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 PDFInfo
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- 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
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 229960002866 duloxetine Drugs 0.000 title abstract description 12
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 title abstract description 11
- 238000011914 asymmetric synthesis Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- YEJVVFOJMOHFRL-ZETCQYMHSA-N (1s)-3-(methylamino)-1-thiophen-2-ylpropan-1-ol Chemical compound CNCC[C@H](O)C1=CC=CS1 YEJVVFOJMOHFRL-ZETCQYMHSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- YEJVVFOJMOHFRL-UHFFFAOYSA-N 3-(methylamino)-1-thiophen-2-ylpropan-1-ol Chemical compound CNCCC(O)C1=CC=CS1 YEJVVFOJMOHFRL-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 229960005335 propanol Drugs 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 238000006254 arylation reaction Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 2
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 description 2
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- JFTURWWGPMTABQ-SFHVURJKSA-N (3s)-n,n-dimethyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCN(C)C)=CC=CS1 JFTURWWGPMTABQ-SFHVURJKSA-N 0.000 description 1
- 229940044613 1-propanol Drugs 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- UNUUERBHCKDOEI-UHFFFAOYSA-N CNCCCc1ccc[s]1 Chemical compound CNCCCc1ccc[s]1 UNUUERBHCKDOEI-UHFFFAOYSA-N 0.000 description 1
- 108010031797 Candida antarctica lipase B Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ZEUITGRIYCTCEM-UHFFFAOYSA-N duloxetine Chemical compound C=1C=CC2=CC=CC=C2C=1OC(CCNC)C1=CC=CS1 ZEUITGRIYCTCEM-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
Classifications
-
- 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
2) Enzymatic
Chloroketone Resolution (S)-c loroalcohol
Arylation
Duloxetine HCI
Arylation
Chiral ». — Duloxetine HCI
Reduction
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.
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
Path A
Chiral Reduction/ Path B
Resolution
S-(+)- Mandelic acid
Free Base andelate
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.
Claims
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.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/500,829 US20040249170A1 (en) | 2002-01-24 | 2003-01-13 | Process for preparing an intermediate useful for the asymmetric synthesis of duloxetine |
| EP03707289A EP1478641A1 (en) | 2002-01-24 | 2003-01-13 | Process for preparing an intermediate useful for the asymmetric synthesis of duloxetine |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35162202P | 2002-01-24 | 2002-01-24 | |
| US60/351,622 | 2002-01-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003062219A1 true WO2003062219A1 (en) | 2003-07-31 |
Family
ID=27613516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2003/000018 WO2003062219A1 (en) | 2002-01-24 | 2003-01-13 | Process for preparing an intermediate useful for the asymmetric synthesis of duloxetine |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US20040249170A1 (en) |
| EP (1) | EP1478641A1 (en) |
| WO (1) | WO2003062219A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1730132A2 (en) * | 2004-12-23 | 2006-12-13 | Teva Pharmaceutical Industries Ltd | Process for preparing pharmaceutically acceptable salts of duloxetine and intermediates thereof |
| EP1856087A1 (en) * | 2005-03-08 | 2007-11-21 | Teva Pharmaceutical Industries Limited | Crystal forms of (s)-(+)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate and the preparation thereof |
| WO2006099457A1 (en) * | 2005-03-14 | 2006-09-21 | Teva Pharmaceutical Industries Ltd. | (s)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine-di-p-toluoyl-l-tartarate and methods of preparation thereof |
| WO2007067581A1 (en) * | 2005-12-05 | 2007-06-14 | Teva Pharmaceutical Industries Ltd. | 2-(n-methyl-propanamine)-3-(2-naphthol) thiophene, an impurity of duloxetine hydrochloride |
| EP1844034A1 (en) * | 2006-01-23 | 2007-10-17 | Teva Pharmaceutical Industries Ltd | Dnt-fumarate and methods of preparation thereof |
| CN101448815A (en) * | 2006-05-23 | 2009-06-03 | 特瓦制药工业有限公司 | Duloxetine HCI polymorphs |
| HU227730B1 (en) | 2006-12-22 | 2012-01-30 | Richter Gedeon Nyrt | Process for the preparation of duloxetine and for their the intermediates |
| WO2009147687A2 (en) * | 2008-06-03 | 2009-12-10 | Shodhana Laboratories Limited | An improved process for the separation of enantiomerically pure compounds |
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| US4956388A (en) * | 1986-12-22 | 1990-09-11 | Eli Lilly And Company | 3-aryloxy-3-substituted propanamines |
| US6245804B1 (en) * | 1997-05-30 | 2001-06-12 | Schering Aktiengesellschaft | Nonsteroidal gestagens |
| AU3877500A (en) * | 1999-04-09 | 2000-11-14 | Eli Lilly And Company | Methods for preparing 3-aryloxy-3-arylpropylamines and intermediates thereof |
| CA2415678A1 (en) * | 2000-07-13 | 2003-01-10 | Sankyo Company Limited | Amino alcohol derivatives |
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2003
- 2003-01-13 WO PCT/US2003/000018 patent/WO2003062219A1/en not_active Application Discontinuation
- 2003-01-13 EP EP03707289A patent/EP1478641A1/en not_active Withdrawn
- 2003-01-13 US US10/500,829 patent/US20040249170A1/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3855227A (en) * | 1972-05-08 | 1974-12-17 | C Hollander | ({31 )-di-o-isopropylidene-2-keto-l-gulonates |
| US4036852A (en) * | 1974-10-23 | 1977-07-19 | Stamicarbon B.V. | Optical resolution of phenyl-glycine amide |
| US5023569A (en) * | 1989-06-29 | 1991-06-11 | Motorola, Inc. | Variable gain amplifier |
| US5362886A (en) * | 1993-10-12 | 1994-11-08 | Eli Lilly And Company | Asymmetric synthesis |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| US8877475B2 (en) | 2008-08-27 | 2014-11-04 | Codexis, Inc. | Polynucleotides encoding engineered ketoreductase polypeptides |
| 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 |
| US8673607B2 (en) | 2008-08-27 | 2014-03-18 | Codexis, Inc. | Ketoreductase polypeptides for the production of a 3-aryl-3-hydroxypropanamine from a 3-aryl-3-ketopropanamine |
| US9228213B2 (en) | 2008-08-27 | 2016-01-05 | Codexis, Inc. | Polynucleotides encoding engineered ketoreductase polypeptides |
| US9657320B2 (en) | 2008-08-27 | 2017-05-23 | Codexis, Inc. | Engineered ketoreductase polypeptides |
| US10006069B2 (en) | 2008-08-27 | 2018-06-26 | Codexis, Inc. | Engineered ketoreductase polypeptides |
| US10752926B2 (en) | 2008-08-27 | 2020-08-25 | Codexis, Inc. | Engineered ketoreductase polypeptides |
| US11512332B2 (en) | 2008-08-27 | 2022-11-29 | Codexis, Inc. | Engineered ketoreductase polypeptides |
| WO2011128370A1 (en) | 2010-04-13 | 2011-10-20 | Krka, D.D., Novo Mesto | Synthesis of duloxetine and/or pharmaceutically acceptable salts thereof |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20040249170A1 (en) | 2004-12-09 |
| EP1478641A1 (en) | 2004-11-24 |
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