MXPA00003560A - Process to make chiral compounds - Google Patents

Abstract

A process to make the S(+)mandelic acid salt of i(N)-methyl-3i(R)-hydroxy-3-phenylpropylamine comprising reacting i(N)-methyl-3(i(R,S))-hydroxy-3-phenylpropylamine with S(+)mandelic acid is described and claimed. Also described and claimed are processes to make i(N)-methyl-3i(R)-(2-methylthiophenoxy)-3-phenylpropylamine and i(N)-methyl-3i(R)-(2-methylphenoxy)-3-phenylpropylamine.

Description

PROCESS TO DEVELOP QUIRAL COMPOUNDS Description of the invention. This invention relates to the art of synthetic organic chemistry. Specifically, the invention is a process for separating enantiomers from a mixture, such that the individual enantiomers can be used in the synthesis of valuable chiral pharmaceuticals. The structural formula: represents N-methyl-3í? - (2-methylfe oxy) -3-f-enylpropylamine when Rr is methyl, and represents N-methyl-3R- (2-methyloxy-enoxy) -3-f-enylpropylamine, when Rr is methylthio. N-methyl-3R- (2-methylfenoxy) -3-f-enylpropylamine and N-met1-3.R- (2-methylthiophenoxy) -3-f-enylpropylamine act as selective and potent inhibitors in the uptake from norepinef ri a. The syntheses of N-methyl-3R- (2-methyl-enoxy) -3- REF .: 33056 phenylpropylamine are described in U.S. Pat. No. 4,018,895, 4,194,009, 4,314,081 and 4,777,291, the disclosure of which is incorporated herein by reference. A synthesis of N-met il-3J? - (2-methylthiophenoxy) -3-phenylpropylamine is described in U.S. Pat. ?or. 5,281,624, the description of which is incorporated herein by reference. In known synthesis of these compounds, a mixture containing the R and S enantiomers of the desired compound is formed, and then the desired R-enantiomer is separated from the mixture using techniques known in the art. It is desirable to develop an alternative process that allows the individual enantiomers to be made directly. This invention relates to a process for making the S- (+) - mandelic acid salt of N-met i-3J? -hydroxy-3-phenylpropylamine, which comprises reacting N-methyl-3. { R, S) -hydroxy-3-phenylpropylamine with S- (+) - mandelic acid. This invention also relates to a process for making the R- (-) -mandelic acid salt of N-met il-3S-hydroxy-3-phenylpropylamine, which comprises reacting N-met il-3 (R, S) -hydroxy-3-phenylpropylamine with R- (-) - mandelic acid. This invention also relates to a compound of formula: which is called the S- (+) -mandelate salt of N-methyl-3J-hydroxy-3-phenylpropylamine. This invention also relates to a compound of formula: which is called R- (-) -mandelate salt of N-methyl-35-hydroxy-3-phenylpropylamine. This invention also relates to a process for making N-methyl-3i? - (2-methyl-enoxy) -3-phenylpropylamine; the improvement comprises using salt S - (+) - mandelate of N-methyl-3i? -hydroxy-3-phenylpropylamine in the synthesis. This invention also relates to a process for making N-methyl-3f? - (4-trifluoromethyl-1-phenoxy) -3-phenylpropylamine; the improvement comprises using salt S - (+) - mandelate of N-methyl-3'-hydroxy-3-phenylpropylamine in the synthesis. This invention also relates to a process for making N-met i 1-3 S- (4-trifluoromethyl phenoxy) -3-phenylpropylamine; the improvement comprises using salt R - (+) - mandelate of N-methyl-3S-hydroxy-3-phenylpropylamine in the synthesis. This invention also relates to a process for making N-methyl-3i? - (2-methylthiophenoxy) -3-phenylpropylamine; the improvement comprises using salt S - (+) - mandelate of N-methyl-3i * "- hydroxy-3-phenylpropylamine in the synthesis N-methyl-3 { R, S) -hydroxy-3-phenylpropylamine to a compound of formula: S- (+) - mandelic acid refers to a compound of formula R- (-) -mandelic acid refers to a compound of the formula: Salt S- (+) -mandelate of N-methyl-3-yl-hydroxy-3-phenylpropylamine refers to a compound of formula Sal R- (-) -mandelate of N-met i l- 3S-hydroxy-3-phenylpropylamine refers to a compound of formula Unless otherwise noted, all reactions described herein are preferably conducted under an inert atmosphere. The preferred inert atmosphere is nitrogen. The process for making the S- (+) -mandelate salt of N-methyl-3-hydroxy-3-phenylpropylamine starts with the compound N-met i l-3 (i?, S) -hydroxy-3-phenylpropylamine (hereinafter PMAP). A synthesis of PMAP is described in the European Patent Application? O. 90104018.8. PMAP is reacted with S- (+) - mandelic acid to make the S- (+) -mandelate salt of N-met i -3J? -hydroxy-3-phenylpropylamine. S- (+) - mandelic acid is commercially available. The reaction that forms the salt is conducted in a solvent. The solvent is selected from the group consisting of inert organic solvents, which includes, but is not limited to, toluene, benzene, xylene, ethyl acetate, acetone, methyl-tert-butyl ether, ethanol, and mixtures thereof. The preferred solvent is ethyl acetate. The process is carried out at a temperature of about 25 ° C to about 78 ° C. The preferred temperature is from about 50 ° C to about 55 ° C. The reaction is carried out for a period of from about five minutes to about 1 hour. When the reaction temperature is from about 50 ° C to about 55 ° C the preferred reaction time is about five minutes. After five minutes at about 50 ° C to about 55 ° C, the reaction mixture is actively cooled to room temperature of about 25 ° C for a period of about 24 hours. The mixture is then kept at room temperature for about one and a half hours. After this time at room temperature the S - (+) - mandelate salt of solid N-met il-3f? -hydroxy-3-phenylpropylamine could be separated from the reaction mixture using standard techniques known to the person skilled in the art, such as filtering the reaction mixture and collecting the solid. The same procedure described above can be used to make the salt R- (-) -mandelate of N-met i l- 35-hydroxy-3-phenylpropylamine; with the proviso that R- (-) - mandelic acid is used in place of S - (+) - mandelic acid, which is used to make the S- (+) - mandelate salt of N-methyl-1-3. - idroxy-3-phenylpropylamine. Since 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 mandelic acid be used per mole of PMAP. Since, for example, approximately a 1: 1 ratio of PMAP and the appropriate mandelic acid gives good results, using about 0.45-0.50 molar equivalents of mandelic acid provides comparable yields with more enantiomeric excess. high, i.e., such relationships result in a product of higher purity, from an enantiomer's point of view. The S- (+) - mandelic acid of N-methyl-3? -hydroxy-3-phenylpropylamine can be used to make certain valuable pharmaceuticals, such as N-met i -3. - (4-trifluoromethylphenoxy) -3-phenylpropylamine (R-fluoxetine), N-met I1-3S- (4-trifluoromethylphenoxy) -3-phenylpropylamine (S-fluoxetine), N-methyl-3-R- (2 -methylphenoxy) -3-phenylpropylamine (to oxetine), and N-methyl-3R- (2-methylthiophenoxy) -3-phenylpropylamine. See, e.g., U.S. Patents No. 5,104,899, 5,356,934, 5,281,624, 5,441,985 and 5,658,590 and Patent Application Publication EP 52,492. Therefore, this invention also provides a process for making N-methyl -3f? - (substituted phenoxy) -3-phenylpropylamines comprising: (1) reacting S (+) mandelate salt of N-met il-3f? - hydroxy-3-phenylpropylamine with a suitable base to form an alkoxide of formula (a): formula (a 2) reacting the alkoxide of formula (a) with a halobenzene compound of formula (b): formula (b) wherein X is -F or -Cl, and Ra is 2-methyl, 4-trifluoromethyl, or 2-methylthio to give a compound of formula formula (c).

This process is also applicable for the similar reaction to make S-fluoxetine comprising: (1) reacting R- (+) -mandelate salt of N-methyl-3S-hydroxy-3-phenylpropylamine with a suitable base to form an alkoxide of formula (a): formula (a ') 2) reacting the alkoxide of formula (a ') with a 4-trifluoromethylhalobenzene compound of formula (b'): formula (b; where X is -F or -Cl, to give a compound of formula formula (c ') The following examples are illustrative only and are not intended to limit the scope of the invention in any way.

EXAMPLES The terms and abbreviations used in the present 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 normal; "mmol" refers to millimole or millimole; "g" refers to gram or grams; "" refers to density, "min." refers to minutes, "mL" refers to milliliter or milliliters; "M" refers to molar or molarity; CCF refers to thin layer chromatography, "HPLC" refers to high performance liquid chromatography; ^ -RM refers to Nuclear Magnetic Resonance of proton, 13C-NMR refers to Nuclear Magnetic Resonance of carbon-13, "mm" refers to millimeters; "MTBE" refers to methyl-tert-butyl ether; "cm" refers to centimeters; "nm" refers to nanometers; "PMAP" refers to N-methyl-3. { R, S) -hydroxy-3-enylpropylamine; "tr" refers to retention time, and vol. refers to an amount in mL / grams with respect to the initial material.

Eiemolo 1 ? £ S- (+) - mandelic acid (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 of dimethyl-ketone (DMK) and 200 mL of MTBE. The solution was heated to 50 ° C, and the solution was seeded with S- (+) -mandelate salt of authentic N-methyl-3-R-hydroxy-3-phenylpropylamine Q. The mixture was stirred for 1 hour and then it was cooled for one hour at room temperature, to which it was stirred for 16 hours. The mixture was filtered and the 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 enantiomeric excess was determined to be 93.1%.

Example 2 A £ R- (-) -mandelic acid (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 of dimethylketone (DMK) and 200 mL of MTBE. The solution was heated to 50 ° C, and the solution was seeded with authentic R- (-) -mandelate salt of authentic N-met i l -3S-hydroxy-3-phenylpropylamine. The mixture was stirred for 1 hour and then cooled for one hour at room temperature, to which it was stirred for 16 hours. The mixture was filtered and the crystals obtained were washed with 75 mL 1.5: 1 MTBE: acetone. After drying, the salt R- (-) -mandelate of N-met i l -35-hydroxy-3-phenylpropylamine was obtained. 3 £ PMAP A (400.0 g, 2.42 mol) was placed in a flask containing 6.5 L of ethyl acetate (EtOAc). A solution of (+) - mandelic acid (165.7 g, 1.09 mol) in 1.5 L of EtOAc was added to. the PMAP solution for 10-15 minutes. After the addition, the reaction mixture was heated to 50 ° C, at this point all the solids were dissolved. The solution was slowly cooled to 39-40 ° C and seeded with authentic C_. The reaction was cooled to room temperature and the crystals were collected by filtration. The crystals were washed with 4.0 L of EtOAc and dried in a vacuum oven at 35-40 ° C. A total of 226.4 g (29.5% yield) of £ was obtained. The enantiomeric excess was determined to be 94.0%.

Recrystallization from ("" .. 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 [deg.] 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 acetone / MTBE 1: 1 and dried in a vacuum oven at 35-40 ° C. A total of 186.5 g of salt were collected. S- (+) -mandelate of N-met il-3jR-hydroxy-3-phenylpropylamine (C. The enantiomeric excess was determined to be 99.9% .XH-RM? (CDC13): d 7.45-7.15 (m, 10H ), 4.88 (s, 1H), 4.67 (dd, 1H), 2.85-2.60 (m, 2H), 2.20 (s, 3H), 1.92-1.75 (m, 2H), Cale, for C18H23? 04: _ _ Theory: C 68.12, H. 7.30,? 4.41, Found: C 68.31, H. 7.14,? 4. 4.62; Example 4 The S- (+) -mandelate salt of N-methyl-3. -hydroxy-3-phenylpropylamine (C) (275.0 g, 0.87 mol) was dissolved in 1.925 L of MTBE and 0.55 L of water, and the pH was adjusted to 12.7 by the addition of 50% aqueous? aOH (46.1 mL) . The resulting biphasic mixture was stirred for 5 minutes, and the layers were separated. The aqueous layer was back-extracted with 1.1 L of MTBE. The combined MTBE layers were washed with 0.55 L saturated aqueous NaCl, dried with Na 2 SO 4, filtered and concentrated in vacuo to provide 133.7 g of N-methyl-3i? -hydroxy-3-phenylpropylamine £.

Step B: A 1L jacketed flask was charged with? AH (60% oil dispersion, 31.7 g, 0.792 mol), potassium benzoate (13.0 g, 0.0809 mol), and DMSO (133.6 mL). To this vessel was added a solution of N-me't i l-3iR-hydroxy-3-phenylpropylamine (133.6 g, 0.809 mol) in 133.6 ml of DMSO for 45 minutes, followed by a rinse of 66.8 ml of DMSO. The resulting mixture was stirred for 10 minutes. To this vessel was added 2-fluorothioanisole (126.5 g, 0.809 mol) followed by an additional rinse with 66.8 mL of DMSO. The reaction mixture was heated to 65 ° C and stirred for 18.8 hours. The reaction was then cooled to room temperature and added to a quenching solution consisting of 0.9 L of H20 and 0.7 L of EtOAc followed by an additional rinse with 0.23 L of H20 and 0.18 L of EtOAc. The layers were separated and the aqueous layer was extracted with 0.38 L EtOAc. The combined EtOAc layers were washed with 0.67 L each of H20 and saturated aqueous? ACl. The EtOAc layer was dried with Na 2 SO 4 and filtered. The Na2SO4 was washed with 0.13 L EtOAc. The filtrate was cooled to about 0 ° C and HCl (g) (29.52 g) was added. The thick suspension thus formed was stirred an additional 30 minutes and the crystals were collected by filtration, washed with 0.27 L of cold EtOAc, and placed in a vacuum oven at 35-40 ° C. The (233.1 g) was recrystallized from EtOH (0.700 L) which afforded 188.3 g of N-met il-3j- (2-methylthiophenoxy) -3-phenylpropylamine hydrochloride in 99.6% ee. XH RM? (CDC13): d 9.64 (br s, 2H), 7.40-7.20 (m, 5H), 7.15-7.05 (m, 1H), 6.95-6.82 (m, 2H), 6.65-6.55 (m, 1H), 5.45 (dd, 1H), 3.32-3.18 (m, 2H), 2.66 (t, 3H), 2.56-2.42 (m, 5H). Cale, for C17H22C1? 0S: Theory: C 63.04; H. 6.85; ? 4.33; Found: C 63.34; H. 6.62; ? 4.47.

The S- (+) -mandelate salt of N-methyl l-3f? -hydroxy-3-phenylpropylamine (CJ (9.16 grams, 28.81 mmol) was suspended in a mixture of MTBE (70 mL) and deionized H20 (20 mL) ? aOH 2 ((15 mL) was added to convert the salt to the free base.With the addition of a aOH, the phases were separated The aqueous layer was extracted with MTBE (20 mL, ca. 2 vol.). The organic layers were combined and dried with α2SO4, then the layers were filtered and concentrated in vacuo.The concentrated oil was dissolved in DMSO (3.75 mL), 60% sodium hydride (0.691 g, 28.81 mmol) was added. ) to DMSO (4.75 mL) at room temperature of about 25 ° C. The DMSO / concentrated oil mixture from the previous paragraph was added dropwise (the internal temperature increased to 38 ° C) for five minutes. DMSO / concentrated oil mixture was washed twice (each wash was 1 mL of DMSO) .This "DMSO wash" was added to the sodium hydride / DMSO mixture. heated at 40 ° C for 20 minutes. 2-fluoro-methylthiobenzene £ (4.09 g, 28.81 mmol) in DMSO (2 mL) was added dropwise. The flask containing the DMSO / £ mixture was rinsed twice (each rinse was with 1 mL of DMSO). This "DMSO rinse" was added to the sodium hydride / DMSO mixture. The solution was heated to 53 ° C and stirred for 49 hours. A 1 H-NMR spectrum of an aliquot (taken after quenching with ethyl acetate / water) showed approximately 10% of N-met il-3i? -hydrox i-3-phenylpropylamine D., and some 2-fluorothioanisole and something of product. Another 0.05 equivalents (58 mg) of α to H were added and the reaction proceeded for a further 21 hours at 53 ° C. The analysis of 1H-RM? of an aliquot (taken after quenching with ethyl acetate / water) showed that the reaction was complete. The solution was diluted with 45 L (approximately 9 volumes) of H20 and 35 mL (approximately 7 volumes) of ethyl acetate. The phases were separated with an emulsion layer. The layers were separated (the emulsion layer was maintained with the organic layer). The aqueous layer was extracted with 3 volumes of ethyl acetate and this extraction of ethyl acetate was added to the organic layer / emulsion mixture. The combined organic layers were then washed twice with 5 volumes of diluted aqueous? ACl. To the organic layers were added 28.81 L of 1 H HCl in diethyl ether. The crystals formed almost immediately. The liquid was cooled to 0 ° C and stirred 15 minutes. The crystals were filtered and washed with 25 mL of ethyl acetate. The crystals were placed in a vacuum oven at 45 ° C for 24 hours. The yield was 8.1 grams (87%) of N-methyl-3R- (2-methylthiophenoxy) -3-phenylpropylamine hydrochloride salt. % ee = 92. The salt crystals of N-met i l- 3í? - (2-methylthiophenoxy) -3-phenylpropylamine hydrochloride formed before (8.0 g) were placed in ethanol (24 mL). The ethanol was heated to about 75 ° C and stirred for 30 minutes to dissolve the crystals. The ethanol was cooled to 65 ° C and seeded with authentic N-meth i l-3i? - (2-methylthiophenoxy) -3-phenylpropylamine hydrochloride salt. After sowing, the crystals formed faster. The ethanol was stirred at 65 ° C for twenty minutes and then cooled for 1 hour at room temperature and then at 0 ° C for one hour. The ethanol was filtered, the crystals were collected and then washed with 20 L of ethanol. The yield of the hydrochloride salt of N-met i -3i? - (2-methylthiophenoxy) -3-phenylpropylamine was 6.25 grams (78%) % ee = 99.3.

Example 6 Using any of the methods described in Examples 4 or 5 above (see also Koenig, et al., Tetrahedron Letters, 35 (9) 1339 (1994), Chenevert, et al., Chemistrv Letters, 1603 (1991); Kumar, et al., Tetrahedron Letters 32 (16), 1901 (1991), Gao and Sharpless, J. Ors. Chem., 53. 4081 (1988)) and using the salt S- (+) - (or R- ( -)) -mandelate of N-methyl-3J? (or 35) -hydroxy-3-phenylpropylamine and either 4-chloro-trifluoromethylbenzene or 2-fluorotoluene, R-fluoxetine, S-fluoxetine or tomoxetine or their pharmaceutically acceptable salts can be prepared.

Determination of Enant iomeric Excess 20 g of the subject salt is combined with 5 mL of dichloromethane and 5 mL of saturated aqueous sodium bicarbonate. After stirring well for 2 minutes, 20 μL of acetyl chloride is added and the resulting mixture is stirred well for an additional 2 minutes. The organic phase is separated, dried with sodium sulfate and concentrated under reduced pressure. The residual oil is dissolved in 6-10 mL at 95: 3: 2 UV degree of hexane: n-propanol: UV grade methanol. This solution is analyzed on a Chiral pak AS 4.6 mm x 25 cm column, eluting with 95: 3: 2 UV degree of hexane: n-propanol: UV grade methanol at a rate of 1 mL / min in a 40 ° column. C. The eluent was analyzed at 210 nm. The (R) -enantiomer -acetylated is the enantiomer that elutes faster under these conditions.

The present invention has been described in detail, including preferred embodiments thereof. However, it will be apparent that those skilled in the art, in consideration of the present disclosure, could make modifications and / or improvements that fall within the scope and spirit of the invention as set forth in the following claims.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (11)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for making the S - (+) - mandelic acid salt of N-met il -3i? -hydroxy-3-phenylpropylamine, characterized in that it comprises reacting N-methyl-3 (R, S) -hydroxy-3- phenylpropylamine with S- (+) - mandelic acid.

2. A process for making the R- (-) -mandelic acid salt of N-met il-3S-hydroxy-3-phenylpropylamine, characterized in that it comprises reacting N-methyl-3. { R, S) -hydroxy-3-phenylpropylamine with R- (-) - mandelic acid.

3. A compound of formula characterized in that it is called the S- (+) -mandelate salt of N-methyl-3R-hydroxy-3-phenylpropylamine.

4. A compound of formula: characterized in that it is referred to as the R- (-) -mandelate salt of N-methy1-3-? -hydroxy-3-phenylpropylamine.

5. A process for making N-met i l-3i? - (substituted phenoxy) -3-phenylpropylamines, characterized in that it comprises: a) reacting the S- (+) -mandelate salt of N-methyl-3f? -hydroxy-3 phenylpropylamine with a suitable base to form an alkoxide of formula (a): formula (a); b) reacting the alkoxide of formula (a) with a halobenzene compound of formula (b): formula (b) where X is -F or -Cl, and Ra is 2-methyl, 4-trifluoromethyl, or 2-methylthio to give a compound of formula formula (c).

6. The process of claim 5, characterized in that X is -F.

7. The process of claim 5, characterized in that X is -Cl

8. The process of claim 5, characterized in that Ra is 2-methyl.

9. The process of claim 5, characterized in that Ra is 4-trifluoromethyl.

10. The process of claim 5, characterized in that Ra is 2-methylthio.

11. A process for the preparation of S-fluoxetine, characterized in that it comprises: a) reacting R- (+) -mandelate salt of N-methyl-35-hydroxy-3-phenylpropylamine with a suitable base to form an alkoxide of formula (a) ): formula (a ' b) reacting the alkoxide of formula (a ') with a 4-trifluoromethylhalobenzene compound of formula (b'): formula (b) wherein X is -F or -Cl, to give a compound of formula formula (c ' PROCESS FOR SUMMARY OF THE INVENTION A process for the preparation of S (+) andlic acid salt of N-methyl-3i? -hydroxy-3-phenylpropylamine, which comprises reacting N-methyl-3, is described and claimed. { R, S) -hydroxy-3-phenylpropylamine with S (+) mandelic acid. Processes for the preparation of N-methyl-3iR- (2-methylthiophenoxy) -3-phenylpropylamine and N-m.ethyl-3R- (2-methylphenoxy) -3-phenylpropylamine are also described and claimed.