- Eluent tolerance and enantioseparation recovery of chiral packing materials based on chitosan bis(phenylcarbamate)-(n-octyl urea)s for high performance liquid chromatography
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The goal of the present work was to study the influence of the swelling of chitosan derivatives on the enantioseparation and the separation performance recovery of chiral stationary phases (CSPs) based on these derivatives. Therefore, six chitosan bis(phenylcarbamate)-(n-octyl urea)s were synthesized, which were coated on macroporous 3-aminopropyl silica gel affording new CSPs. Most of the CSPs demonstrated strong enantioseparation capability for the tested chiral compounds. The swelling capacity of the chitosan bis(phenylcarbamate)-(n-octyl urea)s in ethyl acetate, acetone and tetrahydrofuran (THF) was evaluated. Among the chitosan derivatives, the chitosan bis(3,5-dichlorophenylcarbamate)-(n-octyl urea) polymer showed the highest swelling capacity in ethyl acetate and THF. The polymer-based CSPs could be utilized with pure ethyl acetate and a normal phase containing 70% THF, but was damaged by pure THF. On the other hand, the separation performance of the damaged CSP could be recovered after it was allowed to stand for a period of time. The observations are important for the development and application of polysaccharide derivative-based CSPs.
- Wang, Jing,Huang, Shao-Hua,Chen, Wei,Bai, Zheng-Wu
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Read Online
- 1,2-Dihydro-1-hydroxy-2,3,1-benzodiazaborine Bearing an Acridine Moiety as a Circular Dichroism Probe for Determination of Absolute Configuration of Mono-Alcohols
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A new chiral probe molecule for mono-alcohols is developed by using 1,2-dihydro-1-hydroxy-2,3,1-benzodiazaborine (DAB) bearing an acridine moiety 1. In the presence of mono-alcohols, DAB 1 forms borate 2 by boronic ester formation, followed by coordination of the acridine moiety to the boron atom. Borate 2 has a chiral center on the boron atom and works as a stereodynamic circular dichroism (CD) probe molecule for chiral mono-alcohols based on the π–π interaction between the acridine moiety and the carbon–carbon unsaturated moiety on mono-alcohols.
- Shimo, Shunsuke,Takahashi, Kohei,Iwasawa, Nobuharu
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Read Online
- Tridentate nitrogen phosphine ligand containing arylamine NH as well as preparation method and application thereof
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The invention discloses a tridentate nitrogen phosphine ligand containing arylamine NH as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis. The tridentate nitrogen phosphine ligand disclosed by the invention is the first case of tridentate nitrogen phosphine ligand containing not only a quinoline amine structure but also chiral ferrocene at present, a noble metal complex of the type of ligand shows good selectivity and extremely high catalytic activity in an asymmetric hydrogenation reaction, meanwhile, a cheap metal complex of the ligand can also show good selectivity and catalytic activity in the asymmetric hydrogenation reaction, and is very easy to modify in the aspects of electronic effect and space structure, so that the ligand has huge potential application value. A catalyst formed by the ligand and a transition metal complex can be used for catalyzing various reactions, can be used for synthesizing various drugs, and has important industrial application value.
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Paragraph 0115-0116
(2021/06/26)
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- Amino alcohols using the optically active amino alcohol derivative bi- Nord complex boron - -
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Disclosed are an amino alcohol-boron-binol complex as an intermediate, including Complex 3-1-1 shown below, and a method for preparing an optically active amino alcohol by using the same, wherein a racemic amino alcohol is resolved in an enationselective manner using a boron compound and a (R)- or (S)-binol, whereby an amino alcohol derivative with high optical purity can be prepared at high yield.
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Paragraph 0064; 0071-0076; 0260-0262; 0264-0266
(2021/04/16)
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- Chiral amino-pyridine-phosphine tridentate ligand, manganese complex, and preparation method and application thereof
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The invention discloses a chiral amino-pyridine-phosphine tridentate ligand, a manganese complex, and a preparation method and application thereof. The chiral amino-pyridine-phosphine tridentate ligand is shown as a formula II, and the manganese complex of the chiral amino-pyridine-phosphine tridentate ligand can be used for efficiently catalyzing and hydrogenating ketone compounds to prepare chiral alcohol compounds in a high enantioselectivity mode. The chiral amino-pyridine-phosphine tridentate ligand and the manganese complex are simple in synthesis process, good in stability, high in catalytic activity and mild in reaction conditions.
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Paragraph 0597-0600; 0603
(2020/07/13)
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- Preparation method of S-(+)duloxetine hydrochloride intermediate
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The invention discloses a preparation method of a compound of a formula B (shown in the description). The preparation method comprises the steps of dissolving a compound of a formula A (shown in the description) in a solvent, and reacting under the effect of a reducing agent. Furthermore, the ee value of the compound of the formula B obtained by reducing in the presence of a complex, namely ferrocene, is over 98%. The preparation method provided by the invention is simple and feasible, the resolution or the chiral catalysis induction is not required, the product yield and the chiral purity arehigh, and the preparation method is suitable for the industrial production of S-(+)duloxetine hydrochloride intermediate.
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Paragraph 0066-0068
(2019/04/09)
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- Lutidine-Based Chiral Pincer Manganese Catalysts for Enantioselective Hydrogenation of Ketones
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A series of MnI complexes containing lutidine-based chiral pincer ligands with modular and tunable structures has been developed. The complex shows unprecedentedly high activities (up to 9800 TON; TON=turnover number), broad substrate scope (81 examples), good functional-group tolerance, and excellent enantioselectivities (85–98 % ee) in the hydrogenation of various ketones. These aspects are rare in earth-abundant metal catalyzed hydrogenations. The utility of the protocol have been demonstrated in the asymmetric synthesis of a variety of key intermediates for chiral drugs. Preliminary mechanistic investigations indicate that an outer-sphere mode of substrate–catalyst interactions probably dominates the catalysis.
- Zhang, Linli,Tang, Yitian,Han, Zhaobin,Ding, Kuiling
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supporting information
p. 4973 - 4977
(2019/03/17)
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- Synthesis method of key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene
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The invention provides a synthesis method of a key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene and belongs to the technical field of chemical synthesis. The synthesis method comprises the following steps: reacting cyanuric chloride and N,N-dimethylformamide with 2-acetylthiophene to obtain 3-(dimethylamino)-1-(2-thienyl)-2-propenyl-1-one; reducing 3-(dimethylamino)-1-(2-thienyl)-2-propenyl-1-one through lithium aluminum hydride to obtain a duloxetine hydrochloride intermediate which is (R,S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. The synthesis method iscapable of synthesizing a target product which is a key intermediate of duloxetine hydrochloride through two-step reaction, is cheap in raw materials, simple in process, simple and convenient to operate, mild in reaction condition, short in reaction period and free of expensive catalysts, is environmentally friendly, and is suitable for industrial production; the prepared products are high in yield and purity.
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Paragraph 0025; 0026; 0027; 0028; 0029; 0030
(2018/11/03)
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- Preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol
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The invention discloses a preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol shown as the formula (I). The method comprises: taking 2-acetyl thiophene shown in the formula (II) as a raw material, and allowing 2-acetyl thiophene to completely react with di(trichloromethyl)carbonic ester (III) and N,N-disubstituted methanamide (IV) in an organic solvent under the catalysis of an organic base to obtain N,N-disubstituted amino-1-(2-thienyl)-1-acrylketone shown as the formula (V); and performing hydrogenation reduction with lithium aluminium hydride to obtain N,N-disubstituted amino-1-(2-thienyl)-1-propanol shown as the formula (VI); and performing splitting with S-mandelic acid and recrystallization with ethyl acetate to obtain the target product shown as the formula (I). The preparation method is low in cost, mild in reaction condition, less in waste water, waste gas and industrial residue, small in energy consumption, and high in yield. The preparation method is safe and is suitable for industrial production.
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Paragraph 0043; 0044; 0045
(2018/03/24)
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- A west Luo river sandbank chiral intermediate mandelic acid salt preparation method
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A purpose of the present invention is to provide a method for simultaneously recycling (R)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine (II) and S-mandelic acid to prepare a duloxetine chiral intermediate (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine S-mandelate (I). The formulas (I) and (II) are defined in the instruction.
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Paragraph 0037; 0052; 0053
(2017/07/19)
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- Preparation of duloxetine hydrochloride
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The invention belongs to the fields of organic chemistry and pharmaceutical chemistry, and particularly relates to a synthesis technique of duloxetine hydrochloride. By converting the R configuration compound into S configuration, compared with the duloxetine hydrochloride prepared from the single S-configuration compound, the total yield is enhanced by nearly 47%, and the production cost is lowered. 1-chloroethylchloroformate is used instead of phenyl chloro-formate to directly generate the duloxetine hydrochloride during demethylation, thereby reducing the salification step, shortening the production cycle and saving the cost.
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Paragraph 0053-0054
(2017/08/26)
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- New amine compound and use thereof in treatment of depression
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The invention relates to a new amine compound and a use thereof in the treatment of depression, and concretely relates to a compound represented by formula I, optical isomers, solvates or pharmaceutically acceptable salts thereof, and a use thereof in the preparation of antidepressant drugs. Preclinical pharmacological studies show that the compound is comparable to and even better than first-line antidepressants (such as duloxetine).
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- Duloxetine hydrochloride salt of basic and duloxetine (by machine translation)
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[Problem] to suppress toxic byproducts, and suppressing the formation of decomposition products of high purity optical isomers as well as the method for manufacturing a basic duloxetine hydrochloride duloxetine. [Solution] a basic manufacturing method of duloxetine, [...], potassium hydroxide and toluene in the presence of alcohol in the mixing step, and, by heating the reaction mixture obtained, comprising the step of distilling off the solvent in the reaction portion, a basic manufacturing method of duloxetine. [Drawing] no (by machine translation)
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Paragraph 0053
(2017/06/02)
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- Chemoenzymatic synthesis of (S)-duloxetine using carbonyl reductase from Rhodosporidium toruloides
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A chemoenzymatic strategy was developed for (S)-duloxetine production employing carbonyl reductases from newly isolated Rhodosporidium toruloides into the enantiodetermining step. Amongst the ten most permissive enzymes identified, cloned, and overexpressed in Escherichia coli, RtSCR9 exhibited excellent activity and enantioselectivity. Using co-expressed E. coli harboring both RtSCR9 and glucose dehydrogenase, (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol 3a was fabricated with so far the highest substrate loading (1000 mM) in a space-time yield per gram of biomass (DCW) of 22.9 mmol L-1 h-1 g DCW-1 at a 200-g scale. The subsequent synthetic steps from RtSCR9-catalyzed (S)-3a were further performed, affording (S)-duloxetine with 60.2% overall yield from 2-acethylthiophene in >98.5% ee.
- Chen, Xiang,Liu, Zhi-Qiang,Lin, Chao-Ping,Zheng, Yu-Guo
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supporting information
p. 82 - 89
(2016/02/23)
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- METHOD FOR PRODUCING DULOXETINE HYDROCHLORIDE
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PROBLEM TO BE SOLVED: To provide a new method for producing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (general name: duloxetine hydrochloride) useful as an antidepressant. SOLUTION: In a method for producing duloxetine hydrochloride, a solution obtained by dissolving a crude product containing duloxetine hydrochloride in a dissolving solvent (a first dissolution step) and acetone are mixed (a mixing step), the duloxetine hydrochloride precipitated in the obtained mixed solution is temporarily dissolved (a second dissolution step), and then the duloxetine hydrochloride is precipitated. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0063
(2017/05/05)
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- OLIGOMER-ARYLOXY-SUBSTITUTED PROPANAMINE CONJUGATES
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The invention relates to (among other things) oligomer- aryloxy-substituted propanamine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated aryloxy-substituted propanamine compounds.
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Paragraph 0245; 0251
(2016/11/17)
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- Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives
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The present invention relates to a method for preparing an optically active 3-amino-1-arylpropan-1-ol derivative, including the step of making an optically active 3-chloro-1-arylpropan-1-ol compound react with an amine derivative. The method according to the present invention allows direct amination of an optically active 3-chloro-1-arylpropan-1-ol derivative through a single-step reaction. Thus, it is possible to provide a compound functioning as a key intermediate of various optically active molecules through a simple process with high yield, while maintaining the optical purity of the reactant. Therefore, the method may be used for preparing medicines, such as (S)-Duloxetin, (R)-Fluoxetine, (R)- Tomoxetine or (R)- Nisoxetine, with high optical purity by combining the method for preparing an optically active 3-chloro-1-arylpropan-1-ol derivative as a reactant of the method with an additional substitution reaction.(AA) Tomoxetine(BB) Fluoxetine(CC) 3-amino-1-propanol(DD) Nisoxetine(EE) DuloxetineCOPYRIGHT KIPO 2016
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- A method for preparing optically active 3-amino-1-propanol derivatives as an intermediate and a method for preparing (S)-duloxetine using the same
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The present invention relates to a method for preparing optically active 3-AMNO1-propanol derivatives as an intermediate and a method for preparing (s)-duloxetine using the same. This method can obtain optically active 3-AMNO1-propanol with higher yield and optical purity (ee) than any other conventional methods. Using this as an intermediate compound, it is possible to manufacture duloxetine which is enantiomerically pure and has high optical purity (ee).(DD) Nisoxetine(EE) Duloxetine(CC) 3-amino-1-propanol(BB) Fluoxetine(AA) TomoxetineCOPYRIGHT KIPO 2015
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Paragraph 0185; 0192; 0194
(2016/12/01)
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- Asymmetric synthesis of optically active methyl-2-benzamido-methyl-3-hydroxy-butyrate by robust short-chain alcohol dehydrogenases from Burkholderia gladioli
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Three short-chain alcohol dehydrogenases from Burkholderia gladioli were discovered for their great potential in the dynamic kinetic asymmetric transformation of methyl 2-benzamido-methyl-3-oxobutanoate, and their screening against varied organic solvents and substrates. This is the first report of recombinant enzymes capable of achieving this reaction with the highest enantio- and diastereo-selectivity.
- Chen, Xiang,Liu, Zhi-Qiang,Huang, Jian-Feng,Lin, Chao-Ping,Zheng, Yu-Guo
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p. 12328 - 12331
(2015/07/27)
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- Cloning, expression and enzymatic characterization of an aldo-keto reductase from Candida albicans XP1463
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An aldo-keto reductase encoding gene caakr was cloned from Candida albicans XP1463 (CCTCC M 2014382), and heterologously expressed in Escherichia coli. The aldo-keto reductase CaAKR is NADH-dependent with a molecular weight of approximately 38.6 kDal including a His6-Tag. It is active and stable at 30°C and pH 7.0. The maximal reaction rate (Vmax), apparent Michaelis-Menten constant (Km) and catalytic constant (kcat) for t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate ((R)-1a) were 11.50 mmol/L min, 1.91 mmol/L and 218.50 min-1. Besides atorvastatin's chiral synthon t-butyl 6-cyano-(3R,5R)- dihydroxy hexanoate ((R,R)-1b), it can synthesize N,N-2-dimethyl-(3S)-hydroxy-3-(2-thienyl)-1-propanine ((S)-9b) and methyl 1-[E]-2-[3-[3-[2-(7-chloro-2-quinoliny) ethenyl] phenyl]-(3S)-hydroxy propy] benzoate ((S)-10b), the chiral intermediates of duloxetine and montelukast, displaying potential applications in pharmaceutical industry. 2015 Elsevier B.V. All rights reserved.
- Wang, Ya-Jun,Liu, Xiao-Qing,Luo, Xi,Liu, Zhi-Qiang,Zheng, Yu-Guo
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- ARALKYL DIAMINE DERIVATIVES AND USES THEREOF AS ANTIDEPRESSANT
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Aralkyl diamine derivative of the following formula, pharmaceutically acceptable salts or uses thereof as antidepressants. The derivatives have triplex inhibiting activities of the reuptake of 5-HT, dopamine and noradrenalin, which can be administered to the patients in need of such treatment in the form of compositions orally or injectedly et al.
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Paragraph 0031; 0161
(2013/03/28)
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- Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
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The present disclosure provides engineered ketoreductase enzymes having improved properties as compared to a naturally occurring wild-type ketoreductase enzyme. Also provided are polynucleotides encoding the engineered ketoreductase enzymes, host cells capable of expressing the engineered ketoreductase enzymes, and methods of using the engineered ketoreductase enzymes to synthesize a variety of chiral compounds. The engineered ketoreductase polypeptides are optimized for catalyzing the conversion of N,N-dimethyl-3-keto-3-(2-thienyl)-1-ketopropanamine to (S)—N,N-dimethyl-3-hydroxy-3-(2- thienyl)-1-propanamine.
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Page/Page column
(2013/05/08)
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- Synthesis and dual 5-ht1a/ssri activities of some novel arylpiperazine derivatives of duloxetine
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A series of novel arylpiperazine derivatives of duloxetine were designed and synthesized from the key intermediate 5 by acylation, alkylation and reduction based on 5-HT1A/SSRI drugs design strategies. Compound 5 was obtained through the reaction sequence including condensation, reduction, O-etherification, Von Braun reaction, hydrolysis reaction. Structures of the synthesized compounds were confirmed by MS, 1H NMR and HRMS. Furthermore, these compounds were evaluated for their dual 5-HT1A/5-HTT activities. The results indicated that all the compounds exhibited certain affinity to 5-HTT and 5-HT1A receptor.
- Chen, Shao-Rui,Li, Ai-Jun,Chen, Ming-Ming
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experimental part
p. 1680 - 1684
(2012/08/28)
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- IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALT
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The present invention relates to an improved process for racemizing one of the enantiomers, or an enantiomerically enriched mixture, of an optically active compound (S)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a key intermediate used for the preparation of (S)-N-methyl-3-(1-naphthalenyloxy)-3-(2- thienyl) propanamine (duloxetine) or its hydrochloride salt. Moreover, the present invention also relates to an improved process for the preparation of (S)-N-methyl-3- (1-naphthalenyloxy)-3-(2-thienyl) propanamine (duloxetine) or its hydrochloride salt having low content of undesired R-isomer and chiral purity not less than 99%.
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Page/Page column 23
(2011/04/19)
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- AMINE COMPOUNDS AND THEIR PHARMACEUTICAL USE
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The present invention relates to a new amine compound or a pharmaceutically acceptable salt thereof, wherein the definitions of X, R1, R2 and n are given in the description, to a pharmaceutical composition containing the compound as active ingredient, and to use of the amine compound or its pharmaceutically acceptable salt for the manufacture of an anti-depressent drug.
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- Ruthenium catalysts containing rigid chiral diamines and achiral diphosphanes for highly enantioselective hydrogenation of aromatic ketones
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One chiral element is enough: A new ruthenium catalyst containing a rigid chiral diamine (BIDN) and a commercially available inexpensive achiral phosphane (DPPF) is highly efficient for the enantioselective hydrogenation of ketones (see scheme). High reactivity (S/C up to 100 000) and excellent enantioselectivities (up to 99 % ee) were obtained. Copyright
- Zhu, Qiming,Shi, Dengjian,Xia, Chungu,Huang, Hanmin
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supporting information; experimental part
p. 7760 - 7763
(2011/08/05)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE AND SALTS THEREOF
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The present invention relates to improved process for the preparation of Duloxetine of formula (I) and salts thereof wherein said improvement takes place in step of condensation.
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Page/Page column 7
(2010/08/04)
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- PROCESS FOR THE PREPARATION ENANTIOMERICALLY PURE SALTS OF N-METHYL-3-(1-NAPHTHALENEOXY)-3-(2-THIENYL)PROPANAMINE
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The present invention relates to duloxetine salts having enantiomeric purity of 98% or more and a process for such salts.
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Page/Page column 3
(2010/12/29)
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- PROCESS FOR THE PREPARATION OF 3-ARYLOXY-3-ARYLPROPANAMINES
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The present invention provides a process for the preparation of 3-aryloxy-3-arylρropanamine derivatives. Particularly the present invention provides a process for the preparation of duloxetine and pharmaceutically acid addition salts thereof specifically, duloxetine hydrochloride of formula (I), using 3-O-protected propanolamine derivatives. The invention also aims at providing a process for the preparation of highly pure duloxetine hydrochloride of formula (I) from duloxetine free base via its acid addition salts The invention further aims at providing a process for the purification of duloxetine hydrochloride, wherein the level of unwanted R-enantiomer is reduced to nearly 0%.
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Page/Page column 16-17
(2009/04/25)
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- Process for the preparation of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropananine, a duloxetine intermediate
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A chiral resolution process for the preparation of (S)-AT-OL, and a process for the racemization of AT-OL are provided.
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Page/Page column 6
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF DULOXETINE AND ITS SALTS
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The present invention relates to duloxetine salts having enantiomeric purity of 98% or more and a process for such salts.
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Page/Page column 7
(2008/06/13)
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- A PROCESS FOR PREPARATION OF (S)-(+)-N-METHYL-3(1-NAPHTHYLOXY)-3(2-THIENYL)PROPYLAMINE HYDROCHLORIDE
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The present invention provides an improved process for preparation of intermediate of Duloxetine base and hydrochloride salt thereof.
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Page/Page column 9-13
(2008/12/07)
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- Process for preparing duloxetine and intermediates thereof
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Processes for preparing chemically pure duloxetine and chemically pure duloxetine intermediates are provided.
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Page/Page column 5
(2010/11/29)
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- IMPROVED PROCESS FOR PURE DULOXETINE HYDROCHLORIDE
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A process for the preparation of pure Duloxetine hydrochloride comprises the steps of : a) reacting 1-(thiophen-2-yl)ethanone with dimethylamine hydrochloride, b) purifying the component in a solvent, c) reducing the component with an alkali metal borohydride, d) resolving the compound with a chiral acid, and treating the obtained compound with weak inorganic base, e) reacting the compound to give Duloxetine oxalate salt and f) converting the Duloxetine salt into its hydrochloride salt. Further the purifications of the obtained compound and of two intermediate products are described.
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Page/Page column 15
(2008/06/13)
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- A process for the preparation of an intermediate useful for the asymmetric synthesis of (+)duloxetine
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A process for the preparation of (+)duloxetine, or an acid addition salt thereof, comprising: (i) Resolving racemic (±)N-methyl duloxetine with a less than stoichiometric amount of a chiral acid in combination with suitable amounts of a hydrohalogen acid to give a salt of the chiral acid and (+)N-methyl duloxetine, substantially free from (-)N-methyl duloxetine; (ii) Demethylating the (+)N-methyl duloxetine prepared in step (i) to give (+)duloxetine or another acid addition salt in enantiomerically pure form.
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Page/Page column 4-5
(2010/11/28)
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- Synthesis of (S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol: Revisiting Eli Lilly's resolution-racemization-recycle synthesis of duloxetine for its robust processes
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(±)-3-(N,N-Dimethylamino)-1-(2-thienyl)propan-1-ol (6), prepared from 2-acetylthiophene (4) in a two-step overall yield of 79%, is resolved into (S)-6 of 93% ee as its diastereomeric salt (8) with (S)-mandetic acid (7) according to Eli Lilly's procedures developed for the resolution-racemization- recycle (RRR) synthesis of duloxetine (2) with some modifications in terms of practicality. On its liberation from 8, (S)-6 undergoes N-demethylative ethyl carbamate formation in two discrete but successive steps in an overall yield of 87% from 8: (1) O-ethyl carbonate formation and (2) ethyl carbamate formation with concomitant loss of the N-methyl group. Alkaline hydrolysis then affords (S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol (1) of 100% ee, an alleged penultimate precursor to duloxetine (2), in 75% yield after a single recrystallization from ethylcyclohexane. In the overall process thus developed, PhMe is substituted successfully for t-BuOMe, a solvent that has been used favorably in Eli Lilly's original RRR synthesis of 2.
- Fujima, Yoshito,Ikunaka, Masaya,Inoue, Toru,Matsumoto, Jun
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p. 905 - 913
(2012/12/23)
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- Process for the preparation of N-alkyl-N-methyl-3-hydroxy-3-(2-thienyl)-propylamines
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The present invention relates to an improved process for preparing chiral N-substituted N-methyl-3-hydroxy-3-(2-thienyl)-propylamine on an industrial scale using an asymmetric hydrogenation as a key step and optionally a special sequence of subsequent steps, using a catalyst system consisting of rhodium and (2R, 4R)-4-(dicyclohexylphosphino)-2-(diphenyl-phosphino-methyl)-N-methyl-aminocarbonyl-pyrrolidine.
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Page/Page column 4
(2010/02/13)
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- PROPANOLAMINE DERIVATIVES, PROCESS FOR PREPARATION OF 3-N-METHYLAMINO-1-(2-THIENYL)-1-PROPANOLS AND PROCESS FOR PREPARATION OF PROPANOLAMINE DERIVATIVES
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The present invention provides means for preparing a racemate or an optically active substance (S- or R-isomer) of 3-N-methylamino-1-(2-thienyl)-1-propanol represented by the following general formula (I): wherein R1 represents any of a hydrogen atom, a C1-8 acyl group, a substituted or substituted C1-8 alkyloxycarbonyl group and a substituted or substituted phenyloxycarbonyl group and R2 represents any of a hydrogen atom, a C1-8 alkyl group, a substituted or substituted benzyl group, a C1-8 acyl group, a substituted or substituted C1-8 alkyloxycarbonyl group and a substituted or substituted phenyloxycarbonyl group, with the exception that R1 is a hydrogen atom and R2 is a methyl group or a hydrogen atom, in a simple manner at low cost and in high yield.
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Page/Page column 35
(2010/02/10)
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- PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF OPTICALLY ACTIVE 3-AMINO-1-(2-THIENYL)-1-PROPANOL DERIVATIVES
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Enantiomerically enriched 3-amino-1-(2-thienyl)-1-propanols of the fomulae (S)-I or (R)-I wherein R1 and R2 independently denote H, C1-6-alkyl, C5-7-cycloalkyl, aralkyl or aryl, were prepared by reducing a 3-amino-1-(2-thienyl)-1-propanone of the formula (II) wherein R1 and R2 are defined as above, using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base.
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- Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
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A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
- Bymaster,Beedle,Findlay,Gallagher,Krushinski,Mitchell,Robertson,Thompson,Wallace,Wong
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p. 4477 - 4480
(2007/10/03)
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- General asymmetric hydrogenation of hetero-aromatic ketones
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(matrix presented) Het = hetero-aromatic ring (R,R)-Ru cat = trans-RuCl2[(R)-xylbinap][(R)-daipen] trans-RuCl2[(R)-xylbinap][(R)-daipen] or the S,S complex acts as an efficient catalyst for asymmetric hydrogenation of hetero-aromatic ketones. The hydrogenation proceeds with a substrate-to-catalyst molar ratio of 1000-40000 to give chiral alcohols in high ee and high yield. The enantioselectivity appears to be little affected by the properties of the hetero-aromatic ring. This method allows for asymmetric synthesis of duloxetine, an inhibitor of serotonin and norepinephrine uptake carriers.
- Ohkuma, Takeshi,Koizumi, Masatoshi,Yoshida, Makoto,Noyori, Ryoji
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p. 1749 - 1751
(2007/10/03)
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- Treatment of incontinence
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Urinary incontinence in humans is treated by administration of venlafaxine or a compound chosen from a series of aryloxy propanamines.
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- Chiral synthesis of 1-aryl-3-aminopropan-1-ols
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This invention is directed to a process for preparing chiral 1-aryl-3-amino-propan-1-ols. These compounds are important intermediates in the synthesis of pharmacologically active compounds.
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- ASYMMETRIC SYNTHESIS AND ABSOLUTE STEREOCHEMISTRY OF LY248686
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Reduction of 3-(dialkylamino)-1-aryl-1-propanones with a 2 : 1 complex of (8) and lithium aluminum hydride (LAH) provided the corresponding 1,3-diaminoalcohols in high ee's (80-88percent).This process was developed and applied to the synthesis of LY248686 (1), a potent inhibitor of serotonin (5HT) and norepinephrine (NE) uptake.Absolute configurations have been established by single crystal x-ray analysis.
- Deeter, Jack,Frazier, Jeff,Staten, Gilbert,Staszak, Mike,Weigel, Leland
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p. 7101 - 7104
(2007/10/02)
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- 3-aryloxy-3-substituted propanamines
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The present invention provides 3-aryloxy-3-substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine.
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