159213-18-0Relevant articles and documents
A novel method of producing the key intermediate ASI-2 of ranirestat using a porcine liver esterase (PLE) substitute enzyme
Yamamura, Ei-Tora,Tsuzaki, Kazuya,Kita, Shinji
, p. 1124 - 1135 (2019/06/19)
(R)-2-amino-2-ethoxycarbonylsuccinimide (ASI-2) is a key intermediate used in the pharmaceutical industry and is valuable for the industrial synthesis of ranirestat, which is a potent aldose reductase inhibitor. ASI-2 was synthesized in a process combining chemical synthesis and bioconversion. Bioconversion in this study is a key reaction, since optically active carboxylic acid derivative ((R)-1-ethyl hydrogen 3-benzyloxycarbonylamino-3-ethoxycarbonyl-succinate, Z-MME-AE) is synthesized from a prochiral ester, diethyl 2-benzyloxycarbonyla-mino-2-ethoxycarbonylsuccinate, Z-MDE-AE, at a theoretical yield of 100%. Upon screening for microorganisms that asymmetrically hydrolyze Z-MDE-AE, Bacillus thuringiensis NBRC13866 was found. A novel esterase EstBT that produces Z-MME-AE was purified from Bacillus thuringiensis NBRC13866 and was stably produced in Escherichia coli JM109 cells. Using EstBT rather than porcine liver esterase (PLE), ASI-2 was synthesized with a 17% higher total yield by a novel method, suggesting that the esterase EstBT is a PLE substitute enzyme and therefore, may be of interest for future industrial applications.
Synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate
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Page/Page column 9-12, (2019/01/14)
The invention relates to a synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate. According to an asymmetric synthesis method of ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate, 1-benzyl-2,5-dioxapyrrolidine-3-carboxylate (I) is used as a raw material, and in the presence of a chiral amide (III) catalyst, the 1-benzyl-2,5-dioxapyrrolidine-3-carboxylate (I) and di-tert-butyl azodicarboxylate (II) are subjected to addition with Michael, so that R-3-di-tert-butoxy-hydrazide-1-benzyl-2,5-dioxopyrrolidine-3-carboxylic acid ethyl ester (IV) is obtained; the IV is directly subjected to BOC removal in the presence of an acid catalyst without separation, so that R-3-mercapto-1-benzyl-2,5-dioxopyrrolidine-3-carboxylic acid ethyl ester hydrochloride (V ) is obtained; and V is subjected toa hydrogenation reaction in the presence of a hydrogenation catalyst, so that the ethyl R-3-amino-2,5-dioxopyrrole-3-carboxylate (VI) is obtained. The structure of a chiral amide catalyst (III) is shown as below. The synthesis method is simple, the yield of the asymmetric catalysis product is high, the enantioselectivity of products is 95% or above, the synthesis method is mild in condition, simple to operate and low in production cost, and the synthesis method can be used for industrialized production.
First Kilogram-Scale Application of the Lanthanum Catalyzed Asymmetric Amination to Synthesis of the Chiral Succinimide Derivative, A Key Intermediate for the Preparation of AS-3201
Toshima, Minoru,Watanabe, Shoji,Uchiyama, Katsuya,Takasaki, Tsuyoshi,Bhogle, Nandkumar N.,Zhao, Hang,Filios, Mike,Takahashi, Kazuhiko,Snoonian, John R.,Saranteas, Kostas
, p. 1239 - 1245 (2016/07/23)
The process development of ethyl-(R)-3-amino-2,5-dioxopyrrolidine-3-carboxylate (2), the chiral intermediate for the manufacture of AS-3201 (1), is described. A practical and scalable Shibasaki asymmetric amination that generates the chiral quaternary center was developed and demonstrated on kilogram scale. A safe, convenient, and large-scale hydrogenation of the hydrazine intermediate was also developed.
PROCESS FOR PRODUCING OPTICALLY ACTIVE SUCCINIMIDE DERIVATIVES AND INTERMEDIATES THEREOF
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, (2014/04/18)
A process for producing optically active succinimide derivatives as key intermediates of (3R)-2′-(4-bromo-2-fluorobenzyl)spiro{pyrrolidine-3,4′(1′H)-pyrrolo[1,2-a]pyrazine}-1′,2,3′,5(2′H)-tetraone, which comprises the following reaction steps.
SUCCINIC ACID DIESTER DERIVATIVE, PROCESS FOR PRODUCTION THEREOF, AND USE OF THE DERIVATIVE IN THE PRODUCTION OF PHARMACEUTICAL PREPARATION
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Page/Page column 10, (2009/06/27)
The present invention provides with a process of preparing an optically active succinimide derivative, which is a key intermediate for production of ranirestat. A compound (3) is easily prepared by treating the derivative of succinic acid diester of the formula (2): wherein R1 is an amino group protected with a group removed by hydrogenolysis or a tert-butoxycarbonylamino group and R2 is an ethyl group optionally substituted with one or two methyl group(s) at α-position, provided that R2 is not a tert-butyl group when R1 is a tert-butoxycarbonylamino group; with alkali metal alkoxide and the compound (3) can be an important intermediate for production of ranirestat.
Asymmetric dieckmann condensation via memory of chirality: synthesis of the key intermediate for as-3201, an aldose reductase inhibitor
Watanabe, Toshihide,Kawabata, Takeo
experimental part, p. 1593 - 1606 (2009/08/09)
Asymmetric Dieckmann condensation via memory of chirality has been developed. A key intermediate for the synthesis of AS-3201, an aldose reductase inhibitor, has been prepared in 94% ee by asymmetric Dieckmann condensation of 8 derived from L-aspartic acid.
En route to an efficient catalytic asymmetric synthesis of AS-3201
Mashiko, Tomoyuki,Hara, Keiichi,Tanaka, Daisuke,Fujiwara, Yuji,Kumagai, Naoya,Shibasaki, Masakatsu
, p. 11342 - 11343 (2008/03/14)
A catalytic asymmetric synthesis of AS-3201 via catalytic asymmetric amination with a novel lanthanum-amide complex is described. The amination reaction proceeded efficiently with as little as 1 mol % of catalyst loading, allowing for an efficient access to the key intermediate for the synthesis of AS-3201, a potent aldose reductase inhibitor. Copyright
Novel, highly potent aldose reductase inhibitors: (R)-(-)-2-(4-bromo-2- fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-4-spiro-3'- pyrrolidine-1,2',3,5'-tetrone (AS-3201) and its congeners
Negoro, Toshiyuki,Murata, Makoto,Ueda, Shozo,Fujitani, Buichi,Ono, Yoshiyuki,Kuromiya, Akelmi,Komiya, Masanobu,Suzuki, Kenji,Matsumoto, Jun-Ichi
, p. 4118 - 4129 (2007/10/03)
A series of novel tetrahydropyrrolo[1,2-α]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin- induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo-[1,2-α]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo-[1,2-α]pyrazine-4- spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10-8 M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)-enantiomer 44 (SX-3202). From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single- crystal X, ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.
