| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | December 28, 1999 |
| PATENT TITLE |
Process to make chiral compounds |
| PATENT ABSTRACT | The present invention relates to processes for resolving N-methyl-3(R,S)-hydroxy-3-phenylpropylamine and N,N-dimethyl-3 (R,S) -hydroxy-3-phenylpropylamine with the isomers of mandelic acid and the resulting salts |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | March 26, 1999 |
| PATENT REFERENCES CITED | Robertson, D. W., et al., Absolute Configurations and Pharmaceutical Activities of the Optical Isomers of Fluoxetine, A Selective Serotonin-Uptake Inhibitor Journal of Medicinal Chemistry, vol. 31, No. 7, Jul. 1, 1988, pp. 1412-1417. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A process to make the S-(+)-mandelic acid salt of N-methyl-3 R-hydroxy-3-phenylpropylamine comprising reacting N-methyl-3(R,S)-hydroxy-3-phenyipropylamine with S-(+)-mandelic acid. 2. A process to make the R-(-)-mandelic acid salt of N-methyl-3 S-hydroxy-3-phenylpropylamine comprising reacting N-methyl-3(R,S)-hydroxy-3-phenylpropylamine with R-(-)-mandelic acid. 3. A compound of the formula: ##STR39## which is named N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt. 4. A compound of the formula: ##STR40## which is named N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt. 5. A process to make the R-(-)-mandelic acid salt of N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine comprising reacting N,N-dimethyl-3(R,S)-hydroxy-3-phenylpropylamine with R-(-)-mandelic acid. 6. A process to make the S-(+)-mandelic acid salt of N,N-dimethyl-3 S-hydroxy-3-phenylpropylamine comprising reacting N,N-dimethyl-3(R,S)-hydroxy-3-phenylpropylamine with S-(+)-mandelic acid. 7. A compound of the formula: ##STR41## which is named N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine R-(-)-mandelate salt. 8. A compound of the formula: ##STR42## which is named N,N-dimethyl-3 S-hydroxy-3-phenylpropylamine S-(+)-mandelate salt. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
-------------------------------------------------------------------------------- FIELD OF THE INVENTION This invention relates to the art of synthetic organic chemistry. Specifically, the invention is a process to separate enantiomers from a mixture so that the individual enantiomers can be used in the syntheses of valuable chiral pharmaceutical compounds. BACKGROUND OF THE INVENTION The structural formula: ##STR1## represents N-methyl-3 R-(2-methylphenoxy)-3-phenylpropylamine when R.sup.r is methyl, and represents N-methyl-3 R-(2-methylthiophenoxy)-3-phenylpropylamine, when R.sup.r is methylthio. Both N-methyl-3 R-(2-methylphenoxy)-3-phenylpropylamine and N-methyl-3 R-(2-methylthiophenoxy)-3-phenylpropylamine act as selective and potent inhibitors of norepinephrine uptake. Syntheses of N-methyl-3 R-(2-methylphenoxy)-3-phenylpropylamine are described in U.S. Pat. Nos. 4,018,895, 4,194,009, 4,314,081 and 4,777,291, the disclosures of which are hereby incorporated by reference. A synthesis of N-methyl-3 R-(2-methylthiophenoxy)-3-phenylpropylamine is described in U.S. Pat. No. 5,281,624, the disclosure of which is hereby incorporated by reference. The structural formula: ##STR2## represents N-methyl-3 R-(4-trifuoromethylphenoxy)-3-phenylpropylamine, (R)-fluoxetine. Syntheses of (R)-fluoxetine, (R)-N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine, are known in the art and taught in U.S. Pat. No. 5,708,035. In known syntheses of these compounds either a mixture comprising both the R and S enantiomers of the desired compound is formed and then the desired enantiomer is separated from the mixture using techniques known in the art or the desired enatiomer is prepared directly from a chiral substrate. It is desirable to develop an alternate process that allows for making of the individual enantiomers directly. SUMMARY OF THE INVENTION This invention refers to a process to make the S-(+)-mandelic acid salt of N-methyl-3 R-hydroxy-3-phenylpropylamine comprising reacting N-methyl-3(R,S)-hydroxy-3-phenylpropylamine with S-(+)-mandelic acid. This invention also refers to a process to make the R-(-)-mandelic acid salt of N-methyl-3 S-hydroxy-3-phenylpropylamine comprising reacting N-methyl-3 (R,S)-hydroxy-3-phenylpropylamine with R-(-)-mandelic acid. This invention refers to a process to make the R-(-)-mandelic acid salt of N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine comprising reacting N,N-dimethyl-3 (R,S)-hydroxy-3-phenylpropylamine with R-(-)-mandelic acid. This invention also refers to a process to make the S-(+)-mandelic acid salt of N,N-dimethyl-3 S-hydroxy-3-phenylpropylamine comprising reacting N,N-dimethyl-3 (R,S)-hydroxy-3-phenylpropylamine with S-(+)-mandelic acid. This invention also refers to a compound of the formula: ##STR3## which is named N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt. This invention also refers to a compound of the formula: ##STR4## which is named N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt. This invention also refers to a compound of the formula: ##STR5## which is named N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine R-(-)- mandelate salt. This invention also refers to a compound of the formula: ##STR6## which is named N,N-dimethyl-3 S-hydroxy-3-phenylpropylamine S-(+)-mandelate salt. This invention also refers to a process to make N-methyl-3 R-(2-methylphenoxy)-3-phenylpropylamine; the improvement comprising using N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt in the synthesis. This invention also refers to a process to make N-methyl-3 R-(4-trifluoromethylphenoxy)-3-phenylpropylamine; the improvement comprising using N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt in the synthesis. This invention also refers to a process to make N-methyl-3 S-(4-trifluoromethylphenoxy)-3-phenylpropylamine; the improvement comprising using N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt in the synthesis. This invention also refers to a process to make N-methyl-3 R-(2-methylthiophenoxy)-3-phenylpropylamine; the improvement comprising using N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt in the synthesis. This invention also refers to a process to make N-methyl-3 R-(4-trifluoromethylphenoxy)-3-phenylpropylamine; the improvement comprising using N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine R-(-)-mandelate salt in the synthesis. This invention also refers to a process to make N-methyl-3 S-(4-trifluoromethylphenoxy)-3-phenylpropylamine; the improvement comprising using N,N-dimethyl-3 S-hydroxy-3-phenylpropylamine S-(+)-mandelate salt in the synthesis. This invention also refers to a process to make N-methyl-3 R-(2-methylthiophenoxy)-3-phenylpropylamine; the improvement comprising using N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine R-(-)-mandelate salt in the synthesis. DETAILED DESCRIPTION OF THE INVENTION N-methyl-3(R,S)-hydroxy-3-phenylpropylamine refers to a compound of the formula: ##STR7## N,N-dimethyl-3(R,S)-hydroxy-3-phenylpropylamine refers to a compound of the formula: ##STR8## S-(+)-mandelic acid refers to a compound of the formula: ##STR9## R-(-)-mandelic acid refers to a compound of the formula: ##STR10## N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt refers to a compound of the formula: ##STR11## N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt refers to a compound of the formula: ##STR12## N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt refers to a compound of the formula: ##STR13## N,N-dimethyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt refers to a compound of the formula: ##STR14## Unless otherwise noted, all reactions described herein are preferably conducted under an inert atmosphere. The preferred inert atmosphere is nitrogen. The process to make the S-(+)-mandelate salt of N-methyl-3 R-hydroxy-3-phenylpropylamine begins with the compound N-methyl-3(R,S)-hydroxy-3-phenylpropylamine (hereinafter PMAP). A synthesis of PMAP is described in European Pat. Application No. 90104018.8. PMAP is reacted with S-(+)-mandelic acid in order to make N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt. S-(+)-mandelic acid is available commercially. The salt-forming reaction is conducted in a solvent. The solvent is selected from the group consisting of inert organic solvents, including, but not limited to, toluene, benzene, xylene, ethyl acetate, acetone (dimethylketone, DMK), methyl-tert-butyl ether, ethanol and mixtures thereof. The preferred solvent is ethyl acetate. The process is conducted at a temperature of from about 25.degree. C. to about 78.degree. C. The preferred temperature is from about 50.degree. C. to about 55.degree. C. The reaction is conducted for a time period of from about five minutes to about 1 hour. When the reaction temperature is from about 50.degree. C. to about 55.degree. C. the preferred time for the reaction is about five minutes. After five minutes at from about 50.degree. C. to about 55.degree. C. the reaction mixture is actively cooled to room temperature of about 25.degree. C. over a period of about 24 hours. Then the mixture is held at room temperature for about one-and-a-half hours. Following this time at room temperature the solid N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt may be separated from the reaction mixture using standard techniques known to one of ordinary skill in the art, such as by filtering the reaction mixture and collecting the solid. The same procedure described above can be used to make N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt; providing that R-(-)-mandelic acid is used in place of the S-(+)-mandelic acid that is used to make the N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt. While virtually any molar ratio of PMAP to the respective mandelic acid provides an operational process, it is preferred that from about 0.2 to 2 molar equivalents of the mandelic acid be used per mole of PMAP. While, for example, approximately a 1:1 ratio of PMAP and the appropriate mandelic acid provides good results, using approximately 0.45-0.50 molar equivalents of the mandelic acid provides comparable yields with higher enantiomeric excess, i.e., such ratios result in a much purer, from an enantiomer standpoint, product. N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelic acid can be used to make certain valuable pharmaceutical products such as N-methyl-3 R-(4-trifluoromethylphenoxy)-3-phenylpropylamine (R-fluoxetine), N-methyl-3 R-(2-methylphenoxy)-3-phenylpropylamine (tomoxetine), and N-methyl-3 R-(2-methylthiophenoxy)-3-phenylpropylamine. See, e.g., U.S. Pat. Nos. 5,104,899, 5,356,934, 5,281,624, 5,441,985 and 5,658,590 and EP Patent Application Publication 52,492. N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelic acid can be used to make certain valuable pharmaceutical products such as N-methyl-3 S-(4-trifluoromethylphenoxy)-3-phenylpropylamine (S-fluoxetine). Accordingly, this invention also provides for a process to make N-methyl-3 R-(substituted phenoxy)-3-phenylpropylamines comprising: (1) reacting N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt with a suitable base to form an alkoxide of formula (a): ##STR15## (2) reacting the alkoxide of formula (a) with a halobenzene compound of formula (b): ##STR16## where X is --F or --Cl, and R.sub.a is 2-methyl, 4-trifluoromethyl, or 2-methylthio to give a compound of the formula ##STR17## This process is also applicable for the similar reaction for making S-fluoxetine comprising: (1) reacting N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt with a suitable base to form an alkoxide of formula (a): ##STR18## 2) reacting the alkoxide of formula (a') with a 4-trifluoromethylhalobenzene compound of formula (b'): ##STR19## where X is --F or --Cl, to give a compound of the formula ##STR20## The process to make the R-(-)-mandelate salt of N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine begins with the compound N,N dimethyl-3(R,S)-hydroxy-3-phenylpropylamine which is commercially available and is readily prepared by reduction of the Mannich product prepared by the reaction of formaldehyde, dimethylamine, and acetophenone as is known in the art. N,N- dimethyl-3(R,S)-hydroxy-3-phenylpropylamine is reacted with R-(-)mandelic acid in order to make N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine R-(-)-mandelate salt. The salt-forming reaction is conducted in a solvent. The solvent is selected from the group consisting of inert organic solvents, including, but not limited to, toluene, benzene, xylene, ethyl acetate, acetone, methyl-tert-butyl ether, ethanol and mixtures thereof. The preferred solvent is methyl-tert-butyl ether and acetone. The process is conducted at a temperature of from about 25.degree. C. to about 80.degree. C. The preferred temperature is from about 50.degree. C. to about 60.degree. C. The reaction is conducted for a time period of from about five minutes to about 1 hour. After the reaction mixture is formed it is preferably cooled slowly to give the product as a solid. N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine R-(-)-mandelate salt may be separated from the reaction mixture using standard techniques known to one of ordinary skill in the art, such as by filtering the reaction mixture and collecting the solid. The same procedure described above can be used to make N,N-dimethyl-3 S-hydroxy-3-phenylpropylamine S-(+)-mandelate salt; providing that S-(+)-mandelic acid is used in place of the R-(-)-mandelic acid that is used to make the N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine R-(-)-mandelate salt. Accordingly, this invention also provides for a process to make N-methyl-3 R-(substituted phenoxy)-3-phenylpropylamines comprising: (1) reacting N,N-dimethyl-3 R-hydroxy-3-phenylpropylamine R-(-)-mandelate salt with a suitable base to form an alkoxide of formula (a): ##STR21## 2) reacting the alkoxide of formula (a1) with a halobenzene compound of formula (b): ##STR22## where X is --F or --Cl, and R.sub.a is 4-trifluoromethyl or 2-methylthio to give a compound of the formula ##STR23## 3) N-demethylation of a compound of formula (c1) to give a compound of the formula ##STR24## This process is also applicable for the similar reaction for making S-fluoxetine comprising: (1) reacting N,N-dimethyl-3 S-hydroxy-3-phenylpropylamine S-(+)-mandelate salt with a suitable base to form an alkoxide of formula (a): ##STR25## 2) reacting the alkoxide of formula (a1') with a 4-trifluoromethylhalobenzene compound of formula (b): ##STR26## where X is --F or --Cl, to give a compound of the formula ##STR27## 3) N-demethylation of a compound of formula (c1g') to give a compound of the formula ##STR28## As is understood by the skilled artisan, the processes depicted in this application to prepare N-methyl-3 R-(substituted phenoxy)-3-phenylpropylamines utilizing a mandelic acid salt can be carried out on the base isolated from the mandelic acid salt, as well as, other salts prepared from the mandelic acid salt or the isolated base. The following examples are illustrative only and are not intended to limit the scope of the invention in any way. The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. For example "C" refers to degrees Celsius; %ee refers to percent enantiomeric excess, "N" refers to normal or normality; "mmol" refers to millimole or millimoles; "g" refers to gram or grams; "d" refers to density, "min." refers to minutes, "mL" means milliliter or milliliters; "M" refers to molar or molarity; TLC refers to thin-layer chromatography, "HPLC" refers to high performance liquid chromatography; .sup.1 H-NMR refers to proton Nuclear Magnetic Resonance, .sup.13 C-NMR refers to carbon-13 Nuclear Magnetic Resonance, "mm" refers to millimeters; MTBE refers to methyl tert-butyl ether; "cm" refers to centimeters; "nm" refers to nanometers; PM refers to N-methyl-3(R,S)-hydroxy-3-phenylpropylamine; "rt" refers to retention time, and vol. refers to an amount in mL/grams relative to starting material. ##STR29## S-(+)-Mandelic acid B (10.37 g, 0.0682 mol) was added in one portion to a solution of PMAP A (25.0 g, 0.152 mol) in 200 mL dimethylketone (DMK) and 200 mL of MTBE. The solution was heated to 50.degree. C., and the solution was seeded with authentic N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt C . The mixture was stirred for 1 hour and then was cooled over one hour to room temperature where it was stirred for 16 hours. The mixture was filtered and crystals obtained were washed with 75 mL 1.5:1 MTBE:acetone. 13.5 grams of C were recovered for a calculated yield of 28% based on PMAP. The enantiorneric excess was 93.%. ##STR30## R(-)-Mandelic acid B (10.37 g, 0.0682 mol) is added in one portion to a solution of PMAP A (25.0 g, 0.152 mol) in 200 mL dimethylketone (DMK) and 200 mL of MTBE. The solution is heated to 50.degree. C., and the solution is seeded with authentic N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt. The mixture is stirred for 1 hour and then is cooled over one hour to room temperature where it is stirred for 16 hours. The mixture is filtered and crystals obtained are washed with 75 mL 1.5:1 MTBE:acetone. After drying, N-methyl-3 S-hydroxy-3-phenylpropylamine R-(-)-mandelate salt is obtained. ##STR31## PMAP A (400.0 g, 2.42 mol) was placed in a flask containing 6.5 L of ethyl acetate (EA). A solution of (+)-mandelic acid B (165.7 g, 1.09 mol) in 1.5 L ethyl acetate was added to the PMAP solution over 10-15 minutes. After addition, the reaction mixture was heated to 50.degree. C. at which point all the solids had dissolved. The solution was slowly cooled to 39-40.degree. C. and seeded with authentic C . The reaction was cooled to ambient temperature and the crystals were collected by filtration. The crystals were washed with 4.0 L of ethyl acetate and dried in a vacuum oven at 35-40.degree. C. A total of 226.4 g (29.5% yield) of C were obtained. The enantiomeric excess was determined on a derivative to be 94.0 %. Recrystallization of C . C (226.4 g) was placed in a flask with acetone (2.9 L) and MTBE (0.90 L) and the mixture was heated to 50.degree. C. The reaction was seeded with authentic C and the mixture was cooled to room temperature. The crystals were collected by filtration, washed with 0.905 L of 1:1 acetone/MTBE and dried in a vacuum oven at 35-40.degree. C. A total of 186.5 g of N-methyl-3 R-hydroxy-3-phenylpropylamine S-(+)-mandelate salt (C) were collected. The enantiomeric excess was determined on to be 99.9%. MS: 166 (M+1) .sup.1 H NMR (CDCl.sub.3): .delta. 7.45-7.15 (m, 10 H), 4.88 (s, 1 H), 4.67 (dd, 1 H), 2.85-2.60 (m, 2 H), 2.20 (s, 3 H), 1.921.75 (m, 2 H). EA: Calcd. for C.sub.18 H.sub.23 NO.sub.4 : Theory: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.31; H, 7.14; N, 4.62. |
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