- En route to an efficient catalytic asymmetric synthesis of AS-3201
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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
- Mashiko, Tomoyuki,Hara, Keiichi,Tanaka, Daisuke,Fujiwara, Yuji,Kumagai, Naoya,Shibasaki, Masakatsu
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Read Online
- Process for production of 2,5 dioxopyrrolidine 3 carboxylate
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The present invention provides a novel intermediate which enable to prepare tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives such as Ranirestat being promising therapeutic agents for diabetic complications in a short process and in an economically advantageous and safe manner, and a process for preparing the same. That is, the present invention provides a process for preparing a compound of the following formula (I) wherein R1 is an amino group protected with a protecting group, etc., and R2 is a lower alkyl group, etc., comprising the following steps (1) and (2): (1) a step of converting a cyano group in a compound of the following formula (II) wherein n and m are each independently 0 or 1; provided when n is 0 and m is 1, then R2 and R3 are the same or different protecting groups for a carboxyl group; and when n is 1 and m is 0, then R2 and R3 are the same protecting groups for a carboxyl group; and R1 is as defined above, into a carbamoyl group in the presence of divalent palladium compound(s), primary amide(s) and water; and (2) a step of cyclizing the product obtained in the step (1).
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Page/Page column 8
(2011/08/08)
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- A concise enantioselective synthesis of (-)-ranirestat
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Chemical Equation Presented A concise enantioselective synthesis of the potent aldose reductase inhibitor ranirestat (1) is reported. The synthesis was accomplished employing inexpensive, commercially available starting materials. A palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) of malonate 4 was utilized as a key transformation to construct the tetrasubstituted chiral center in the target.
- Trost, Barry M.,Osipov, Maksim,Dong, Guangbin
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supporting information; experimental part
p. 1276 - 1279
(2010/06/17)
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- 3-HYDRAZINO-2,5-DIOXOPYRROLIDINE-3-CARBOXYLATES, PROCESS FOR PRODUCTION OF THE SAME, AND USE OF THE SAME
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The present invention provides 3-hydrazino-2,5-dioxopyrrolidine-3-carboxylates of the formula (I): wherein R1 is a C1-6 alkyl group, etc., R2 is a hydrogen atom or a COOR3 group, wherein R3 is a tert-C4-6 alkyl group, a 2,2,2-trichloroethyl group or a benzyl group in which the benzene ring moiety may be optionally substituted by one or two atoms or groups independently selected from the group consisting of a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a cyano group and a nitro group, and a salt thereof, which are useful as a novel intermediate for preparing tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives such as Ranirestat being promising therapeutic agents for diabetic complications in a short process and in an economically advantageous and safe manner, and the process for preparing the same.
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Page/Page column 10
(2009/10/18)
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- SUCCINIC ACID DIESTER DERIVATIVE, PROCESS FOR PRODUCTION THEREOF, AND USE OF THE DERIVATIVE IN THE PRODUCTION OF PHARMACEUTICAL PREPARATION
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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.
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Page/Page column 12
(2009/06/27)
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- 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
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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.
- Negoro, Toshiyuki,Murata, Makoto,Ueda, Shozo,Fujitani, Buichi,Ono, Yoshiyuki,Kuromiya, Akelmi,Komiya, Masanobu,Suzuki, Kenji,Matsumoto, Jun-Ichi
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p. 4118 - 4129
(2007/10/03)
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