking (S)-mandelic acid as a resolving agent. According to the method, chloroacetonitrile, which is cheap and is readily available, serves as a raw material and is subjected to substitution reaction twice, Wittig-Horner reaction with isobutylaldehyde, catalytic hydrogenation, hydrolyzing acid precipitation and chiral resolution, thereby obtaining Pregabalin. The reaction route is simple, and the yield of reaction of each step is relatively high, so that the total yield and purity of final Pregabalin are guaranteed.
- -
-
Paragraph 0048; 0053
(2016/10/08)
-
- Method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as intermediate
-
The invention discloses a method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as an intermediate. The method comprises the steps: carrying out Knoevenagel condensation on isovaleraldehyde and methyl cyanoacetate in an ethanol solvent by taking piperidine as a catalyst; carrying out Michael addition on the condensation product and diethyl malonate in a n-hexane solvent by taking di-n-propylamine as a catalyst; carrying out hydrolyzing decarboxylation on the addition product under the catalysis of strong acid and under the condition of heating; dehydrating the hydrolyzing decarboxylation product in a THF solvent under the catalysis of phosphorus pentoxide and under the condition of heating; enabling the dehydrated hydrolyzing decarboxylation product to subject to ammonolysis reaction with urea; carrying out Hoffman degradation on the ammonolysis reaction product; and finally, carrying out chiral resolution on the Hoffman degradation product by taking (S)-(+)-mandelic acid as a resolving agent. According to the method, isovaleraldehyde and methyl cyanoacetate, which are cheap and are readily available, serve as raw materials and are subjected to Knoevenagel condensation, Michael addition, acid hydrolyzing decarboxylation and dehydrating, so as to obtain the intermediate gamma-isobutylglutaric anhydride; and the gamma-isobutylglutaric anhydride is subjected to ammonolysis, Hoffman degradation and chiral resolution, thereby obtaining Pregabalin. The reaction route is simple, and the yield of reaction of each step is relatively high, so that the total yield and purity of final Pregabalin are guaranteed.
- -
-
-
- Method for synthesis of pregabalin from methyl cyanoacetate and isovaleraldehyde as raw materials
-
The invention discloses a method for synthesis of pregabalin from methyl cyanoacetate and isovaleraldehyde as raw materials. The method comprises that isovaleraldehyde and methyl cyanoacetate undergo a Knoevenagel condensation reaction in an ethanol solvent in the presence of piperidine as a catalyst, the product and diethyl malonate undergo a Michael addition reaction in a n-hexane solvent in the presence of di-n-propylamine as a catalyst, the product undergoes an acid hydrolysis/decarboxylation reaction under conditions of heating and strong acid catalysis, the product and urea undergo an aminolysis reaction, the product undergoes a Hoffman degradation reaction and the product undergoes a chiral resolution reaction in the presence of (S)-(+)-mandelic acid as a resolving agent. Pregabalin is prepared from cheap and easily available isovaleraldehyde and methyl cyanoacetate as raw materials through Knoevenagel condensation, Michael addition, acid hydrolysis/decarboxylation, aminolysis, Hoffman degradation and chiral resolution. The method has a simple reaction route and a high yield in each reaction and guarantees a pregabalin overall yield and purity.
- -
-
-
- A process for the preparation of pregabalin
-
The invention discloses a preparation method of pregabalin. According to the preparation method, (R)-(-)-3-(carbamyl methyl)-5-methylhexanol has a Hofmann degradation reaction under the action of N-chlorosuccinimide in the presence of an alkali to produce pregabalin. By adopting N-chlorosuccinimide as a reagent of Hofmann degradation reaction, the use of bromine is avoided, the reaction yield is improved and the content of impurities in the product is reduced, so that the reaction is suitable for industrial production.
- -
-
Paragraph 0026-0028
(2017/03/18)
-
- Preparation method for asymmetrical synthesis of pregabalin
-
The invention discloses a preparation method for asymmetric synthesis of pregabalin.The preparation method includes: using 3-isobutylglutaric anhydride as a starting raw material; under catalytic action of chiral thiourea ammonium salt, enabling the starting raw material to be in asymmetric alcoholysis with mercaptan to generate mercaptide; enabling mercaptide to react with diphenylphosphoryl azide and benzyl alcohol sequentially to generate benzyloxy carbonyl methyl mercaptide; obtaining pregabalin through hydrolysis and hydrogenation reduction.The synthetic method is adopted to synthesize pregabalin, asymmetric catalysis is adopted to synthesize a key intermediate, a chemical resolution reagent is not used, total yield is greater than 50%, and ee value is greater than 94%.The preparation method has the advantages of novel synthesis path, few steps, mild reaction condition and the like.
- -
-
-
- Preparation method of pregabalin chiral intermediate
-
The invention provides a preparation method of a pregabalin chiral intermediate. The pregabalin chiral intermediate is (S)-4-isobutyl-dihydro-3H-furan-2-one. The preparation method comprises following steps: S1, a chiral hydroxyl compound 3 is obtained from an S-epoxypropane compound 2 via ring-opening reaction under Grignard reagent conditions; S2, sulfonylation protection of hydroxy groups in the chiral hydroxyl compound 3 is carried out so as to obtain a compound 4 with chiral leaving groups; and S3, the compound 4 and an acetate compound or malonic ester are subjected to substitution reaction, and a compound 1 is obtained via hydrolysis, decarboxylation, and ring closing reaction under acidic conditions. The raw materials used in preparation of the pregabalin chiral intermediate are cheap and easily available; reaction route is short; operation is simple; reaction process is safe and is friendly to the environment; the entire yield is high; the preparation method is convenient for large scale production; and an economical feasible route is provided for production of high purity pregabalin.
- -
-
Paragraph 0026
(2016/10/17)
-
- High-purity (+)-pregabalin and (-)-pregabalin method for the preparation of
-
The invention provides a new method for preparing high-purity (+)-pregabalin and (-)-pregabalin by using a chemical resolution reagent and separating a raceme of a diastereoisomer ester. The method comprises the following steps: performing an esterification reaction on (-)-menthol serving as a separating reagent and the raceme; separating and purifying the obtained crude product through preparative liquid chromatography to respectively obtain two pure diastereoisomer esters; performing one-step Hoffman degradation to respectively obtain the high-purity (+)-pregabalin and (-)-pregabalin. Through liquid chromatography detection, the prepared (+)-pregabalin has the chemical purity of 99.8 percent and the specific rotation of [alpha]D10.43(c=1.0,H2O), and can be used as a homemade reference substance; the separating reagent can be extracted for recycling by an extracting agent after a Hoffman reaction.
- -
-
Paragraph 0034; 0035
(2017/04/11)
-
- Unprecedented hydrophobic amplification in noncovalent organocatalysis "on water": Hydrophobic chiral squaramide catalyzed michael addition of malonates to nitroalkenes
-
In this study, water was demonstrated to be an exceptionally efficient reaction medium for the noncovalent, hydrogen-bonding-promoted enantioselective Michael addition of malonates to diverse nitroolefins using cinchona-based squaramide catalysts. A significant increase in the reaction rate was observed when the reaction was performed "on water" rather than in the conventional organic solvents, because of the hydrophobic hydration effect. This hydrophobic amplification was significantly dependent upon the hydrophobicity of the C3-substituent (vinyl or ethyl) of cinchona-based catalysts. Thus, the use of more hydrophobic catalyst with an ethyl group at the C3-position, even a highly challenging Michael donor such as dimethyl methylmalonate was also smoothly converted to the desired adduct. Furthermore, because of the remarkable rate acceleration under "on water" conditions, the catalyst loading also significantly decreased. Thus, in the case of β-ketoesters, even 0.01 mol % of catalyst loading was enough to complete the reaction at room temperature, affording the corresponding Michael adducts with perfect diastereo- and enantioselectivity (up to >99:1 d.r., up to 99% ee). The developed "on water" protocol was successfully applied for the scalable syntheses of an antidepressant (S)-rolipram and an anticonvulsant (S)-pregabalin.
- Bae, Han Yong,Song, Choong Eui
-
p. 3613 - 3619
(2015/06/16)
-
- Chemical assembly systems: Layered control for divergent, continuous, multistep syntheses of active pharmaceutical ingredients
-
While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels - choice of starting material, reagent, or order of reaction modules - enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, β-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49-75%).
- Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
-
supporting information
p. 678 - 682
(2015/03/04)
-
- PROCESS FOR THE PREPARATION OF PREGABALIN
-
The present invention provides an improved process for the preparation of a compound of formula (I), which comprises the steps of: formula (I), (a) reacting isovaleraldehyde of formula (II) and alkyl cyanoacetate of formula (III) optionally in presence of salts of weak acid and weak base or weak base in a suitable solvent to get 2-cyano-5-methyl-hex-2-enoic acid alkyl ester of formula (IV); (b) reacting 2-cyano-5-methyl-hex-2-enoic acid alkyl ester of formula (IV) with a suitable cyanide source in water or in an organic solvent or mixture thereof to get 2-isobutylsuccinonitrile of formula (V); (c) obtaining optionally 2-isobutylsuccinonitrile of formula (V) by reacting isovaleraldehyde of formula (II) and alkyl cyanoacetate of formula (III) in presence of suitable cyanide source in water or in an organic solvent or mixture thereof in single step; (d) converting 2-isobutylsuccinonitrile of formula pa (V) to racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) with a genetically modified nitrilase enzyme (Nit pt 9N_56_2) in water or optionally with an organic co-solvent at appropriate pH and temperature; (e) converting racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) to racemic alkyl 3-cyano-5-methyl-hexanoate of formula (VII) by treatment with alcohol (R3OH) and acidic catalyst or alkyl halide (R3X) in presence of a base in a suitable solvent or a mixture of solvents thereof; (f) obtaining (S)-alkyl 3-cyano-5-methyl-hexanoate of formula (VIII) and (R)-3-cyano-5-methyl-hexanoic acid or salt thereof of formula (X) by enzymatic enantioselective hydrolysis in water or organic solvent or a mixture thereof from racemic alkyl 3-cyano-5-methyl-hexanoate of formula (VII); (g) obtaining optionally the compound of formula (VII) by racemizing unwanted (R)-3-cyano-5-methyl-hexanoic acid or salt thereof of formula (X) or substantially enriched (R)-3-cyano-5-methyl-hexanoic acid salt thereof of formula (X) in presence of a base in organic solvent or a mixture thereof; (h) converting (S)-alkyl 3-cyano-5-methyl-hexanoate of formula (VIII) to pregabalin of formula (I) by hydrolyzing ester group with suitable alkali or alkaline earth metal base followed by hydrogenation optionally in one pot in a solvent selected from water or other organic solvents or a mixture thereof in presence of a suitable hydrogenation catalyst.
- -
-
-
- Development and Scale-up of an Organocatalytic Enantioselective Process to Manufacture (S)-Pregabalin
-
Herein is reported the development of a new process to manufacture (S)-pregabalin. The method comprises six steps, run under the catalysis of a recyclable polymer bound phase transfer catalyst, and afforded (S)-pregabalin in overall 54% yield, starting from building blocks acetylacetone, isovaleraldehyde, and nitromethane.
- Moccia, Maria,Cortigiani, Mauro,Monasterolo, Claudio,Torri, Federica,Del Fiandra, Claudia,Fuller, Geoffrey,Kelly, Brian,Adamo, Mauro F. A.
-
p. 1274 - 1281
(2015/09/28)
-
- METHOD FOR THE PREPARATION OF BETA-SUBSTITUTED GAMMA-AMINO CARBOXYLIC ACIDS
-
The present invention relates to the preparation of β-substituted γ-amino carboxylic acids, preferably in enantiomerically enriched or even enantiomerically pure form, by a one-pot conversion of a β-substituted γ-nitro dicarboxylic acid ester or of a β-substituted γ-nitro dicarboxylate of general formula to a β-substituted γ-nitro carboxylic acid and a subsequent reduction of the γ-nitro group to an amine group. In particular, the present invention relates to the preparation of ( S ) -pregabalin. In addition, the formation of enantiomerically enriched β-substituted γ-amino carboxylic acids and β-substituted γ-nitronate carboxylic acid salts are also described.
- -
-
Page/Page column 35
(2016/01/01)
-
- An improved procedure to prepare 3-methyl-4-nitroalkylenethylisoxazoles and their reaction under catalytic enantioselective Michael addition with nitromethane
-
Herein, we describe a short synthesis of 3-methyl-4-nitro-5-alkylethenyl isoxazoles and their reactivity as Michael acceptors. The title compounds reacted with nitromethane under phase-transfer catalysis to provide highly enantioenriched adducts (up to 93% ee) which were then converted to the corresponding γ-nitroacids. This journal is
- Moccia, Maria,Wells, Robert J.,Adamo, Mauro. F. A.
-
supporting information
p. 2192 - 2195
(2015/03/05)
-
