- A concise and efficient route to the Alzheimer's therapeutic agent (R)-arundic acid
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A short and efficient procedure for the preparation of (R)-arundic acid, a therapeutic agent for the treatment of Alzheimer's disease, has been developed. Based on cheap and commercially available (1R)-(+)-camphor as the source of chiral information, (R)-arundic acid is synthesized in a four-step cyclic sequence with 55% overall yield and high optical purity, ≥98% ee. Alkyl halide and acetylene constitute the only consumable carbon sources of this method, which allows obtaining of both enantiomers and recycling of chiral auxiliary.
- García, Jesús M.,Odriozola, José M.,Lecumberri, Ainara,Razkin, Jesús,González, Alberto
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- A diethyltartrate-based synthesis of both (-)- and (+)-arundic acid
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A diethyltartrate-based synthesis of both enantiomers of the acute ischemic stroke therapeutic agent, arundic acid is presented. Separable diastereomers were obtained through the Johnson-Claisen rearrangement of the chiral vicinal diol based on the diethyltartrate skeleton and were converted separately into the two enantiomers of arundic acid.
- Fernandes, Rodney A.,Dhall, Abhinav,Ingle, Arun B.
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- A new process for synthesis of the astrocyte activation suppressor, ONO-2506
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Development of a new process for the synthesis of ONO-2506, an agent that suppresses astrocyte activation, is described. Previous processes that involved asymmetric synthesis with a chiral auxiliary were unsatisfactory from a cost perspective because the relatively expensive chiral auxiliaries were not recyclable. To develop a more cost-effective process, we designed a new process starting from chiral 1,2-epoxyoctane, which was readily prepared catalytically by Prof. Jacobsen's method. The new five-step process was developed with the establishment of a modified cyanation condition, in which lithium cyanide was prepared in situ by combining lithium hydroxide with acetone cyanohydrin. Then the mechanisms for racemization and the side reaction until the cyanation step were clarified, and these problems were solved. The main features of this process are crystallization of the amide intermediate, since its optical purity is readily improved by recrystallization up to 100% ee in addition to formation of the dibenzylamine salt with ONO-2506 that leads to improved chemical and optical purity of the final product The shorter synthesis, including a one-pot reaction was ruled out because of the hazardous nature of the Katriztky hydrolysis conditions for the conversion of nitrile to amide in the presence of sodium cyanide.
- Hasegawa, Tomoyuki,Kawanaka, Yasufumi,Kasamatsu, Eichi,Ohta, Chisa,Nakabayashi, Kazuhiro,Okamoto, Masaki,Hamano, Masaya,Takahashi, Keiji,Ohuchida, Shuichi,Hamada, Yasumasa
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- Asymmetric synthesis of both (R)-and (S)-arundic acid
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The asymmetric synthesis of both (R)-and (S)-arundic acid has been achieved via the key step of a stereoselective alkylation reaction using non-cross-linked polystyrene (NCPS) supported (4R)- and (4S)-2-phenylimino-2- oxazolidine as chiral auxiliaries. This method is efficient (both enantiomers were obtained in 99% ee and 60% overall yield) and the chiral auxiliaries can be recovered quantitatively by simple filtration.
- Lu, Cuifen,Zhang, Longduo,Su, Hang,Yang, Guichun,Chen, Zuxing
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- Stereodivergent approach to Alzheimer's therapeutic agent (R)-(?) and (S)-(+)-arundic acid employing chiral 4-pentenol derivatives as building blocks
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An efficient stereodivergent total synthesis of anti-Alzheimer agent (R)-(?) and (S)-(+)-arundic acid has been achieved from both chiral and nonchiral materials. This strategy features an efficient approach to separable diastereomeric C-2 chiral 4-pentenol intermediates employing proline catalysed asymmetric α-aminooxylation and [3,3] sigmatropic Claisen rearrangement are the highlights of present synthesis.
- Bhosale, Viraj A.,Waghmode, Suresh B.
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- Synthesis of anti-Alzheimer (R)-arundic acid
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The asymmetric synthesis of the anti-Alzheimer agent (R)-arundic acid has been performed via a diastereoselective photodeconjugation reaction as the key-step. The synthetic approach involves a readily available chiral auxiliary, diacetone-d-glucose, and allows access to either enantiomer as illustrated by the synthesis of (S)-arundic acid. Both enantiomers were obtained in 88% ee using the same chiral auxiliary.
- Pelotier, Beatrice,Holmes, Ta'id,Piva, Olivier
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- PROCESSES FOR THE SYNTHESIS OF CHIRAL 1-ALKANOLS
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The invention relates to highly enantioselective processes for the synthesis of chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes.
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Paragraph 0242; 0243
(2016/12/01)
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- PROCESSES FOR THE SYNTHESIS OF CHIRAL 1-ALKANOLS
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The invention relates to highly enantioselective processes for the synthesis of chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes.
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Paragraph 00124
(2015/07/23)
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- Widely applicable synthesis of enantiomerically pure tertiary alkyl-containing 1-alkanols by zirconium-catalyzed asymmetric carboalumination of alkenes and palladium- or copper-catalyzed cross-coupling
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A highly enantioselective and widely applicable method for the synthesis of various chiral 2-alkyl-1-alkanols, especially those of feeble chirality, has been developed. It consists of zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA), lipase-catalyzed acetylation, and palladium- or copper-catalyzed cross-coupling. By virtue of the high selectivity factor (E) associated with iodine, either (S)- or (R)-enantiomer of 3-iodo-2-alkyl-1- alkanols (1), prepared by ZACA reaction of allyl alcohol, can be readily purified to the level of ≥99 % ee by lipase-catalyzed acetylation. A variety of chiral tertiary alkyl-containing alcohols, including those that have been otherwise difficult to prepare, can now be synthesized in high enantiomeric purity by Pd- or Cu-catalyzed cross-coupling of (S)-1 or (R)-2 for introduction of various primary, secondary, and tertiary carbon groups with retention of all carbon skeletal features. These chiral tertiary alkyl-containing alcohols can be further converted into the corresponding acids with full retention of the stereochemistry. The synthetic utility of this method has been demonstrated in the highly enantioselective (≥99 % ee) and efficient syntheses of (R)-2-methyl-1-butanol and (R)- and (S)-arundic acids. Look, mom, one hand! 2-Alkyl-1-alkanols of feeble chirality have been synthesized by a sequence of zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA), lipase-catalyzed acetylation, and Pd- or Cu-catalyzed cross-coupling in high enantiomeric purity of ≥99 % ee. The synthetic utility of this method has been demonstrated in highly enantioselective and efficient syntheses of (R)-2-methyl-1-butanol, (R)- and (S)-arundic acids. Copyright
- Xu, Shiqing,Lee, Ching-Tien,Wang, Guangwei,Negishi, Ei-Ichi
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p. 1829 - 1835
(2013/09/02)
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- Control of diastereoselectivity in orthoester Johnson-Claisen rearrangement of tartrate-based allyl alcohol: An efficient synthesis of arundic acid, a potential therapeutic agent for Alzheimer's disease
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A diastereoselective orthoester Johnson-Claisen rearrangement has been employed in the synthesis of both enantiomers of arundic acid, a potential therapeutic agent against Alzheimer's disease. The effect of solvent, olefin geometry and alcohol chirality on the diastereoselectivity of the orthoester Johnson-Claisen rearrangement of a tartrate-based allyl alcohol has been studied. A diastereoselective orthoester Johnson-Claisen rearrangement has been employed in the synthesis of both enantiomers of arundic acid, a potential therapeutic agent for Alzheimer's disease. The effect of solvent, olefin geometry and alcohol chirality on the diastereoselectivity of the orthoester Johnson-Claisen rearrangement ofa tartrate-based allyl alcohol has beenstudied. Copyright
- Fernandes, Rodney A.,Ingle, Arun B.,Chaudhari, Dipali A.
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experimental part
p. 1047 - 1055
(2012/04/04)
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- Highly enantioselective α alkylation of aldehydes with 1,3-benzodithiolylium tetrafluoroborate: A formal organocatalytic α alkylation of aldehydes by the carbenium ion
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A formal formyl: The organocatalytic stereoselective addition of formyl equivalents to aldehydes (see scheme) tolerates a large variety of functional groups to afford products with high enantioselectivity (92-97% ee) and good yields (up to 95%). The benzodithiol group can be easily removed with Raney Ni or metalated with nBuLi, thus giving access to a methyl group or to a wide range of useful intermediates.
- Gualandi, Andrea,Emer, Enrico,Capdevila, Montse Guiteras,Cozzi, Pier Giorgio
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p. 7842 - 7846
(2011/10/05)
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- CRYSTAL COMPRISING (2R)-2-PROPYLOCTANOIC ACID AND DIBENZYLAMINE
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According to the present invention, crystals comprising (2R)-2-propyloctanoic acid and an amine, which can be used as bulk drugs for safely orally administrable solid preparations with keeping the pharmacological effect, are provided. Among these crystals, the crystal with dibenzylamine per se is particularly useful as bulk drug for pharmaceuticals and can be used as an intermediate to produce (2R)-2-propyloctanoic acid having an optical purity of more than 99.5%e.e. which has not been obtained.
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Page/Page column 32; 33
(2010/11/25)
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- Process for producing (2r)-2-propyloctanoic acid and intermediate therefor
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The present invention relates to a process for producing (2R)-2-propyloctanoic acid, which comprises subjecting (2R)-2-hexyloxirane to a two-carbon adding reaction with ring-opening reaction, followed by a protecting reaction of a hydroxyl group to convert it to a compound represented by formula (I): (wherein X represents an optionally protected hydroxyl group) and then subjecting the compound to a one-carbon adding reaction to convert it to (2R)-2-propyloctanamide, followed by recrystallization and hydrolysis. According to the process of the present invention, (2R)-2-propyloctanoic acid can be produced by less steps as compared with the conventional method without a dangerous reaction.
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Page/Page column 6
(2008/06/13)
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- Process development of ONO-2506: A therapeutic agent for stroke and Alzheimer's disease
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A process for the synthesis of ONO-2506, an agent that suppresses astrocyte activation, has been developed. Significant improvement of the level of impurities in the final product has been achieved compared with the laboratory-scale procedure. Kilogram quantities of the compound have been supplied for preclinical studies by this improved process, with both a high quality (99.8%) and a high optical purity (99.6% ee). This was achieved by formation of a crystalline salt of an intermediate which could be recrystallized to give high purity. Toward the future launch of this product, residual problems such as byproduct formation during stereoselective allylation and removal of chiral auxiliary steps were also solved by further investigation.
- Hasegawa, Tomoyuki,Kawanaka, Yasufumi,Kasamatsu, Eiji,Iguchi, Yoichi,Yonekawa, Yoshihira,Okamoto, Masaki,Ohta, Chiaki,Hashimoto, Shinsuke,Ohuchida, Shuichi
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p. 168 - 171
(2013/09/05)
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- Development of new chiral auxiliary derived from (S)-(-)-phenylethylamine for a synthesis of enantiopure (R)-2-propyloctanoic acid
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A new chiral auxiliary, {[(1S)-1-phenylethyl]amino}phenol, derived from (S)-(-)-1-phenylethylamine was developed for asymmetric synthesis of (R)-2-propyloctanoic acid (1) with moderate diastereoselectivity and good crystalline property.
- Hasegawa, Tomoyuki,Yamamoto, Hisashi
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p. 1181 - 1186
(2007/10/03)
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- Process for the preparation of (2R)-2-propyloctanoic acid
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A process for the preparation of (2R)-2-propyloctanoic acid which is characterized by subjecting (2S)-2-(2-propynyl)octanoic acid or (2S)-2-(2-propenyl)octanoic acid to reduction using platinum on carbon. This process gives (2R)-2-propyloctanoic acid having high optical purity without isomerization.
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- Intermediates and processes for the preparation of optically active octanoic acid derivatives
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Novel intermediates, i.e., N-(2S-(2-propenyl)octanoyl)-(1S)-(?)-2, 10-camphorsultam, N-(2S-(2-propynyl)octanoyl)-(1S)-(?)-2,10-camphorsultam and N-(2R-(2-propyl)octanoyl)-(1S)-(?)-2,10-camphorsultam; processes for the preparation of the intermediates; and processes for the preparation of optically active 2S-(2-propenyl)octanoic acid, 2S-(2-propynyl)octanoic acid and 2R-propyloctanoic acid by using the same. Optically active 2R-propyloctanoic acid equivalent or superior to that prepared by the process of the prior art in optical purity can be efficiently prepared in shorter reaction steps.
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Page column 11-12
(2010/02/05)
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- A practical synthesis of optically active (R)-2-propyloctanoic acid: Therapeutic agent for Alzheimer's disease
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(R)-2-Propyloctanoic acid has been developed as a novel therapeutic agent for Alzheimer's disease. A large-scale synthesis of this candidate was achieved by using Oppolzer's camphorsultam as a chiral auxiliary under improved conditions. It was essential for the successful synthesis of this compound to utilize a new removal method for the chiral source with a combination of tetrabutylammonium hydroxide and hydrogen peroxide. The present process afforded the desired product in high yield with high optical purity.
- Hasegawa, Tomoyuki,Yamamoto, Hisashi
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p. 423 - 428
(2007/10/03)
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- A practical removal method of camphorsultam
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A mild and efficient removal of camphorsultam was realized using tetrabutylammonium hydrogen peroxide as a key reagent.
- Hasegawa, Tomoyuki,Yamamoto, Hisashi
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p. 882 - 884
(2007/10/03)
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