cas 82248-59-7, Atomoxetine hydrochloride | Articles data

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Preparation method of cefamoxetine hydrochloride
The invention discloses a preparation method of tamoxidectin hydrochloride, belongs to the technical field of drug synthesis, and uses 3 - chlorine -1 - phenylpropanone as a raw material to undergo a reduction reaction. The synthesis route has the advantages of few reaction steps, mild reaction conditions,3 - simple 2 - operation, cheap -3 - and easily available raw materials, and low production cost 3 - and -1 - R-chloro - N - phenylpropanone is used as a raw material.
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Paragraph 0009; 0018; 0020; 0023; 0026; 0029

(2021/10/27)

Preparation method of atomoxetine hydrochloride
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of atomoxetine hydrochloride serving as a medicine for treating attention deficit hyperactivity. According to the invention, commercially available (E)-N-methyl-3-phenyl-2-propylene-1-amine is adopted as a starting material, and addition, substitution and salification are carried out so as to prepare atomoxetine hydrochloride. The preparation method provided by the invention is simple in preparation process, simple and convenient to operate, relatively high in yield and suitable for industrial production, and can provide sufficient bulk drugs for research and development of medicines.
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Paragraph 0015

(2020/06/09)

R-(-)-atomoxetine hydrochloride preparation method
The invention provides an R-(-)-atomoxetine hydrochloride preparation method, which comprises: preparing 3-methylamino-1-phenyl-1-propanol by using 1-phenyl-2-propenyl-1-one as a starting raw material, carrying out etherification on the 3-methylamino-1-phenyl-1-propanol and o-halo toluene in an inorganic alkali environment, splitting with L-(+)-mandelic acid to obtain R-(-)-tomoxetine-S-(+)-mandelate, refining the R-(-)-tomoxetine-S-(+)-mandelate, and carrying out hydrochloride forming to obtain the R-(-)-atomoxetine hydrochloride. According to the present invention, the method eliminates theoxalate refining step so as to reduce the reaction step, has advantages of cheap and easily available raw materials, less side reactions, low toxicity of the reaction solvent, high yield, high purity,low cost and the like, and is suitable for industrial production.
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Paragraph 0087; 0091-0093; 0097-0099; 0103-0104; 0109

(2019/09/14)

Preparation method of atomoxetine hydrochloride
The invention relates to the field of medicine chemistry, and provides a preparation method of atomoxetine hydrochloride. N-methyl-3-hydroxyl-benzedrine is used as an initial raw material to take an aromatic nucleophilic substitution with o-fluorotoluene; then, through (S)-racemic ethyl mandelate resolution, salt is obtained, and the atomoxetine hydrochloride is obtained. In the route, the multistep reaction uses the continuous operation; reaction post treatment extraction and chiral resolution salt forming solvents use methyl tertiary butyl ether; during the post treatment, reduced pressure concentration operation and anhydrous sodium sulfate drying steps are not used; the operation is simple; the total yield reaches 20 to 25 percent; the purity is 99.5 percent or higher; the relevant quality standard is met. The process does not have the special reaction parameter and equipment requirements; the yield is high; byproducts are few; the post treatment is simple; the reaction yield is high; the method is suitable for industrialized production.
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Paragraph 0041; 0044-0047

(2019/10/15)

Preparation for atomoxetine hydrochloride
The invention belongs to the technical field of medicine, and particularly relates to a method for preparing atomoxetine hydrochloride with an N-methyl-3-phenoxy-benzenepropanamine content of less than 0.2%. The atomoxetine hydrochloride is a first non-excitatory drug used for treatment of attention deficit hyperactivity disorder in children and a high-selectivity norepinephrine reuptake inhibitor, has very low affinity with other neurotransmitters and does not induce a tic syndrome or increase movement disorders; and the N-methyl-3-phenoxy-benzenepropanamine is a impurity of an atomoxetine hydrochloride process and very difficult to remove by refining due to structural similarity, according to an European Pharmacopoeia, the content of the N-methyl-3-phenoxy-benzenepropanamine is not higher than 0.3, and the method disclosed by the invention can effectively control the content of the N-methyl-3-phenoxy-benzenepropanamine in the product, and improve quality of the medicine.
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Paragraph 0023

(2019/01/05)

Preparation of atomoxetine hydrochloride
The invention belongs to the technical field of medicine, and more speficially relates to a preparation method of atomoxetine hydrochloride used for treating attention deficit hyperactivity disorders. According to the preparation method, commercially easily available 3-methylamino-1-phenylpropanol and o-fluorotoluene are taken as initial raw materials, and substitution reaction, chiral resolution, and salt forming reaction are carried out so as to obtain an atomoxetine hydrochloride product high in purity and stable in yield. The advantages of the preparation method are that: the reaction conditions are suitable for industrialized production, solvents can be recycled, more than one kind of solvents is used, and less environment pollution is caused.
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Paragraph 0023; 0024

(2017/08/30)

Method for preparing atomoxetine hydrochloride
The invention belongs to the technical field of medicines, and particularly relates to a method for preparing atomoxetine hydrochloride which is a medicine for treating attention deficit hyperactivity disorder. The atomoxetine hydrochloride is made of commercially easily available intermediates 3-methylamino-1-propiophenone hydrochloride. The method includes carrying out reduction, salt decomposition, resolving, substitution and salt forming to obtain the atomoxetine hydrochloride. The method has the advantages that technologies for preparing the atomoxetine hydrochloride are simple and stable and are easy and convenient to implement, high in yield and applicable to industrial production, and sufficient raw materials can be provided for research and development of medicines.
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Paragraph 0011

(2017/05/20)

"AN IMPROVED PROCESS FOR THE PREPARATION OF 3-ARYLOXY-3- PHENYLPROPYLAMINE AND SALT THEREOF"
The present invention relates to an industrially feasible and economically viable process for the preparation of 3-aryloxy-3-phenylpropylamine and salt of formula (I) thereof.
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Page/Page column 15

(2015/01/16)

Process for the preparation of enantiomerically pure 3-hydroxy-3-arylpropylamines and their optical stereoisomers
The invention provides a process for the preparation of enantiomerically pure 3-hydroxy-3-arylpropylamines via novel semiester derivatives containing o-carboxy benzoyl group as intermediates. The 3-hydroxy-3-arylpropylamines serve as precursor for the preparation of serotonin or noradrenalin reuptake inhibitors such as duloxetine, atomoxetine, fluoxetine, nisoxetine and norfluoxetine.
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Page/Page column 10

(2009/06/27)

AN IMPROVED PROCESS FOR SYNTHESIZING HIGHLY PURE ATOMOXETINE
The present invention relates to a process for the preparation of highly pure atomoxetine of formula (I) and pharmaceutically acceptable salts thereof Formula (I) The present invention also aims at novel processes for the preparation and purification of intermediates involved in the process of the present invention.
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Page/Page column 16

(2009/12/27)

Regio- and stereoselective ring opening of enantiomerically enriched 2-aryl oxetanes and 2-aryl azetidines with aryl borates
(Chemical Equation Presented) The regioselective ring opening of 2-aryl-substituted four-membered heterocyclic rings with phenols, including catechol, was achieved by the use of aryl borates in mild and neutral reaction conditions without the aid of any transition metal catalysts. While β-alkyl azetidines were found not to be reactive, optically active N-tosyl azetidines gave the corresponding β-aryloxy amines in a racemic form, thus indicating the considerable carbocationic character of the transition state. The introduction of a hydroxyl group in the azetidine ring (i.e., an azetidinol), able to anchor the aryl borate and to direct the subsequent nucleophilic delivery, was shown to determine the ring-opening process with predominant inversion of configuration. When enantiomerically enriched 2-aryl oxetanes were used, the reduced extent of racemization observed (up to 93:7 er) was rationalized by an intramolecular delivery through a six-membered transition state, giving β-aryloxy alcohols with a predominant retention of configuration (i.e., a syn-stereoselective ring opening). The aryloxy alcohols obtained, endowed with suitable functionalities, can be cyclized to give access to enantiomerically enriched 2-aryl-1,5-benzodioxepins.
Bertolini, Ferruccio,Crotti, Stefano,Di Bussolo, Valeria,Macchia, Franco,Pineschi, Mauro
supporting information; experimental part
p. 8998 - 9007
(2009/04/11)

A PROCESS FOR THE PREPARATION OF ATOMOXETINE HYDROCHLORIDE
Provided is the process for the preparation of Atomoxetine hydrochloride by the condensation of N,N-dimethyl 3-phenyl-3-chloropropyl amine acid addition salt with o- cresol in presence of a phase transfer catalyst and base followed by demethylation and resolution. Also provided preparation of crystalline Atomoxetine hydrochloride.
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Page/Page column 11

(2008/06/13)

PROCESS FOR PREPARING ATOMOXETINE HYDROCHLORIDE
The present invention relates to the process for preparing Atomoxetine hydrochloride which is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl is chemically known as (-)-iV-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride and represented by formula (I). More particularly, the invention relates to crystalline form of N-methyl-3-phenyl-3-(o- tolyloxy) propylamine oxalate (here in after referred as "(±) Atomoxetine Oxalate"), which is an useful intermediate for the synthesis of Atomoxetine hydrochloride.
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Page/Page column 19; 20

(2008/12/05)

A METHOD FOR THE PREPARATION OF (R)-N-METHYL-3-(2-METHYLPHENOXY)-3-PHENYLPROPYLAMINE HYDROCHLORIDE (ATOMOXETINE)
Racemic N-benzyl-N-methyl-3-(2-methylphenoxy)-3-phenylproρylamine (VIII) is an intermediate for obtaining atomoxetine. Racemic N-benzyl-N-methyl-3-(2-methylphenoxy)-3- phenylpropylamine (VIII) further reacts in a solution of an organic solvent with an optically active acid producing a mixture of diastereoisomers, which are subsequently resolved by crystallization and converted to the respective (R) and (S) enantiomers of N-benzyl-N-methyl- 3-(2-methylphenoxy)-3-phenylpropylamine by treatment with an organic or inorganic base. The (R)-enantiomer of N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine ((R)-VIII) is further subjected to debenzylation by means of an alkyl or aryl chloro formate yielding an alkyl/aryl (R)-3-(2-methylphenoxy)-3-phenylpropylmethylcarbamate ((R)-IX), which is then hydrolyzed in the basic environment yielding the base of (R)-N-methyl-3-(2-methylphenoxy)- 3-phenylpropaneamine, which is finally converted to (R)-N-methyl-3-(2-methylphenoxy)-3- phenylpropanamine hydrochloride ((R)-I) by treatment with hydrochloric acid.
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Page/Page column 12-13

(2010/11/25)

PROCESS FOR PREPARING A 3-ARYLOXY-3-ARYLPROPYLAMINE
The invention relates to the use of copper-catalyzed nucleophilic aromatic substitution reaction for preparing 3-aryloxy-3-arylpropylamines and more specifically to a method of preparing certain 3-aryloxy-3-arylpropylamines and the pharmaceutically acceptable addition salts thereof, comprising reacting an amino alcohol with a haloaromatic compound in the presence of a base and a catalytic copper source, and in the absence of a separate ligand.
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Page/Page column 18-19

(2008/06/13)

Efficient method for preparing 3-aryloxy-3-arylpropylamines and their optical stereoisomers
Provided is an efficient method for the preparation of 3-aryloxy-3-arylpropylamines, their optical stereoisomers, and pharmaceutically acceptable salts thereof. The process allows for the isolation of 3-aryloxy-3-arylpropylamines in high yield and purity. The present invention further relates to a process for producing fluoxetine, tomoxetine, norfluoxetine, duloxetine, nisoxetine, and their optically enriched (R)— and (S)-enantiomers.
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Page/Page column 7

(2008/06/13)

AN EFFICIENT METHOD FOR PREPARING 3-ARYLOXY-3- ARYLPROPYLAMINES AND THEIR OPTICAL STEREOISOMERS
Provided is an efficient method for the preparation of 3-aryloxy-3- arylpropylamines, their optical stereoisomers, and pharmaceutically acceptable salts thereof. The process allows for the isolation of 3-aryloxy-3- arylpropylamines in high yield and purity. The present invention further relates to a process for producing fluoxetine, tomoxetine, norfluoxetine, duloxetine, nisoxetine, and their optically enriched (R)- and (S)-enantiomers.
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Page/Page column 20

(2010/11/25)

Process for the preparation of atomoxetine hydrochloride
The present invention provides improved processes for the preparation of atomoxetine hydrochloride under reaction conditions that improve reaction yields and facilitate commercial synthesis. In particular, the invention is directed to the synthesis of atomoxetine HCl by adding HCl to a mixture of (R)-(?)-tomoxetine (S)-(+)-mandelate with an organic solvent, with or without a base and water.
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Page/Page column 4

(2008/06/13)

SYNTHESIS OF ATOMOXETINE HYDROCHLORIDE
(±)-Atomoxetine oxalate having crystalline Form II and a solid (±)-atomoxetine free base are useful in preparing atomoxetine hydrochloride.
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Page/Page column 20

(2010/10/20)

POLYMORPHS OF ATOMOXETINE HYDROCHLORIDE
The present invention provides novel crystalline polymorph forms of atomoxetine hydrochloride denominated Forms B and C and methods for their preparation, as well as methods for the preparation of Form A. The present invention provides pharmaceutical compositions that comprise atomoxetine hydrochloride Form B, Form C, or mixtures thereof that can be used to treat attention deficit/ hyperactivity disorder.
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Page/Page column 19 - 20

(2008/06/13)

3-ARYLOXY-3-ARYLPROPYLAMINE SYNTHESIS
A process for preparing a 3-aryloxy-3-arylpropylamine comprises reacting a 3-hydroxy-3-arylpropylamine with a substituted aryl compound, in a solvent comprising N-N-dimethylacetamide or hexamethylphosphorous triamide.
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Page/Page column 13-14

(2008/06/13)

Candida Rugosa lipase-catalyzed kinetic resolution of β-hydroxy- β-arylpropionates and δ-hydroxy-δ-aryl-β-oxo-pentanoates
A simple and convenient method was reported for the preparation of optically active β-hydroxy-β-arylpropionates, δ-hydroxy-δ- aryl-β-oxo-pentanoates and their butyryl derivatives via CRL-catalyzed hydrolysis. The optically active products are potential precursors of some chiral pharmaceuticals and natural products.
Xu, Chengfu,Yuan, Chengye
p. 2169 - 2186
(2007/10/03)

Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides
A convenient synthetic route to (R)-tomoxetine hydrochloride (90% ee) and (S)-fluoxetine hydrochloride (84% ee) is described. (S)-3-Phenyl-3-hydroxypropyl p-toluenesulphonate, the key intermediate, is obtained by the oxidative kinetic resolution of the corresponding racemic 3-phenyl-3-hydroxypropyl p-toluenesulphonate using (-)-sparteine/Pd(II)/O2 (1 atm) catalytic system.
Ali, Iliyas Sayyed,Sudalai, Arumugam
p. 5435 - 5436
(2007/10/03)

A convenient method for preparing enantiomerically pure norfluoxetine, fluoxetine and tomoxetine
A convenient synthesis for enantiomers of norfluoxetine, fluoxetine and tomoxetine is described. All final products were derived from a common intermediate, 3-phenyl-3-hydroxypropylamine.
Koenig, Thomas M.,Mitchell, David
p. 1339 - 1342
(2007/10/02)

A novel chemoenzymatic enantioselective synthesis of some clinically effective CNS drugs and related compounds
We have demonstrated in this study a novel route for the synthesis of benzothiopyran and benzothiazepin ring systems along with the synthesis of optically pure, clinically effective drugs tomoxetine, fluoxetine and thiazesim.
Kumar, Ashok,Ner, D H,Dike, Suneel
p. 803 - 809
(2007/10/02)

A new chemoenzymatic enantioselective synthesis of R-(-)-tomoxetine, (R)- and (S)-fluoxetine
A new chemoenzymatic synthesis of optically pure (R)-Tomoxetine and both the enantiomers of Fluoxetine starting from (S)-ethyl-3-hydroxy-3-phenyl propionate obtained by enzymatic methods, is described.
Kumar, Ashok,Ner, Dilip H.,Dike, Suneel Y.
p. 1901 - 1904
(2007/10/02)

Racemization process
The present invention provides a process for the epimerization of (+)-N-methyl-3-(2-methylphenoxy)- 3-phenylpropylamine to its racemic form with an anion forming compound in a suitable solvent.
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(2008/06/13)

Chiral Synthesis via Organoboranes. 18. Selective Reductions. 43. Diisopinocampheylchloroborane as an Excellent Chiral Reducing Reagent for the Synthesis of Halo Alcohols of High Enantiomeric Purity. A Highly Enantioselective Synthesis of Both Optical Isomers of Tomoxetine, Fluoxetine, a
Diisopinocampheylchloroborane, dIpc2BCl, reduces ring and chain sustituted haloaralkyl ketones to the corresponding halo alcohols in excellent enantiomeric excess.In certain cases these alcohols can be upgraded by simple methods to essentially 100percent ee.For instance, (+)- or (-)-3-chloro-1-phenyl-1-propanol is initially obtained in 97percent ee.Simple recrystallisation then furnishes the pure enantiomers.These chiral halo alcohols are highly versatile intermediates.They can be readily cyclized to oxiranes and 2-substituted tetrahydrofurans with retention of chirality.Utilizing this methodology, we have developed an efficient, highly enantioselective synthesis of both optical isomers of the antidepressant drugs, Tomoxetine, Fluoxetine, and Nisoxetine, from the common intermediates (+)-or (-)-3-chloro-1-phenyl-1-propanol.
Srebnik, Morris,Ramachandran, P.V.,Brown, Herbert C.
p. 2916 - 2920
(2007/10/02)