99469-99-5Relevant articles and documents
Synthesis method of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid
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Paragraph 0036; 0038-0039; 0041-0042; 0044-0045; 0047-0048, (2021/01/24)
The invention relates to a synthesis method of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid, and belongs to the technical field of medicine synthesis. In order to solve the problems of long reaction route and low yield in the prior art, the invention provides the synthesis method of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid, which comprises the following steps: under the actions of a catalytic amount of phase transfer catalyst and cocatalyst, carrying out etherification and esterification reaction on 4-methylsalicylic acid and diethyl carbonate in a water-insoluble solvent to obtain a corresponding intermediate is obtained, in the presence of lithium diisopropylamide, carrying out methylation reaction on the intermediate and dimethyl carbonate or diethyl carbonate at the temperature of -50 DEG C or below, and carrying out acid regulation treatment to control the pH value of the system to be 3.5 or below, thereby obtaining the corresponding product compound 3-ethoxy-4-ethoxycarbonylphenylacetic acid shown in the formula III. According to the method, the operation of each step of reaction post-treatment is simple and easy, the method has the advantage of short reaction route, and the yield of the final product is high.
Preparation method of repaglinide key intermediate
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, (2019/12/02)
The invention discloses a preparation method of a repaglinide key intermediate (I). The preparation method comprises the following steps: reacting ethyl 4-methyl-2-ethoxybenzoate (II) with carbon monoxide and alcohol under the conditions of a catalyst and an oxidant, and selectively hydrolyzing reactants to obtain an intermediate (I). The preparation method is simple, efficient, mild in condition,good in reproducibility, high in yield and suitable for industrial production.
Bridging C?H Activation: Mild and Versatile Cleavage of the 8-Aminoquinoline Directing Group
Berger, Martin,Chauhan, Rajan,Rodrigues, Catarina A. B.,Maulide, Nuno
, p. 16805 - 16808 (2016/11/16)
8-Aminoquinoline has emerged as one of the most powerful bidentate directing groups in history of C?H activation within the last decade. However, cleavage of its robust amide bond has shown to be challenging in several cases, thus jeopardizing the general synthetic utility of the method. To overcome this limitation, we herein report a simple oxidative deprotection protocol. This transformation rapidly converts the robust amide to a labile imide, allowing subsequent cleavage in a simple one-pot fashion to rapidly access carboxylic acids or amides as final products.
A new route for the synthesis of the repaglinide key intermediate 3-ethoxy-4-ethoxycarbonylphenylacetic acid
Zhang, Yue,Liu, Tingting,Niu, Zhaohuan,Fu, Yajing,Yang, Jixia,Song, Yongxing,Zhao, Shuchun
, p. 506 - 510 (2016/08/13)
A new method is described for manufacturing 3-ethoxy-4-ethoxycarbonylphenylacetic acid, which is a key intermediate of the antidiabetic drug repaglinide, starting from 3-hydroxyphenylacetic acid and involving esterification, formylation, oxidation, etherification and selective hydrolysis. The effect of reaction temperature, time, solvent and substrate ratios on the yield were studied in detail and the optimal conditions are presented in the paper. The new method makes the scale-up operation easier and the environmental problems are fewer. The impurities in the intermediate of the new route were also determined. Characterisation of the product and intermediates involved was achieved by FTIR, 1H NMR, 13C NMR, HRMS and DSC.
TETRAHYDROISOQUINOLINE DERIVED PRMT5-INHIBITORS
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Page/Page column 103-104, (2016/03/19)
A compound of formula I wherein: n is 1 or 2: p is 0 or 1; R1 is optionally one or more halo or methyl groups; R2a and R2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R2c and R2d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH2OH; R3a and R3b are independently selected from H and Me; R4 is either H or Me; R5 is either H or Me; R6a and R6b are independently selected from H and Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C5-12 heteroaryl.
Process for the preparation of 3-ethoxy-4-(alkoxy carbonyl)-phenyl acetic acid. (an intermediate of repaglinide)
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Page 4; 5, (2008/06/13)
The present invention relates to an improved and convenient process for the preparation of 3-Ethoxy-4-(alkoxy carbonyl)-phenyl acetic acid, which can be represented by formula (Ia) where R1 represents ethyl or methyl. Specifically the present invention relates to an improved process for the preparation of compound of formula (Ia), which is the key intermediate for Repaglinide of formula (I), by the process, which involves non-hazardous raw materials with an easy handling, and cost effective process
Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide
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Page column 4, (2010/02/05)
The present invention relates to a new and industrially advantageous process for the preparation of 3-ethoxy-4-ethoxy-carbonyl-phenyl acetic acid. This compound is a key intermediate for the synthesis of Repaglinide, an oral hypoglycemic agent.
An efficient and cost-effective synthesis of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid: A key acid synthon of repaglinide
Salman, Mohammad,Babu, Suresh J.,Ray, Purna C.,Biswas, Sujoy,Kumar, Naresh
, p. 184 - 186 (2013/09/06)
This report describes an efficient and commercially viable synthesis of 3-ethoxy-4-ethoxy-carbonyl-phenylacetic acid (1), a key intermediate for the preparation of repaglinide, an oral hypoglycemic agent, from 2-hydroxy-4-methylbenzoic acid in two steps. Thus, 2-hydroxy-4-methylbenzoic acid was first alkylated with ethyl bromide in a polar aprotic solvent and in the presence of an inorganic base to afford ethyl 2-ethoxy-4-methylbenzoate; deprotonation with lithium diisopropylamide (LDA) and quenching the resulting carbanion with carbon dioxide provided the desired compound with improved yield and excellent purity. This procedure is significantly better than a previously published synthesis which involves five steps and requires use of expensive and hazardous reagents.
Repaglinide and related hypoglycemic benzoic acid derivatives
Grell, Wolfgang,Hurnaus, Rudolf
, p. 5219 - 5246 (2007/10/03)
The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethylpiperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5- fluoro, and the α-methyl residue were replaced by a 2-piperidino, a 5- hydrogen, and a larger α-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)- enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 μg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known - the acidic group (COOH; S02NH) and the amidic spacer (CONH; NHCO) - the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.
