- Semi-rational protein engineering of a novel esterase from Bacillus aryabhattai (BaCE) for resolution of (R,S)-ethyl indoline-2-carboxylate to prepare (S)-indoline-2-carboxylic acid
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A gene encoding an esterase from Bacillus aryabhattai (BaCE) was identified, synthesized and efficiently expressed in the Escherichia coli system. A semi-rational protein engineering was applied to further improve the enzyme's enantioselectivity. Under the guidance of the molecular docking result, a single mutant BaCE-L86Q and a double mutant BaCE-L86Q/G284E were obtained, with its Emax value 6.4 times and 13.9 times of the wild-type BaCE, respectively. The recombinant BaCEs were purified and characterized. The overwhelming E value demonstrated that BaCE-L86Q/G284E was a promising biocatalyst for the biological resolution to prepare (S)-indoline-2-carboxylic acid.
- Zhang, Hongjun,Cheng, Zeguang,Wei, Litian,Yu, Xinjun,Wang, Zhao,Zhang, Yinjun
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- Optimized method for synthesizing S-indolinyl-2-carboxylic acid
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The invention relates to an optimized method for synthesizing S-indolinyl-2-carboxylic acid. An intermediate indolyl-2-carboxylic acid used as the raw material is subjected to catalytic reduction under the actions of a solvent and a catalyst to obtain the S-indolinyl-2-carboxylic acid. The solvent is composed of an organic solvent and carbon bisulfide; and the catalyst is composed of iodo-phosphonium and concentrated hydriodic acid. By using the organic solvent and carbon bisulfide as the solvent, the catalytic reduction is carried out in the presence of carbon bisulfide to synthesize the S-indolinyl-2-carboxylic acid, thereby reducing the possibility of side reaction, avoiding the decomposition of the S-indolinyl-2-carboxylic acid, reducing the impurities in the product, and further greatly enhancing the purity of the product.
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Paragraph 0014; 0015; 0016; 0017
(2017/08/29)
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- Of enantiomerically enriched indoline - 2 - formic acid
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The invention discloses a synthesis method of enantiomer-enriched indoline-2-formic acid shown in a formula (I). The synthesis method of the enantiomer-enriched indoline-2-formic acid comprises the following steps: by adopting low-cost and available ortho-position halogen substituted benzaldehyde and N-benzoyl substituted glycine as starting materials, carrying out Erlenmeyer-Plochl cyclization, alkaline hydrolysis and asymmetric catalytic hydrogen for constructing a chiral center, and then carrying out acid catalysis, deprotection and cyclization sequentially or cyclization, acid catalysis and deprotection sequentially, so that the enantiomer-enriched indoline-2-formic acid is obtained. The synthesis method of the enantiomer-enriched indoline-2-formic acid has the advantages that raw materials used in the whole process route are low-cost and easily available, harmful substances or multiple danger special processes are not used, reaction conditions are mild, technological operation is simple, production is safe and stable, the product yield is high, the purity is high, less three wastes are produced, and the energy consumption is low, so that the synthesis method of the enantiomer-enriched indoline-2-formic acid is a process route especially applicable to industrial production. The formula (1) is described in the specification.
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Paragraph 0105; 0106; 0107
(2017/09/01)
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- Characterization of an enantioselective amidase from Cupriavidus sp. KNK-J915 (FERM BP-10739) useful for enzymatic resolution of racemic 3-piperidinecarboxamide
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A novel amidase (CsAM) acting on (R,S)-N-benzyl-3-piperidinecarboxamide was purified from Cupriavidus sp. KNK-J915 (FERM BP-10739) and characterized. The enzyme acts on (R,S)-N-benzyl-3-piperidinecarboxamide S-selectively to yield (R)-N-benzyl-3-piperidinecarboxamide. Analytical gel filtration column chromatography and SDS-PAGE revealed that the enzyme is a tetramer with a subunit of approximately 47 kDa. It has a broad substrate spectrum against nitrogen-containing heterocyclic amides. Its optimal pH and temperature are 8.0-9.0 and 50 °C, respectively. The CsAM gene was cloned and sequenced, and it was found to comprise 1341 bp and encode a polypeptide of 46,388 Da. The deduced amino acid sequence exhibited 78% identity to that of a putative amidase (CnAM) from Cupriavidus necator JMP134. The cultured cells of recombinant Escherichia coli producing CnAM could be used for the S-selective hydrolysis of (R,S)-N-benzyl-3-piperidinecarboxamide but could not be used for the S-selective hydrolysis of (R,S)-3-piperidinecarboxamide because of its very low level of selectivity. In contrast, the cultured cells of recombinant E. coli producing CsAM could hydrolyze both (R,S)-N-benzyl-3-piperidinecarboxamide and (R,S)-3-piperidinecarboxamide with high S-selectivity.
- Nojiri, Masutoshi,Taoka, Naoaki,Yasohara, Yoshihiko
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p. 136 - 142
(2014/12/10)
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- Asymmetric synthesis of chiral heterocyclic amino acids via the alkylation of the Ni(II) complex of glycine and alkyl halides
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An investigation into the reactivity profile of alkyl halides has led to the development of a new method for the asymmetric synthesis of chiral heterocyclic amino acids. This protocol involves the asymmetric alkylation of the Ni(II) complex of glycine to form an intermediate, which then decomposes to form a series of valuable chiral amino acids in high yields and with excellent diastereoselectivity. The chiral amino acids underwent a smooth intramolecular cyclization process to afford the valuable chiral heterocyclic amino acids in high yields and enantioselectivities. This result paves the way for the development of a new synthetic method for chiral heterocyclic amino acids.
- Chen, Hui,Wang, Jiang,Zhou, Shengbin,Liu, Hong
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p. 7872 - 7879
(2015/03/18)
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- Transformation of l-phenylalanine to (S)-indoline-2-carboxylic acid without group-protection
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(S)-Indoline-2-carboxylic acid was synthesized by use of a nitro amination approach with l-phenylalanine as chiral pool. The first step of the synthesis was nitration of l-phenylalanine, with urea nitrate (UN)/H2SO 4 as nitrating reagent, to give 2,4-dinitro-l-phenylalanine in 75.7 % yield in one-pot synthesis and 69.1 % yield by step-wise nitration. Intramolecular nitro amination of 2,4-dinitro-l-phenylalanine gave (S)-6-nitro-indoline-2-carboxylic acid in 65.7 % yield and more than 99.5 % enantiomeric excess (ee). The title compound, (S)-indoline-2-carboxylic acid, was obtained in 85.9 % yield and high ee by one-pot transformation of (S)-6-nitroindoline-2-carboxylic acid. The total synthesis consisted of three operations and gave the title compound in 42 % yield and more than 99.5 % ee.
- Liu, Jin-Qiang,Chen, Xin-Zhi,Ji, Baoming,Zhao, Bang-Tun
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p. 1143 - 1152
(2013/06/05)
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- Resolution of Racemic Organic Acids with (1S, 4S)-4[3,4-Dichlorophenyl]-1,2,3,4-Tetrahydro-N-Methyl-1-Naphthaloneamine
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The present invention relates to novel chiral resolving agents and a process for resolution of racemic organic acids and their derivatives of the formula (+, ?)—R1R2CHCOOR3 with Cis-(1S,4S)-4[3,4-dichlorophenyl]-1,2,3,4-tetrahydro-N-methyl-1-naphthaloneamine and its Cis-(1R,4R)-isomer as well as Trans-(1S,4R)-4[3,4-dichlorophenyl]-1,2,3,4-tetrahydro-N-methyl-1-naphthaloneamine and its Trans-(1R,4S)-isomer.
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Page/Page column 3
(2009/10/18)
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- NEW PROCESSES FOR THE PREPARATION OF OPTICALLY PURE INDOLINE-2-CARBOXYLIC ACID AND N-ACETYL-INDOLINE-2-CARBOXYLIC ACID
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Processes for: a) separating the enantiomers of indoline-2-carboxylic acid of formula (I): comprising of: (i) combining the (R, S) indoline-2-carboxylic acid with (1S)- or (1R)-10- camphorsulfonic acid as the resolving agent in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)- or (R)-indoline-2-carboxylic acid with optically pure (1S)- or (1R)-10-camphorsulfonic acid; (ii) regenerating the (S)- or (R)-indoline-2-carboxylic acid from the crystallized diastereomeric salt by using a suitable base or basic ion-exchange resin; and b) for the optical resolution of N-acetyl-indoline-2-carboxylic acid of formula, (II): comprising of: (i) combining the (R, S)-N-acetyl-indoline-2-carboxylic acid with (S)- or (R)- phenylglycinol as the resolving agent in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)- or (R)-N-acetyl-indoline-2-carboxylic acid with optically pure phenylglycinol; (ii) regenerating the (S)- or (R)-N-acetyl-indoline-2-carboxylic acid from the crystallized salt by using a suitable acid or acidic ion-exchange resin. The non-selected enantiomer may then be racemized and the process (a) or (b) repeated thus to obtain substantial conversion of the material to one enantiomer.
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Page/Page column 16
(2008/06/13)
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- Novel method for the synthesis of s-indoline-2- carboxylic acid and application thereof in the synthesis of perindopril
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Process for the synthesis of (2S)-indoline-2-carboxylic acid of formula (I): Application in the synthesis of perindopril and its pharmaceutically acceptable salts.
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Page/Page column 3
(2008/06/13)
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- Process for the preparation of enantiomerically enriched indoline-2-carboxylic acid
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The present invention relates to a process for the preparation of an enantiomerically enriched optionally substituted indoline-2-carboxylic acid or a salt thereof, said process comprising subjecting an enantiomerically enriched chiral 2-amino-3-(2-X-substituted aryl)-propionic acid or 2-yl-substituted-amino -3-(2-X-substituted aryl)-propionic acid or a salt thereof, wherein X is a leaving group, to cyclisation, preferably at a temperature of below about 140°C, and in case of the yl-substituted compound, removing said yl-substituent by hydrolysis either prior to or after said cyclisation.
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Page/Page column 16
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED INDOLINE-2-CARBOXYLIC ACID
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The present invention relates to a process for the preparation of an enantiomerically enriched optionally substituted indoline-2-carboxylic acid or a salt thereof, wherein an enantiomerically enriched chiral ortho-X-substituted phenylalanine compound, wherein X is a leaving group, is subjected to cyclisation, preferably at a temperature of below about 140°C, upon formation of the enantiomerically enriched indoline-2-carboxylic acid compound.
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Page/Page column 28-29
(2008/06/13)
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- METHOD FOR PREPARING (S)-INDOLINE-2-CARBOXYLIC ACID AND (S)-INDOLINE-2-CARBOXYLIC ACID METHYL ESTER USING HYDROLYTIC ENZYME
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Disclosed is a method for preparing (S)-indoline-2-carboxylic acid and (S)-indoline-2-carboxylic acid methyl ester using an inexpensive industrially available enzyme capable of assuring superior optical purity and yield. At this time, the hydrolytic enzyme is selected from the group consisting of Savinase, Alcalase, Novozym 243, Everlase, Esperase, Protease 7 and Acylase, whereby (S)-indoline-2-carboxylic acid and methyl ester thereof having an optical purity of at least 99%e.e. can be obtained through a simplified preparation process, thus generating economic benefits.
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Page/Page column 10-11
(2008/06/13)
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- Free radical-mediated aryl amination and its use in a convergent [3 + 2] strategy for enantioselective indoline α-amino acid synthesis
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The scope of aryl radical additions to the nitrogen of azomethines is described. Aryl, trifluoromethyl alkyl, and α,β-unsaturated ketimines engage in regioselective aryl-nitrogen bond formation via 5-exo cyclizations of an aryl radical to azomethine nitrogen. Selectivity for carbon-nitrogen over carbon-carbon bond formation is generally high (>95:5) and competes only with direct aryl radical reduction by stannane (0-10%). α-Ketoimines are a promising new class of carbon radical acceptors for which no competitive aryl radical reduction is observed. The reaction conditions are pH-neutral and are therefore among the mildest methods available for amination of an aromatic ring. The ketimines examined did not suffer from competitive reduction by stannane, offering an advantage over the use of diazo and azide functional groups as nitrogen sources for carbon radicals. The free radical-mediated aryl amination was sequenced with the O'Donnell phase transfer-catalyzed enantioselective alkylation strategy of glycinyl imine to provide either enantiomer of indoline α-amino acids with high ee. These new constrained phenyl alanine derivatives are now readily available for evaluation across a variety of applications.
- Viswanathan, Rajesh,Prabhakaran, Erode N.,Plotkin, Michael A.,Johnston, Jeffrey N.
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p. 163 - 168
(2007/10/03)
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- Process for the preparation of an optically active indoline-2-carboxylic acid or derivative thereof
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Process for the preparation of an optically active N-acyl-indoline-2-carboxylic acid in which a mixture of enantiomers of N-acyl-indoline-carboxylic acid is contacted with an optically active resolving agent and the optically active N-acyl-indoline-2-carboxylic acid is liberated from the resulting diastereomeric salt, as resolving agent use being made of a compound of formula 1, where R1 represents an alkyl group and R2 a hetero-aryl group or where R1 and R2 together with the C atoms to which they are bound form a cycloalkyl group with 5-8 C atoms, fused with a hetero-aryl group. Preferably, a mixture of enantiomers of an N-acyl-indoline-2-carboxylic acid is prepared in a process comprising the steps of Fischer indole cyclization of a 2-phenylhydrazone propionic acid or a derivative thereof in the presence of an acid catalyst, if necessary hydrolysis of the derivative to the corresponding acid, acylation at the N-position and reduction of the indole compound to the corresponding indoline compound, after which the resulting N-acyl-indoline-2-carboxylic acid is subjected to the resolution. The 2-phenylhydrazonopropionic acid or a derivative thereof is preferably obtained from phenylhydrazine and pyruvic acid or the corresponding derivative thereof.
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- Process for the industrial synthesis of perindopril
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Process for the industrial synthesis of perindopril, in which (2S,3aS,7aS)-2-carboxyperhydroindole is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine after protection of the carboxyl group, the product resulting from the condensation being then subjected to deprotection of the carboxyl carried by the heterocyclic ring. The (2S,3aS,7aS)-2-carboxyperhydroindole and N-[(S)-1-carbethoxybutyl]-(S)-alanine are themselves obtained in excellent conditions from 2-carboxyindole and from L-alanine respectively, both available on an industrial scale.
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- Application of Microbes and Microbial Esterases to the Preparation of Optically Active N-Acetylindoline-2-Carboxylic Acid
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Methylotrophic bacteria, isolated from soil samples or from sewage sludge, proved to be useful sources of esterases for catalyzing the enantioselective hydrolysis of racemic N-acetyl-indoline-2-carboxylic acid methyl ester (7) to the corresponding (2S) or (2R)-N-acetyl amino acid (6) with high optical yields.From the DMF-utilizer Pseudomonas DMF 5/8 and the methanol-utilizer Isolate EE 210, the corresponding esterases were isolated.Reactions with whole cells as well as with the purified enzymes are described.
- Ramos Tombo, Gerardo M.,Schaer, Hans-Peter,Ghisalba, Oreste
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p. 1833 - 1838
(2007/10/02)
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- Process for the asymmetric synthesis of chiral indoline-2-carboxylic acids
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Disclosed herein is a process for producing an asymmetric indoline-2-carboxylic acid of the structural Formula: STR1 wherein X is hydrogen, bromine, chlorine, C1-4 alkyl or C1-4 alkoxy, which comprises: (a) assymetrically reducing an o-nitrophenylpyruvic acid III by contacting the acid III with a reducing complex formed from (R)-proline or (S)-proline, respectively, and sodium borohydride in an inert solvent to form, respectively, an (S) or (R)-α-hydroxy-2-nitrobenzenepropanoic acid IV; (b) reacting, respectively, said (S) or (R)-α-hydroxy-2-nitrobenzenepropanoic acid III with a Vilsmeier chlorinating reagent in which the chlorinating agent thereof is selected from a group consisting of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride and sulfuryl chloride and the amide thereof is selected from a group consisting of dimethylformamide, diethylformamide, dimethylacetamide and diethylacetamide, said reaction being run at temperatures of at least 20° C., in order to obtain, respectively, and (R) or (S)-α-chloro-2-nitrobenzenepropanoic acid IV; (c) reducing the nitro group of said (R) or (S)-α-chloro-2-nitrobenzenepropanoic acid (V) to an amino group; and (d) cyclizing the resulting (R) or (S)-α-chloro-2-aminobenzenepropanoic acid in aqueous base.
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- Substituted iminodiacids, their preparation and pharmaceutical compositions containing them
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Compounds of the general formula: STR1 wherein: the ring A is saturated and n=0 or 1, or the ring A is a benzene ring and n=1, R1 represents a lower alkyl group which can carry an amino group, R2 represents a hydrogen atom or a lower alkyl group, R3 represents a straight or branched alkyl group, a mono- or di-cycloalkylalkyl or phenylalkyl group having no more than a total of 9 carbon atoms, or a substituted alkyl group, and also the salts thereof. These compounds are useful as therapeutic drugs.
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- (Mercaptopropanoyl)indoline-2-carboxylic Acids and Related Compounds as Potent Angiotensin Converting Enzyme Inhibitors and Antihypertensive Agents
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1-(3-Mercapto-2-methyl-1-oxopropyl)indoline-2-carboxylic acids (7b) and related compounds were synthesized in order to examine their ability to inhibit angiotensin converting enzyme (ACE) and to reduce the systolic blood pressure of spontaneously hypertensive rats (SHR).All four possible stereoisomers of the precursor 1-indoline-2-carboxylic acid (6b) were characterized with absolute stereochemical assigment.The removal of the benzoyl group of the precursor to give 7b was conveniently carried out by treatment with 2-methoxyethylamine.Three of the four stereoisomers of the benzoyl derivative 6 showed in vitro ACE inhibitory activity in the following order: 6b(S,S) > 6b(S,R) > 6b(R,S).The stereoisomer having the R,R configuration was essentialy inactive.The substitution at the C5 of the indoline nucleus with the Et or OMe group caused only marginal changes in the inhibitory activity.The mercaptan 7b(S,S) was the most active ACE inhibitor synthesized in this study, showing in vitro potency 3 times that of captopril.The augmentation of the potency may be due to the increased hydrophobicity of 7b (S,S) compared with captopril and suggests the presence of a hydrophobic pocket at the active site of ACE.When tested in spontaneously hypertensive rats, 7b(S,S) exhibited oral antihypertensive activity 27 times that of captopril.The corresponding benzoyl derivative 6b(S,S) was 24 times as potent as captopril.The thio lactone 10 obtained by cyclization of 7b(S,S) as a potential prodrug was less potent than the parent compound, 7b(S,S), in the ACE inhibitory and antihypertensive tests.
- Kim, Dong H.,Guinosso, Charles J.,Buzby, George C.,Herbst, David R.,McCaully, Ronald J.,et al.
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p. 394 - 403
(2007/10/02)
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