- A kind of improved mitiglinide preparation method (by machine translation)
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The invention relates to an improved mitiglinide preparation method, the method comprises the steps of (1): preparation of acyl chloride; step (2): active preparation of amides; step (3): 2 - (S)- benzyl - 4 - oxo - (cis - full hydrogenation isoindol - 2 - yl) butyric acid preparation; step (4): mitiglinide preparation, the process of the method is simple, high yield, low production cost, compared with the prior-anhydride method process, the purity of the product is obviously improved, easy to industrial production. (by machine translation)
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Paragraph 0052; 0055; 0060-0061; 0070
(2019/01/14)
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- Preparation method of mitiglinide calcium
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The invention relates to a preparation method of mitiglinide calcium, which includes steps of step 1, synthesis of benzal butanedioic acid; step 2, synthesis of benzylsuccinic acid; step 3, synthesisof (S)-benzylsuccinic acid (R)-alpha- phenylethylamine; step 4, synthesis of (S)-benzylsuccinic acid; step 5, synthesis of 2S-dihydro-isoindole indolebutyric acid; step 6, synthesis of crude product of mitiglinide calcium; step 7, refining of mitiglinide calcium.
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Paragraph 0060-0061; 0072-0073
(2018/05/07)
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- A kind of improved mitiglinide industrial preparation method
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The invention provides an improved mitiglinide calcium (I) preparation method, and is characterized in that the preparation method successively comprises the steps: step 1, preparation of 2-benzyl succinic acid; step 2, preparation of (S)-2-benzyl succinic acid; step 3, preparation of 2-(S)-benzyl-4-oxo-(cis-perhydroisoindole-2-yl)butyric acid; and step 4, preparation of mitiglinide calcium. The invention provides the mitiglinide calcium industrialized preparation method having the advantages of being economical and practical, simple to operate, short in reaction period and high in yield.
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- Technology for synthesizing Mitiglinide intermediate
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The invention relates to the field of pharmaceutical synthesis, in particular to a technology for synthesizing a Mitiglinide intermediate, namely 2-(s)-benzyl-4-oxo-(cis-octahydroisoindole-2-yl) benzyl butyrate. The synthesis technology comprises the steps that N,N'-carbonyldiimidazole and S-2-benzylsuccinic acid are sequentially added to ethyl acetate, cis-octahydroisoindole hydrochloride is added after reaction, then purified water is added, the pH value is adjusted by the addition of hydrochloric acid, the purified water is added to an ethyl acetate layer obtained after standing and liquid separation, the pH value is adjusted by the addition of a NaOH solution, ethyl acetate is added to a water layer obtained after standing and liquid separation, the pH value is adjusted by the addition of hydrochloric acid, standing and liquid separation are conducted and then the ethyl acetate layer is subjected to drying, filtering and washing; anhydrous potassium carbonate and benzyl bromide are sequentially added to the obtained ethyl acetate solution for reflux reacting, the purified water is added after cooling, standing and liquid separation are conducted, an organic layer is subjected to crystallization and further subjected to post-treatment to obtain a crude product of a target compound, and the target pure product is obtained after purification. By means of the synthesis technology, the high-content and high-purity Mitiglinide intermediate can be prepared.
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Paragraph 0029-0030
(2017/07/01)
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- Mitiglinide calcium method for the preparation of
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The invention provides a novel preparation method for Mitiglinide calcium hydrate. The method comprises the following steps: adopting cis-hexahydroisoindole as a raw material, conducting acylation reaction, hydrocarbonylation reaction, hydrolysis reaction
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Paragraph 0030
(2017/04/03)
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- Mitiglinide preparation method
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The invention discloses a high purity mitiglinide calcium preparation method including the following steps: synthesis of (2S)-2-benzyl-3-(cis-hexahydro isoindole-2-carbonyl) propionic acid; synthesis of (2S)-2-benzyl-3-(cis-hexahydro isoindole-2-carbonyl) benzyl propionate; hydrolysis of the (2S)-2-benzyl-3-(cis-hexahydro isoindole-2-carbonyl) benzyl propionate; and synthesis of mitiglinide calcium. The method simplifies synthetic route, and has the characteristics of convenient operation, low cost of raw materials, low equipment requirement, economy, environmental protection and simple technology. According to the method, the (2S)-2-benzyl-3-(cis-hexahydro isoindole-2-carbonyl) propionic acid can be crystallized after esterification, and is easy for purification and preservation and easy for realization of industrialized production. Tests confirm that the preparation method is easy in postprocessing, good in reaction area selectivity, high in product purity and relatively low in cost, and is conducive to industrial production.
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Paragraph 0029-0031
(2017/04/04)
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- Novel mitiglinide calcium preparing method
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The invention provides a novel mitiglinide calcium preparing method. According to the method, (S)-2-benzyl succinic acid is taken as the raw material, and deacidification is conducted to generate (S)-2-benzyl succinic anhydride; amidation is conducted between (S)-2-benzyl succinic anhydride and cis-hexahydroisoidolin to generate mitiglinide acid and an isomer byproduct; the isomer byproduct is separated out and subjected to isomerization to generate mitiglinide acid; acid-base salifying and salt exchange are conducted on the obtained mitiglinide acid to generate the product mitiglinide calcium. Compared with an existing anhydride-method technology, the method has the advantage that the purity of the product is improved remarkably. Compared with an active ester method and an amide method, the method has the advantages that the technology is simple, the yield is high, and production cost is low.
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Paragraph 0059; 0060
(2016/10/10)
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- Method for the preparation of Mitiglinide Calcium Dihydrate
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The present invention refers to a photomask, a proximity [...] dihydrate of provides manufacturing method. According to of the present invention manufacturing method, including imidazoles to solution chloride reclamation material-benzyl (S) blended solution high draw child factor pebble cis-same and a pumping process is carried out in direct response the hydrochloride salt a photomask, a proximity which includes directing an [...] dihydrate according to the voltage by rated excess, a photomask, a proximity-purity compound in a dihydrate [...] , prepared in high yield to be as well as safety the fabrication procedure relatively mild conditions, and the mass production method by using the mask pattern..
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Paragraph 0052; 0076; 00077
(2016/12/16)
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- Identification, synthesis and characterization of impurities of (S)-Mitiglinide calcium dihydrate
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(S)-Mitiglinide Calcium dihydrate (1), an important potent hypoglycemic agent. During laboratory optimization and later in bulk synthesis the formation of various impurities was observed. The method of preparation of most of these impurities is not availa
- Umasankara Sastry,Nageswara Rao,Appi Reddy,Gandhi
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p. 2417 - 2421
(2014/06/09)
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- PROCESS FOR OBTAINING (S)-2-BENZYL-4-((3AR,7AS)-HEXAHYDRO-1 H-ISOINDOL- 2(3H)-YL)-4-OXOBUTANOIC ACID AND SALTS THEREOF
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Comprising reacting compound (IV) with compound (V) in a solvent to give (S)-mitiglinide (II) and compound (III) as a by- product; removing the solvent and adding ethyl acetate to precipitate compound (III); collecting the solid and applying at least one cycle process comprising: - refluxing the solution of compound (III) with an organic solvent to give (S)-mitiglinide (II) and further compound (III) as a by-product, - removing the organic solvent and adding ethyl acetate to precipitate compound (III); and - separating the mother liquors from the solid, and mixing all the mother liquors; removing the ethyl acetate from the mother liquors to obtain (S)-mitiglinide.
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Page/Page column 12
(2014/01/09)
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- PROCESS FOR THE PREPARATION OF PERHYDROISOINDOLE DERIVATIVE
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The present invention relates to a novel, efficient and industrially advantageous process for preparing perhydroisoindole derivative, particularly (S)-mitiglinide of formula (I): and pharmaceutically acceptable salts thereof. Further, it relates to novel amide intermediates of formula (VI), including salts, solvates, hydrates, polymorphs, isomers and racemic mixtures thereof useful in the process of present invention. Formula (VI): wherein R is selected from straight chain or branched C1-6 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl. The present invention also relates to amorphous form of mitiglinide calcium, its preparation and process for its conversion to crystalline mitiglinide calcium.
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Page/Page column 24
(2009/05/28)
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- Novel convenient synthesis of mitiglinide
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A novel convenient synthesis of the hypoglycemic agent mitiglinide was developed. (2S)-4-[(3aR,7aS)-Octahydro-2H-isoindol-2-yl]-4-oxo-2-benzyl-butanoic acid (6) was prepared by selective hydrolysis of ethyl 4-[(3aR,7aS)-octahydro- 2H-isoindol-2-yl]-4-oxo-
- Huang, Wei,Cen, Jun-Da
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p. 2153 - 2157
(2008/02/07)
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- USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
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The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
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- An effective and convenient method for the preparation of KAD-1229
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A new convenient method for the asymmetric synthesis of the potent hypoglycemic agent KAD-1229 was developed. The key step of this method is diasteroselective alkylation of 1 to give crude 2 (d.e. > 93%) in good yield with the easily available Oppolzer's
- Liu, Jianchao,Yang, Yushe,Ji, Ruyun
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p. 1935 - 1939
(2007/10/03)
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- Preparation of optically active succinic acid derivatives. II. Efficient and practical synthesis of KAD-1229
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For large-scale synthesis of monocalcium bis[(2s)-2-benzyl-3-(cis- hexahydroisoindolin-2-ylcarbonyl)propionate]dihydrate (1, KAD-1229), we investigated regioselective reactions of (S)-2-benzylsuccinic acid (2) with cis-hexahydroisoindoline (4). It was difficult to obtain a half amide regioselectively through coupling reaction of the (S)-acid 2 with the amine 4. Therefore, the succinic acid 2 was converted to bis-activated esters 3a-c and these were reacted with 4 to give the amides 5a-c in good yields, regioselectively. The amides 5a-c were derived to KAD-1229, which has a potent hypoglycemic effect, in good yields.
- Yamaguchi, Toshiaki,Yanagi, Takashi,Hokari, Hiroshi,Mukaiyama, Yuko,Kamijo, Tetsuhide,Yamamoto, Iwao
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p. 337 - 340
(2007/10/03)
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- Preparation of optically active succinic acid derivatives: I. Optical resolution of 2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)-propionic acid
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(+)-Monocalcium bis[(2S)-2-benzyl-3-(cis-hexahydroisoindolin-2- ylcarbonyl)propionate] dihydrate (KAD-1229, 1) is an optically active succinic acid calcium salt derivative with potent hypoglycemic effect. We investigated two optical resolution method. 2-B
- Yamaguchi, Toshiaki,Yanagi, Takashi,Hokari, Hiroshi,Mukaiyama, Yuko,Kamijo, Tetsuhide,Yamamoto, Iwao
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p. 1518 - 1520
(2007/10/03)
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