WO2003062219A1 - Process for preparing an intermediate useful for the asymmetric synthesis of duloxetine - Google Patents

Process for preparing an intermediate useful for the asymmetric synthesis of duloxetine Download PDF

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Publication number
WO2003062219A1
WO2003062219A1 PCT/US2003/000018 US0300018W WO03062219A1 WO 2003062219 A1 WO2003062219 A1 WO 2003062219A1 US 0300018 W US0300018 W US 0300018W WO 03062219 A1 WO03062219 A1 WO 03062219A1
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Prior art keywords
thienyl
methylamino
propanol
isopropanol
duloxetine
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PCT/US2003/000018
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French (fr)
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Alfio Borghese
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Eli Lilly And Company
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Priority to US10/500,829 priority Critical patent/US20040249170A1/en
Priority to EP03707289A priority patent/EP1478641A1/en
Publication of WO2003062219A1 publication Critical patent/WO2003062219A1/en

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    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • This invention belongs to the fields of pharmaceutical chemistry and synthetic organic chemistry, and provides a process for the synthesis of a key intermediate in the preparation of duloxetine, (+) N-methyl-3(l-naphthalenyloxy)-3-(2-thienyl)propanamine, hydrochloric acid salt.
  • Duloxetine is a pharmaceutical now under development as an anti-depressant. It inhibits the uptake of both norepinephrine and serotonin and is presently in clinical evaluation.
  • the compound was disclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388 by Robertson, et al. and the synthesis of it was discussed in more detail by Berglund, R.A., Org. Proc. Res. Devel, 1, 328 (1997) and Deeter, et al., In Tetrahedron Letters, 31(40), 7101-04 (1990) and aspects patented in U.S. Patent Nos. 5,362,886 and 5,491,243. Synthetic schemes and processes have been reported for conversion to duloxetine.
  • the present invention provides improved conditions for carrying out the resolution of ((R/S)-3-Methylamino-l-(2-thienyl))-l-propanol whereby resolved compound I is obtained in greater enantiomeric purity and yield than has previously been possible.
  • the present invention provides a process for preparing (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thienyl)-propanamine comprising resolving racemic ((S)-3- Methylamino-l-(2-thienyl))-l -propanol with 2,3,4,6-di-O-isopropylidene-2-keto-L- gulonic acid or S-(-)-2-pyrrolidone-5-carboxylic acid in a first organic solvent, and if desired, racemizing a stereomericalry enriched mixture in an isopropanol/hydrochloric acid mixture; and if desired, crystallizing (S)-3-Methylamino-l-(2-thienyl)-l -propanol by resolving racemic ((R/S)-3-Methylamino-l -(2 -thienyl))-l
  • the present invention provides a process for preparing the specific enantiomer shown above as compound I in Schemes 1 and 2 above. It is named (S)-3-Methylamino- 1 -(2-thienyl)- 1 -propanol.
  • the resolution step of the present invention is prepared by adding 1 molar equivalent of 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid or (S)-(-)-2-pyrolidinone- 5-carboxylic acid, preferably 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid, to racemic (S)-3-Methylamino-l-(2-thienyl)-l-propanol in an organic solvent at room temperature, yielding after crystallization a mixture of diastereomeric salts.
  • the organic solvent may be, for example, isopropanol, tetrahydrofuran, acetone or ethyl acetate.
  • Isopropanol. is the preferred solvent. If the resolution is performed as part of a process which later involves crystallization of (S)-3-methylamino-l-(2-thienyl)-l -propanol, the above solvent is a first organic solvent. Diastereomerically enriched crystals are obtained by additional crystallizations. Example 1, below, illustrates this procedure in detail. Chiral analysis was done by capillary electrophoresis(ce) and the results summarized in Table 1 below.
  • This process or another acid catalysis can be used to recycle the mixture of salts of (S)-3-Methylamino-di-O-isopropylidene-2-keto-L-gulonic acid enriched in the unwanted stereoisomer.
  • a second order asymmetric induced crystallization was achieved by performing the optical resolution of racemic (S)-3 -Methylamino- 1 -2-thienyl)- 1 -propanol with 1 equivalent of 2,3,4,6,-di-O-isopropylidene-2-keto-L-gulonic acid in an organic solvent such as isopropanol, tetrahydrofuran, acetone or ethyl acetate, preferably isopropanol, at 40°C, and the reaction mixture left agitated at that temperature for 66 hours.
  • the organic solvent used in the crystallization step is a second organic solvent.
  • An example is provided below.
  • Analysis of the mass balance of each diastereomer (crystal + mother liquors), shows that a second order asymmetric induced crystallization occurred during this optical resolution process.
  • the advantage of the present invention is found in its ability to prepare the desired product in high optical purity, with very little racemization, in short periods of time with resolution via diastereomeric salt formation as described above.
  • the synthesis of duloxetine is discussed in detail by Deeter, et al., in Tetrahedron Letters, 31(49), 7101-7104 (1990). Further synthetic Schemes 1 and 2 above, both of which are described in the prior art, provide enablement for making the racemic starting material for the current invention.
  • Demethylation of the dimethylamino intermediate maybe achieved by, for example, protecting the alcohol as a carbonate and using additional chloroformate to demethylate intermediate C above in Scheme 4 by organic chemistry methods shown in the art.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

This invention provides a process for the synthesis of (S)-3-Methylamino-1-2-thienyl)-1-propanol, a key intermediate in the synthesis of duloxetine.

Description

PROCESS FOR PREPARING AN INTERMEDIATE USEFUL FOR THE ASYMMETRIC SYNTHESIS OF DULOXETINE
BACKGROUND OF THE INVENTION This invention belongs to the fields of pharmaceutical chemistry and synthetic organic chemistry, and provides a process for the synthesis of a key intermediate in the preparation of duloxetine, (+) N-methyl-3(l-naphthalenyloxy)-3-(2-thienyl)propanamine, hydrochloric acid salt.
Duloxetine is a pharmaceutical now under development as an anti-depressant. It inhibits the uptake of both norepinephrine and serotonin and is presently in clinical evaluation. The compound was disclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388 by Robertson, et al. and the synthesis of it was discussed in more detail by Berglund, R.A., Org. Proc. Res. Devel, 1, 328 (1997) and Deeter, et al., In Tetrahedron Letters, 31(40), 7101-04 (1990) and aspects patented in U.S. Patent Nos. 5,362,886 and 5,491,243. Synthetic schemes and processes have been reported for conversion to duloxetine.
Two particular reported synthetic schemes in Liu, H.; Hoff, B.H.; Authonsen, T. Chirality, 12, 26 (2000) and Wheeler, W.J.; Kuo, F.S. Labelled Compd. Radiopharm., 36, 213 (1995), have a common chloroalcohol intermediate. In both cases this chloroalcohol intermediate is converted to an aminoalcohol, in two steps and then arylated to give duloxetine. These processes, as reported in the above articles, are outlined in Schemes 1 and 2.
Scheme 1
1 ) NaBHd Reduction
Figure imgf000002_0002
Figure imgf000002_0001
2) Enzymatic
Chloroketone Resolution (S)-c loroalcohol
Arylation
Duloxetine HCI
Figure imgf000002_0003
Scheme 2
Figure imgf000003_0001
Arylation
Chiral ». — Duloxetine HCI
Reduction
Figure imgf000003_0002
Although the arylation of (S)-3-Methylamino-l-(2-thienyl)-l-propanol, compound I in in Schemes 1 and 2, has been disclosed, its resolution via diastereomeric salt formation has not been shown . Further, while Racemic ((R/S)-3-Methylamino-l-(2- thienyl))-l -propanol has been disclosed in Bopp, R.J.; Kennedy, J. H., LC-GC, 5, 514 (1998), the resolution of this key intermediate has not been successful.
The present invention provides improved conditions for carrying out the resolution of ((R/S)-3-Methylamino-l-(2-thienyl))-l-propanol whereby resolved compound I is obtained in greater enantiomeric purity and yield than has previously been possible.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thienyl)-propanamine comprising resolving racemic ((S)-3- Methylamino-l-(2-thienyl))-l -propanol with 2,3,4,6-di-O-isopropylidene-2-keto-L- gulonic acid or S-(-)-2-pyrrolidone-5-carboxylic acid in a first organic solvent, and if desired, racemizing a stereomericalry enriched mixture in an isopropanol/hydrochloric acid mixture; and if desired, crystallizing (S)-3-Methylamino-l-(2-thienyl)-l -propanol by resolving racemic ((R/S)-3-Methylamino-l -(2 -thienyl))-l -propanol with 2,3,4,6-di-O- isopropylidene-2-keto-L-gulonic acid in a third organic solvent.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention provides a process for preparing the specific enantiomer shown above as compound I in Schemes 1 and 2 above. It is named (S)-3-Methylamino- 1 -(2-thienyl)- 1 -propanol. The resolution step of the present invention is prepared by adding 1 molar equivalent of 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid or (S)-(-)-2-pyrolidinone- 5-carboxylic acid, preferably 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid, to racemic (S)-3-Methylamino-l-(2-thienyl)-l-propanol in an organic solvent at room temperature, yielding after crystallization a mixture of diastereomeric salts. The organic solvent may be, for example, isopropanol, tetrahydrofuran, acetone or ethyl acetate. Isopropanol. is the preferred solvent. If the resolution is performed as part of a process which later involves crystallization of (S)-3-methylamino-l-(2-thienyl)-l -propanol, the above solvent is a first organic solvent. Diastereomerically enriched crystals are obtained by additional crystallizations. Example 1, below, illustrates this procedure in detail. Chiral analysis was done by capillary electrophoresis(ce) and the results summarized in Table 1 below.
Table 1 Optical resolution and purification of racemic (S)-3-Methylamino-l-(2-thienyl)-l- propanol in isopropanol.
Figure imgf000004_0001
ML= mother liquor
The enriched diastereomer salts (diasteromeric excess (d.e.) = 78%) were obtained with 33 % overall yield. The optical resolution of (S)-3-Methylamino-l-(2-thienyl)-l- propanol (d.e. = 78%) measured in methanol is [α]D 25 = -9.6 (MeOH, C = 4.4). The sign and the value of this optical rotation compared with the literature value [α]π25 = -12.5 (MeOH, C = 4.4), Huiling Liu, Bard, Helge, Hoff and Thorleif Authorsen, Chirality, 12, 26-29 (2000) of the (S) enantiomer demonstrates that the wanted stereomer is obtained with the resolving agent 2,3 ,4,6-di-O-isopropylidene-2-keto-(-gulonic acid with an optical purity of 76.8%. Additional crystallization steps would be necessary to obtain optical pure (S)-3 -methylamino- 1 -(2-thienyl)- 1-1 -propanyl .
The racemization step of (S)-3-Methylamino-l-(2-thienyl)-l-propanol is achieved by partially racemizing a stereomerically enriched mixture (d.e. = 76%) of (S)-3- Methylamino- 1 -(2-thienyl)- 1 -propanol (as a salt form with 2,3 ,4,6-di-O-isopropylidene-2- keto-L-gulonic acid) in isopropanol/hydrochloric acid mixture at room temperature as shown in Example 2 below. This process or another acid catalysis can be used to recycle the mixture of salts of (S)-3-Methylamino-di-O-isopropylidene-2-keto-L-gulonic acid enriched in the unwanted stereoisomer. Finally a second order asymmetric induced crystallization was achieved by performing the optical resolution of racemic (S)-3 -Methylamino- 1 -2-thienyl)- 1 -propanol with 1 equivalent of 2,3,4,6,-di-O-isopropylidene-2-keto-L-gulonic acid in an organic solvent such as isopropanol, tetrahydrofuran, acetone or ethyl acetate, preferably isopropanol, at 40°C, and the reaction mixture left agitated at that temperature for 66 hours. If the crystallization is performed after the resolution step described above, the organic solvent used in the crystallization step is a second organic solvent. An example is provided below. The diastereomeric crystals were obtained with a yield of 76% (diastereomeric composition (-)/(+) = 88%/12%); (M.L.: yield = 18%, d.e. = 50%, (diastereomeric composition (-)/(+)( = 25%/75%)). Analysis of the mass balance of each diastereomer (crystal + mother liquors), shows that a second order asymmetric induced crystallization occurred during this optical resolution process. These results show the formation of the desired diastereomer at the expense of the unwanted one.
Example 1
Optical Resolution
To the free base racemic (S)-3 -Methylamino- 1 -(2-thienyl)- 1 -propanol (1 g) dissolved in isopropanol (45 ml) was added the 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid (1.634 g) at room temperature and stirred for 4 hours.
The resulting salt is filtrated and dried under reduced pressure at 40°C to yield 1.945 g. of a white solid (y = 74%, d.e. = 12%). Optical purifications
The resulting solid of Example 1 (1.873 g, d.e. = 12%) is suspended in isopropanol (82 ml) and stirred at room temperature for 69 hours.
The suspension is filtrated, dried under vacuum at 40°C to yield 1.483 g of the diastereomeric salt (y = 79%, d.e. = 24%). The resulting solid (1.382 g, d.e. = 24%) is suspended in isopropanol (159 ml) and stirred at room temperature for 16 hours. The suspension is filtrated, dried under vacuum at 40°C to yield 0.803 g of the diastereomeric salt (y = 58%, d.e. = 78%)
Example 2
Racemization procedure
To the diastereomeric salt (d.e. = 75%) suspended in isopropanol (1 ml) was added HC1 IN (216 L). At that time solubilization of the salt occurred. The reaction mixture was stirred for 2 hours 30 minutes and concentrated under vacuum. The resulting solid has a d.e. = 32% (CE analysis).
Example 3
Second order induced crystallization
To the free base racemic (S)-3-Methylamino-l-(2-thienyl)-l-propanol (1 g) dissolved in isopropanol (31.3 ml) was added the 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid (1.634 g) at room temperature. The reaction mixture was heated to 40°C and stirred for 66 hours at that temperature. After cooling to room temperature, the solid was filtrated and dried under reduced pressure at 40°C, to yield 1.993 g of a white solid (yield = 76%, d.e. = 76%).
Analysis of the mass balance of each diastereomeric (crystal + mother liquors), shows that a second order asymmetric induced crystallization occurred during this optical resolution process. These results show the formation of the desired diastereomer at the expense of the unwanted one.
The advantage of the present invention is found in its ability to prepare the desired product in high optical purity, with very little racemization, in short periods of time with resolution via diastereomeric salt formation as described above. The synthesis of duloxetine is discussed in detail by Deeter, et al., in Tetrahedron Letters, 31(49), 7101-7104 (1990). Further synthetic Schemes 1 and 2 above, both of which are described in the prior art, provide enablement for making the racemic starting material for the current invention.
Briefly, as described in Scheme 2, the process described in Liu, H.; Hoff, B.H.; Anthonsen, T. Chirality, 12, 26 (2000), the (S)-chloroalcohol is derived from a Friedel- Crafts reaction of thiophene and 3-chloropropionyl chloride. The chloroketone was reduced and the racemic alcohol is resolved enzymatically with immobilized Candida Antarctica Lipase B to give (S)-chloroalcohol in 35%. Yield (97% enantiomeric excess). See Liu et, al.
In Scheme 2 above, Wheeler, W.J.; Kuo, F.J. Labelled Compound Radiopharm., 36, 213 (1995) took a longer route to prepare "C -labeled duloxetine." The chloroketone was reduced with a chiral borane reagent to give the (S)-chloroalcohol directly in 85% yield. Iodination and amination as before complete the synthesis of duloxetine.
A final route to either optically pure or racemic (S)-3-Methylamino-l-(2-thienyl)- 1 -propanol employs demethylation of the dimethylamino intermediate as shown below in Scheme 3 and 4. Precedent for the final route may be found in U.S. Patent No. 5,225,585.
Scheme 3
Figure imgf000007_0001
annich ketone racemic
Path A
Chiral Reduction/ Path B
Resolution
S-(+)- Mandelic acid
Figure imgf000007_0002
Free Base andelate
Figure imgf000008_0001
In Scheme 3 above, the starting material 2-acetylthiophene is converted to the Mannich ketone as described in Blicke, F.F.; Berckhalter, S.H., J. Amer. Chem. Soc, 64, 451 (1941). The ketone is reduced to give racemic amino alcohol as described in Nalenta, N.; Nilkova, M.; Valchar, M.; Dobrovsky, K.; Polivka, 7, Collect Czech. Chem. Commun. 1991, 56, 1525; Jakobsen, P.; Kanstrup, A.; Lundbeck, J.M., Eur. Pat. Appl. EP 571,685, 1993 and Klosa, J., J. Prakt. Chem., 1966, 34, 312 (Path A). Alternatively, the Mannich ketone can be reduced with chiral reducing agent to give the chiral S-amino alcohol directly (Path B).
Demethylation of the dimethylamino intermediate maybe achieved by, for example, protecting the alcohol as a carbonate and using additional chloroformate to demethylate intermediate C above in Scheme 4 by organic chemistry methods shown in the art.
While the racemic compound I shown below as disclosed in Bopp, R. J. Kennedy, J.H., LC-GC, 6, 514 (1988), the resolution of this key intermediate has not been accomplished. The present invention achieves this resolution with high optical purity.
Figure imgf000008_0002

Claims

WE CLAIM :
1. A process for preparing (S)-3-Methylamino-l-(2-thienyl)-l-propanol comprising: resolving racemic - (S)-3-Methylamino-l-(2-thienyl)-l-propanol with (S)-(-)-2- pyrroliodone-5-carboxylic acid or 2,3,4,5-di-O-isopropylidine-2-keto-L-gulonic acid in a first organic solvent; racemizing a stereomerically enriched mixture; and crystallizing (S)-3- Methylamino-1 -(2-thienyl)- 1 -propanol by resolving racemic (S)-3-Methylamino- 1 -(2-thienyl)- 1 -propanol with 2,3 ,4,6-di-O-isopropylidine in a second organic solvent.
2. The process of Claim 1 wherein the resolution of racemic (S)-3- Methylamino-1 -(2-thienyl)- 1 -propanol is with 2,3,4,6-di-O-isopropylidine-2-keto-L- gulonic acid.
3. The process of any one of Claims 1 or 2 wherein the first organic solvent is selected from isopropanol, tetrahydrofuran, acetone or ethyl acetate.
4. The process of any one of Claims 1 , 2 or 3 wherein the first organic solvent is isopropanol.
5. The process of any one of Claims 1 through 4 wherein the second organic solvent is selected from isopropanol, tetrahydrofuran, acetone or ethyl acetate.
6. The process of any one of Claims 1 through 5 wherein the second organic solvent is isopropanol.
PCT/US2003/000018 2002-01-24 2003-01-13 Process for preparing an intermediate useful for the asymmetric synthesis of duloxetine WO2003062219A1 (en)

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WO2004056795A1 (en) * 2002-12-19 2004-07-08 Cipla Ltd A process for preparing duloxetine and intermediates for use therein
EP1510517A1 (en) * 2003-09-01 2005-03-02 Lonza AG Process for the asymmetric hydrogenation of beta-amino ketones
WO2005019199A1 (en) * 2003-08-25 2005-03-03 Hetero Drugs Limited Amorphous duloxetine hydrochloride
WO2008004191A2 (en) 2006-07-03 2008-01-10 Ranbaxy Laboratories Limited Process for the preparation of enantiomerically pure salts of n-methyl-3- ( 1-naphthaleneoxy) -3- (2-thienyl) propanamine
EP1976844A4 (en) * 2006-01-06 2010-11-03 Msn Lab Ltd Improved process for pure duloxetine hydrochloride
US7928250B2 (en) 2006-12-22 2011-04-19 Synthon Bv Process for making duloxetine and related compounds
WO2011128370A1 (en) 2010-04-13 2011-10-20 Krka, D.D., Novo Mesto Synthesis of duloxetine and/or pharmaceutically acceptable salts thereof
US8288141B2 (en) 2008-08-27 2012-10-16 Codexis, Inc. Ketoreductase polypeptides for the production of 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
US8426178B2 (en) 2008-08-27 2013-04-23 Codexis, Inc. Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine
CN108341797A (en) * 2017-01-25 2018-07-31 重庆常捷医药有限公司 A kind of novel synthesis of duloxetine intermediate

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WO2004056795A1 (en) * 2002-12-19 2004-07-08 Cipla Ltd A process for preparing duloxetine and intermediates for use therein
US7645890B2 (en) 2002-12-19 2010-01-12 Cipla Limited Process for preparing duloxetine and intermediates for use therein
WO2005019199A1 (en) * 2003-08-25 2005-03-03 Hetero Drugs Limited Amorphous duloxetine hydrochloride
EP1510517A1 (en) * 2003-09-01 2005-03-02 Lonza AG Process for the asymmetric hydrogenation of beta-amino ketones
WO2005021527A2 (en) * 2003-09-01 2005-03-10 Lonza Ag Process for the asymmetric hydrogenation of beta-amino ketones
WO2005021527A3 (en) * 2003-09-01 2005-07-14 Lonza Ag Process for the asymmetric hydrogenation of beta-amino ketones
EP1976844A4 (en) * 2006-01-06 2010-11-03 Msn Lab Ltd Improved process for pure duloxetine hydrochloride
WO2008004191A2 (en) 2006-07-03 2008-01-10 Ranbaxy Laboratories Limited Process for the preparation of enantiomerically pure salts of n-methyl-3- ( 1-naphthaleneoxy) -3- (2-thienyl) propanamine
US7928250B2 (en) 2006-12-22 2011-04-19 Synthon Bv Process for making duloxetine and related compounds
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