GB2060618A - 3-Aryl-3-Aryloxypropylamines - Google Patents
3-Aryl-3-Aryloxypropylamines Download PDFInfo
- Publication number
- GB2060618A GB2060618A GB8028710A GB8028710A GB2060618A GB 2060618 A GB2060618 A GB 2060618A GB 8028710 A GB8028710 A GB 8028710A GB 8028710 A GB8028710 A GB 8028710A GB 2060618 A GB2060618 A GB 2060618A
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- United Kingdom
- Prior art keywords
- lower alkyl
- general formula
- alcohol
- hydrogen
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
Abstract
Antidepressant 3-aryl-3- aryloxypropylamines of formula <IMAGE> where Ar is phenyl optionally substituted by specified substituents, R<1>, R<2> and R<4> are hydrogen and lower alkyl and R<3> is hydrogen, lower alkyl or benzyl are prepared by a novel process which involves reacting an anion of an alcohol of formula Ar. CH(OH) . CHR<1>R<2>. NR<3>R<4> with a trifluoromethyl substituted fluorobenzene.
Description
SPECIFICATION 3-Aryl-3-aryloxypropylamines This invention relates to 3-aryl-3-aryloxypropylamines, in particular to a novel process for preparing them.
U.S. Patent Specification No. 4,018,895 discloses a class of 3-aryl-3-aryloxypropylamines of the formula
where each R' is independently hydrogen or methyl and R can be a phenyl group optionally substituted by halo, trifluorofluoromethyl, C~4alkyl, Alkoxy and C3-C4alkenyl. Some of the compounds in which R is phenyl substituted by trifluoromethyl are particularly of interest as antidepressants. An especially preferred compound is fluoxetine which is N-methyl-3-phenyl-3-(ptrifluoromethylphenoxy)propylamine. The process described in the prior specification for preparing fluoxetine, which involves reacting p-trifluoromethylphenol with N,N-dim ethyl-3-phenyl-3- chloropropylamine followed by demethylation of the product, suffers from many disadvantages.For example, the phenol starting material is expensive and unstable, the main reaction step is very slow and the subsequent demethylation step is difficult to carry out.
We have now found that fluoxetine and related compounds can be prepared in good yield by a novel process which overcomes the above mentioned disadvantages of the prior process.
Accordingly the present invention provides a process for preparing a 3-aryl-3-aryloxypropylamine of general formula
or a pharmaceutically acceptable acid addition salt thereof wherein R1 and R2 are hydrogen or lower alkyl, RJ is hydrogen, lower alkyl or benzyl, R4 is hydrogen or lower alkyl and Ar is phenyl optionally substituted by one or more halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino groups, which comprises reacting an anion of an alcohol of general formula
(where Ar, R', R2, R3 and R4 are as defined above) with a fluoro compound of general formula
in a dipolar aprotic solvent and, if desired, converting a free base of general formula (I) into a pharmaceutically acceptable acid addition salt thereof.Examples of dipolar aprotic solvents include dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide and sulpholane. Preferably the solvent is dimethylsulphoxide. The anion of the alcohol of general formula (II) is preferably formed by reacting the alcohol with potassium or sodium hydride or an alkyl or phenyl lithium (e.g. butyl lithium) in a compatible dipolar aprotic solvent. Preferably the alcohol is reacted with sodium hydride and the reaction carried out in dimethylsulphoxide.
The process of the invention can be carried out at convenient temperatures, e.g. O to 1 000C (for example room temperature); there is generally no need to use reflux temperatures. Good yields of products are generally obtained in relatively short reaction times (e.g. within two to three hours). These reaction conditions are much more convenient than the reaction conditions of the process exemplified in U.S. Specification 4,018,895.
It is surprising that the process of the invention proceeds in such good yield since it is well known that aryl halides generally undergo nucleophilic substitution only with extreme difficulty and hence aromatic ethers, normally cannot be prepared by nucleophilic substitution of aryl halides. The exceptions in the past have been aryl halides in which the aromatic ring contains, in addition to halogen, an activating group such as nitro, nitroso or cyano (as exemplified in, for example, German Offenlegungsschrift 2,907,217).
If in the process described above the compound of the general formula (I) is obtained as an acid addition salt, such as a pharmaceutically acceptable acid addition salt or an acid addition salt such as oxalate, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with the conventional procedures for preparing acid addition salts from base compounds.
Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids.
Once a compound of general formula (I) is obtained, if desired it can be converted into another 3aryl-3-aryloxypropylamine of general formula (I) by known methods. For example, a 3-aryl-3- aryloxypropylamine in which both R3 and R4 are methyl can be converted to the compound in which one group is methyl and the other hydrogen by treatment with cyanogen bromide or ethyl or phenyl chloroformate followed by basic hydrolysis.
The compounds of general formula (I) possess one or more asymmetric carbon atoms, depending upon the particular substituents. The compounds can therefore exist in various stereochemical forms. It will be realized that if the starting material of formula (II) is a mixture of isomers the product of formula (I) will also be a mixture of isomers which may be separated, if required, by standard procedures. If the starting material is a single isomer then the product will also be a single isomer.
The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms.
The radical preferably contains 1 to 4 carbon atoms. Examples of lower alkyl radicals include methyl, ethyl, propyl and butyl. Examples of lower alkoxy radicals include methoxy, ethoxy, propoxy and butoxy.
When R1, R2 and/or R3 represent lower alkyl, the lower alkyl group is preferably a straight chain radical such as methyl, ethyl, n-propyl or n-butyl although R3 may also be, for example, a branched chain lower alkyl group such as isopropyl. When Ar is substituted by halogen, the halogen may be fluoro, chloro, bromo or iodo.
The compounds of general formula (I) and their pharmaceutically acceptable acid addition salts, are in general known compounds. They possess pharmacological activity. In particular the compounds exhibit activity on the central nervous system, e.g. as antidepressants, as indicated by one or more of the standard pharmacological test procedures such as the reserpine hypothermia procedure based upon B.
M. Askew, Life Sciences (1963), 1, 725-730, the inhibition of noradrenaline or 5-hydroxytryptamine uptake in rat brain slices, the potentiation and prolongation of the effects of amphetamine and the modification of the effects of p-chloroamphetamine.
The following Examples illustrate the invention:
Example 1 N,N-dimethyl-3-phenyl-3-(p-trifluoromethylphenoxy)propylamine A mixture of N,N-dimethyl-3-hydroxy-3-phenylpropylamine (7.16 g, 40 mM), DMSO (100 ml) and sodium hydride (2 g of a 50% dispersion in oil) was heated at 800C until homogeneous, cooled to room temperature and treated with a solution of p-fluorobenzotrifluoride (6.56 g,40 mM) in DMSO (10 mi). The reaction mixture was stirred over night and then poured on to ice water (500 ml) and extracted with ether (3x300 ml). The organic extract was dried and evaporated under reduced pressure to give the title compound as an oil (11.8 g).The oil was dissolved in ethyl acetate (50 ml) and the solution added to oxalic dihydrate (4.6 g) in ethyl acetate (500 ml). The reaction mixture was heated to reflux and allowed to cool slowly to give the oxalate of the title compound (13.6 g), m.p. 11 7 to 11 90C.
Found: C, 58.3; H, 5.7; N, 3.4%
Calc. C, 58.1; H, 5.4; N, 3.4%.
Example 2 N-Methyl-3-phenyl-3-(p-trifluoromethylphenoxy)propylamine A mixture of 3-hydroxy-n-methyl-3-phenylpropylamine (39.2 g, 0.24 mM), DMSO (500 ml) and sodium hydride (12 g of a 50% dispersion in oii) was heated at 800 until homogeneous, cooled to ambient temperature and treated with a solution of p-fluorobenzotrifluoride (39.4 g, 40 mM) in DMSO (10 ml). After 2 hours, the reaction mixture was poured onto cold water (2.5 L) and extracted with ether (4x 1 L). The combined organic phases were washed with brine, dried and the solvent removed under reduced pressure. The residue was dissolved in ether (1.5 L) and treated with an excess of ethereal hydrogen chloride, the resulting precipitate washed well with ether and dried in vacuo to give the title compound as the hydrochloride (52 g), identical with authentic material, m.p. 153--40.
Found: C, 58.9; H, 5.7; N, 4.3%.
C1,H,8F3NO . HCI requires: C, 59.0; H, 5.5; N, 4.0%.
Claims (10)
1. A process for preparing a 3-aryl-3-aryloxypropylamine of general formula:
or a pharmaceutically acceptable acid addition salt thereof wherein R' and R2 are hydrogen or lower alkyl, R3 is hydrogen, lower alkyl or benzyl, R4 is hydrogen or lower alkyl and Ar is phenyl optionally substituted by one or more halogen, trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino groups, which comprises reacting an anion of an alcohol of general formula
(where Ar, R1, R2, R3 and R4 are as defined above) with a fluoro compound of general formula
in a dipolar aprotic solvent and, if desired, converting a free base of general formula (I) into a pharmaceutically acceptable acid addition salt thereof.
2. A process as claimed in Claim 1 wherein the anion of the alcohol of general formula (II) is formed by reacting the alcohol with potassium or sodium hydride or with an alkyl or phenyl lithium in a dipolar aprotic solvent.
3. A process as claimed in Claim 1 wherein the anion of the alcohol is formed by reacting the alcohol with sodium hydride in a dipolar aprotic solvent.
4. A process as claimed in any one of Claims 1 to 3 wherein the reaction is carried out at ambient temperature.
5. A process as claimed in any one of the preceding claims wherein R3 is lower alkyl and R4 is hydrogen or lower alkyl.
6. A process as claimed in any one of the preceding claims wherein Ar is unsubstituted phenyl.
7. A process as claimed in any one of the preceding claims wherein the product is N,N-dimethyl3-phenyl-3-(p-trifluoromethylphenoxy)propylamine or a pharmaceutically acceptable acid addition salt thereof.
8. A process as claimed in any one of Claims 1 to 6 wherein the product is N-methyl-3-phenyl-3 (p-trifluoromethylphenoxy)propylamine or a pharmaceutically acceptable acid addition salt thereof.
9. A process as claimed in Claim 1 substantially as hereinbefore described with reference to either of the Examples.
10. A 3-aryl-3-aryloxypropylamine whenever prepared by a process claimed in any one of the preceding claims.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8028710A GB2060618A (en) | 1979-09-14 | 1980-09-05 | 3-Aryl-3-Aryloxypropylamines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7932046 | 1979-09-14 | ||
| GB8028710A GB2060618A (en) | 1979-09-14 | 1980-09-05 | 3-Aryl-3-Aryloxypropylamines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2060618A true GB2060618A (en) | 1981-05-07 |
Family
ID=26272890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8028710A Withdrawn GB2060618A (en) | 1979-09-14 | 1980-09-05 | 3-Aryl-3-Aryloxypropylamines |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2060618A (en) |
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4876282A (en) * | 1987-11-25 | 1989-10-24 | Eli Lilly And Company | 1-Phenylalkylamines as selective serotonin uptake inhibitors |
| US4902710A (en) * | 1988-12-14 | 1990-02-20 | Eli Lilly And Company | Serotonin and norepinephrine uptake inhibitors |
| EP0380924A1 (en) * | 1989-01-10 | 1990-08-08 | Grato Magnone | Process for the preparation of fluoxetine hydrochloride |
| US4956388A (en) * | 1986-12-22 | 1990-09-11 | Eli Lilly And Company | 3-aryloxy-3-substituted propanamines |
| EP0391070A1 (en) * | 1989-03-03 | 1990-10-10 | Orion-Yhtymä Oy Fermion | Process for the preparation of N-methyl-3-(p-trifluoro-methylphenoxy)-3-phenyl-propylamine and their salts |
| US4996235A (en) * | 1987-11-25 | 1991-02-26 | Eli Lilly And Company | 3,4-diphenylbutanamines |
| US5135947A (en) * | 1987-04-09 | 1992-08-04 | Eli Lilly And Company | 1-phenyl-3-naphthalenyloxypropanamines and their use as selective serotonin reuptake inhibitors |
| WO1992019210A2 (en) * | 1991-05-01 | 1992-11-12 | The Trustees Of The University Of Pennsylvania | Serotinin reuptake inhibitors for s.p.e.c.t imaging |
| US5166437A (en) * | 1989-03-03 | 1992-11-24 | Orion-Yhtyma Oy | Process for the preparation of fluoxetine |
| EP0529842A2 (en) | 1991-08-27 | 1993-03-03 | Teva Pharmaceutical Industries, Ltd. | Production of fluoxetine and new intermediates |
| US5272144A (en) * | 1988-10-05 | 1993-12-21 | Farmitalia Carlo Erba S.R.L. | Aryloxy-, arylthio-, heteroaryloxy-, heteroarylthio-alkenylene derivatives of amines and pharmaceutical use |
| WO1994000416A1 (en) * | 1992-06-26 | 1994-01-06 | Richter Gedeon Vegyészeti Gyár Rt. | Preparation of n-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine and acid addition salts thereof |
| ES2120368A1 (en) * | 1996-06-14 | 1998-10-16 | Almirall Prodesfarma Sa | Process for obtaining N-methyl-3-(p- trifluoromethylphenoxy)-3-phenylpropylamine and its pharmaceutically acceptable salts |
| WO1999018947A1 (en) * | 1997-10-14 | 1999-04-22 | Eli Lilly And Company | Process to make chiral compounds |
| US5936124A (en) * | 1998-06-22 | 1999-08-10 | Sepacor Inc. | Fluoxetine process from benzoylpropionic acid |
| US6025517A (en) * | 1998-08-03 | 2000-02-15 | Sepracor Inc. | Fluoxetine process from benzoylacetonitrile |
| US6258853B1 (en) | 2001-01-31 | 2001-07-10 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
| US6310250B1 (en) | 2001-01-31 | 2001-10-30 | Grayson Walker Stowell | Form A of fluoxetine hydrochloride |
| US6310251B1 (en) | 2001-01-31 | 2001-10-30 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
| US6313350B1 (en) | 2001-01-31 | 2001-11-06 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
| US6316672B1 (en) | 2001-01-31 | 2001-11-13 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
| US6677485B2 (en) | 1999-12-17 | 2004-01-13 | Ranbaxy Laboratories Limited | Process for the preparation of fluoxetine hydrochloride |
| US6846957B2 (en) | 2002-11-22 | 2005-01-25 | Board Of Regents, The University Of Texas System | Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor |
| CN104058977A (en) * | 2014-07-03 | 2014-09-24 | 南京瑞尔医药有限公司 | Synthesis, purification and content control method of fluoxertine hydrochloride capsule impurity |
-
1980
- 1980-09-05 GB GB8028710A patent/GB2060618A/en not_active Withdrawn
Cited By (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4956388A (en) * | 1986-12-22 | 1990-09-11 | Eli Lilly And Company | 3-aryloxy-3-substituted propanamines |
| US5023269A (en) * | 1986-12-22 | 1991-06-11 | Eli Lilly And Company | 3-aryloxy-3-substituted propanamines |
| US5135947A (en) * | 1987-04-09 | 1992-08-04 | Eli Lilly And Company | 1-phenyl-3-naphthalenyloxypropanamines and their use as selective serotonin reuptake inhibitors |
| US4996235A (en) * | 1987-11-25 | 1991-02-26 | Eli Lilly And Company | 3,4-diphenylbutanamines |
| US4876282A (en) * | 1987-11-25 | 1989-10-24 | Eli Lilly And Company | 1-Phenylalkylamines as selective serotonin uptake inhibitors |
| US5272144A (en) * | 1988-10-05 | 1993-12-21 | Farmitalia Carlo Erba S.R.L. | Aryloxy-, arylthio-, heteroaryloxy-, heteroarylthio-alkenylene derivatives of amines and pharmaceutical use |
| US4902710A (en) * | 1988-12-14 | 1990-02-20 | Eli Lilly And Company | Serotonin and norepinephrine uptake inhibitors |
| EP0380924A1 (en) * | 1989-01-10 | 1990-08-08 | Grato Magnone | Process for the preparation of fluoxetine hydrochloride |
| EP0391070A1 (en) * | 1989-03-03 | 1990-10-10 | Orion-Yhtymä Oy Fermion | Process for the preparation of N-methyl-3-(p-trifluoro-methylphenoxy)-3-phenyl-propylamine and their salts |
| US5166437A (en) * | 1989-03-03 | 1992-11-24 | Orion-Yhtyma Oy | Process for the preparation of fluoxetine |
| US5320825A (en) * | 1991-05-01 | 1994-06-14 | Trustees Of The University Of Pennsylvania | Serotonin reuptake inhibitors for S.P.E.C.T. imaging |
| WO1992019210A3 (en) * | 1991-05-01 | 1993-01-07 | Univ Pennsylvania | Serotinin reuptake inhibitors for s.p.e.c.t imaging |
| WO1992019210A2 (en) * | 1991-05-01 | 1992-11-12 | The Trustees Of The University Of Pennsylvania | Serotinin reuptake inhibitors for s.p.e.c.t imaging |
| EP0529842A2 (en) | 1991-08-27 | 1993-03-03 | Teva Pharmaceutical Industries, Ltd. | Production of fluoxetine and new intermediates |
| WO1994000416A1 (en) * | 1992-06-26 | 1994-01-06 | Richter Gedeon Vegyészeti Gyár Rt. | Preparation of n-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine and acid addition salts thereof |
| ES2120368A1 (en) * | 1996-06-14 | 1998-10-16 | Almirall Prodesfarma Sa | Process for obtaining N-methyl-3-(p- trifluoromethylphenoxy)-3-phenylpropylamine and its pharmaceutically acceptable salts |
| WO1999018947A1 (en) * | 1997-10-14 | 1999-04-22 | Eli Lilly And Company | Process to make chiral compounds |
| US6028224A (en) * | 1998-06-22 | 2000-02-22 | Sepracor Inc. | Fluoxetine process from benzoylpropionic acid |
| US5936124A (en) * | 1998-06-22 | 1999-08-10 | Sepacor Inc. | Fluoxetine process from benzoylpropionic acid |
| US6025517A (en) * | 1998-08-03 | 2000-02-15 | Sepracor Inc. | Fluoxetine process from benzoylacetonitrile |
| US6677485B2 (en) | 1999-12-17 | 2004-01-13 | Ranbaxy Laboratories Limited | Process for the preparation of fluoxetine hydrochloride |
| US6258853B1 (en) | 2001-01-31 | 2001-07-10 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
| US6310250B1 (en) | 2001-01-31 | 2001-10-30 | Grayson Walker Stowell | Form A of fluoxetine hydrochloride |
| US6310251B1 (en) | 2001-01-31 | 2001-10-30 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
| US6313350B1 (en) | 2001-01-31 | 2001-11-06 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
| US6316672B1 (en) | 2001-01-31 | 2001-11-13 | Grayson Walker Stowell | Form a of fluoxetine hydrochloride |
| US6492556B2 (en) | 2001-01-31 | 2002-12-10 | Grayson Walker Stowell | Form A of fluoxetine hydrochloride |
| US6846957B2 (en) | 2002-11-22 | 2005-01-25 | Board Of Regents, The University Of Texas System | Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor |
| CN104058977A (en) * | 2014-07-03 | 2014-09-24 | 南京瑞尔医药有限公司 | Synthesis, purification and content control method of fluoxertine hydrochloride capsule impurity |
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| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |