WO2009074883A2 - Improved process for preparing duloxetine - Google Patents
Improved process for preparing duloxetine Download PDFInfo
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- WO2009074883A2 WO2009074883A2 PCT/IB2008/003875 IB2008003875W WO2009074883A2 WO 2009074883 A2 WO2009074883 A2 WO 2009074883A2 IB 2008003875 W IB2008003875 W IB 2008003875W WO 2009074883 A2 WO2009074883 A2 WO 2009074883A2
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- Prior art keywords
- duloxetine
- approximately
- organic solvent
- dmso
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- 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 claims abstract description 30
- 229960002866 duloxetine Drugs 0.000 title claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- -1 alkoxide salt Chemical class 0.000 claims description 10
- 229960002496 duloxetine hydrochloride Drugs 0.000 claims description 9
- JFTURWWGPMTABQ-UHFFFAOYSA-N n,n-dimethyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine Chemical compound C=1C=CC2=CC=CC=C2C=1OC(CCN(C)C)C1=CC=CS1 JFTURWWGPMTABQ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003880 polar aprotic solvent Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 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 4
- CWLKTJOTWITYSI-UHFFFAOYSA-N 1-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=CC2=C1 CWLKTJOTWITYSI-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 239000012456 homogeneous solution Substances 0.000 claims description 4
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 abstract description 18
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract description 9
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- 239000012312 sodium hydride Substances 0.000 abstract description 9
- 229910000104 sodium hydride Inorganic materials 0.000 abstract description 9
- 239000008240 homogeneous mixture Substances 0.000 abstract description 2
- 239000002585 base Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000006254 arylation reaction Methods 0.000 description 3
- 208000024714 major depressive disease Diseases 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 206010066218 Stress Urinary Incontinence Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940029644 cymbalta Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 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
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
Definitions
- the invention relates to an improved process for preparing duloxetine.
- Duloxetine hydrochloride (Compound I) is the international commonly accepted name for N-methyl-N-[(3S)-(3-( l -naphthyloxy)-3-thien-2-yl)propyl]arnine hydrochloride (which is also known as methyl-[(S)-3-(naphthalene-l-yloxy)-3-thiophen-2- yl-propyl]amine) hydrochloride and has an empirical formula of CigHigNOS ⁇ Cl and a molecular weight of 333.88.
- Duloxetine hydrochloride is a commercially marketed pharmaceutically active substance known to be useful for the treatment of major depressive disorder.
- Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration.
- SSNRI norepinephrine reuptake inhibitor
- duloxetine hydrochloride is marketed under the name Cymbalta ® for the treatment of major depressive disorder and diabetic peripheral neuropathic pain.
- Cymbalta ® for the treatment of major depressive disorder and diabetic peripheral neuropathic pain.
- duloxetine hydrochloride has been approved for the treatment of major depressive disorder and also for the treatment of moderate to severe stress urinary incontinence.
- Duloxetine and its pharmaceutically acceptable salts are described in U.S.
- no examples related to the preparation of (S)-duloxetine, or one of its pharmaceutically acceptable salts ⁇ e.g., the hydrochloride salt) are disclosed.
- Sodium hydride is a strong base that can ignite in air, especially upon contact with water, producing hydrogen which is explosive.
- Sodium hydride is a very dangerous base which is difficult to handle and use, and can cause environmental and safety hazards.
- most of these processes to synthesize duloxetine also utilize DMSO.
- DMSO can form dimsyl anion when coupled with sodium hydride, which can cause racemization of the desired (S)-duloxetine product.
- S desired
- DMSO can form dimsyl anion when coupled with sodium hydride, which can cause racemization of the desired (S)-duloxetine product.
- the combination of sodium hydride with DMSO is particularly dangerous due to the unstable nature of dimsyl anion. The process disclosed above is shown, generally, in Scheme 1.
- No. 2007/0167636 A l describes the same process as Scheme 1 but using an organic solvent utilizing less DMSO, utilizing potassium hydroxide as an alternative base, and carrying out the reaction at a temperature of about 85 0 C.
- potassium hydroxide involves a number of drawbacks. Potassium hydroxide is not soluble in the reaction solvent, and therefore the reaction may be carried out in a heterogeneous mixture which makes the stirring of the reactants troublesome, consequently affecting the efficiency of the reaction. Further, the rate of reaction is also adversely affected, given that particles that form solids move much more slowly than those in solution, resulting in a decrease of the frequency of collisions between reactants.
- DMSO can act as a potential oxidizing agent at temperatures higher than 80 0 C, which may also cause an important reduction of the arylation reaction rate.
- the invention provides an improved process for preparing duloxetine.
- the invention provides an improved process for preparing duloxetine, efficiently and with good reaction rate, which is carried out in a homogeneous mixture, at a temperature lower than 80 0 C, in which chiral integrity is preserved, and neither sodium hydride nor potassium hydroxide is required.
- the invention relates to a process for preparing duloxetine in a homogeneous solution, comprising reacting (S)-3-methylamino-I -(2-thienyl)-l -propanol with a Q-C 6 alkoxide salt, and 1-fluoronaphtalene in an organic solvent or a mixture of organic solvents.
- Ci-C 6 alkoxide salt as a base overcomes drawbacks of known processes.
- the reaction can be carried out efficiently at a temperature lower than approximately 80 0 C, thus avoiding the oxidizing reactivity of DMSO.
- the Ci-C 6 alkoxide salt is soluble in organic solvents, the reaction is performed in a homogeneous solution, facilitating the stirring and contact of the reactants.
- the C]-C 6 alkoxide salt is preferably a Cs alkoxide salt (amylate salt), and more preferably is sodium /er/-pentoxide (sodium ?er/-amylate).
- the organic solvent is preferably a polar aprotic solvent or mixtures thereof, or a mixture of at least a polar aprotic solvent and at least a non-polar organic solvent.
- the polar aprotic solvent is preferably at least one of dimethyl sulfoxide
- DMSO dimethylformamide
- DMA N,N-dimethylacetamide
- DMPU 1.3-dimeth ⁇ l- 3A5.6-tetrahydro-2( l H)-pyrimidinone
- NMP N-methyl-2-pyrrolidone
- the non-polar organic solvent is preferably at least one of pentane, hexane, heptane, toluene, xylene, or mixtures thereof.
- the organic solvent is a mixture of DMSO and toluene.
- the process is preferably carried out at a temperature lower than approximately 80 0 C. More preferably, the process is carried out at a temperature of approximately 50 0 C.
- Another aspect of the invention includes the process described above further characterized by a product (i.e. (S)-duloxetine) in which the enantiomeric purity is greater than or equal to approximately 96:4 ratio of enantiomers, preferably greater than or equal to approximately 98:2, and more preferably greater than or equal to approximately 99.85:0.15.
- a product i.e. (S)-duloxetine
- the enantiomeric purity is greater than or equal to approximately 96:4 ratio of enantiomers, preferably greater than or equal to approximately 98:2, and more preferably greater than or equal to approximately 99.85:0.15.
- the process of the invention further includes the step of converting the obtained duloxetine into duloxetine hydrochloride by means of conventional methods already known in the art, including those described in WO 2007/096707, the disclosure of which is expressly incorporated herein by reference in its entirety.
- Another aspect of the invention includes a fo ⁇ nulation including duloxetine hydrochloride obtained according to the process of the invention.
- the flow rate was 0.5 mL per minute and the chromatograph was recorded at 220 run.
- Test samples (5 ⁇ L) were prepared by dissolving the appropriate amount of sample in the mobile phase in order to obtain 0.5 mg of sample per mL.
- the chromatogram was run for at least 25 minutes.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an improved process for preparing duloxetine. The invention provides an improved process for preparing duloxetine, efficiently and with good reaction rate, which is carried out in a homogeneous mixture, at a temperature lower than 80 °C, in which chiral integrity is preserved, and neither sodium hydride nor potassium hydroxide is required.
Description
IMPROVED PROCESS FOR PREPARING DULOXETINE CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The application claims priority to United States Provisional Application No.
60/985,882, filed November 6, 2007, which application is expressly incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
1. Field of the invention
[0002] The invention relates to an improved process for preparing duloxetine.
2. Related Art
[0003] Duloxetine hydrochloride (Compound I) is the international commonly accepted name for N-methyl-N-[(3S)-(3-( l -naphthyloxy)-3-thien-2-yl)propyl]arnine hydrochloride (which is also known as methyl-[(S)-3-(naphthalene-l-yloxy)-3-thiophen-2- yl-propyl]amine) hydrochloride and has an empirical formula of CigHigNOSΗCl and a molecular weight of 333.88. Duloxetine hydrochloride is a commercially marketed pharmaceutically active substance known to be useful for the treatment of major depressive disorder.
(I)
[0004] Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. In the United States, duloxetine hydrochloride is marketed under the name Cymbalta® for the treatment of major depressive disorder and diabetic peripheral neuropathic pain. In Europe, duloxetine hydrochloride has been approved for the treatment of major depressive disorder and also for the treatment of moderate to severe stress urinary incontinence.
[0005] Duloxetine and its pharmaceutically acceptable salts are described in U.S.
Patent No. 5,023,269. However, no examples related to the preparation of (S)-duloxetine, or one of its pharmaceutically acceptable salts {e.g., the hydrochloride salt), are disclosed.
[0006] There are several known methods for producing duloxetine and its salts.
Among others, the processes described in Wheeler et al., J. Label. Comp. Radiopharm., 36(3), 213-23 (1995); Bymaster et al., Bioorg. Med Chem. Lett., 13(24), 4477-4480 (2003) and Kamal et al., Tetrahedron Letters, 44(25), 4783-4787 (2003) describe the formation of duloxetine via arylation with 1 -fluoronaphthalene of enantiomerically-enriched intermediate compound (S)-3-methylamino-l -(2-thienyl)-l -propanol (Compound of Formula II). However, all these processes involve sodium hydride as a base. The use of sodium hydride has a number of disadvantages. Sodium hydride is a strong base that can ignite in air, especially upon contact with water, producing hydrogen which is explosive. Sodium hydride is a very dangerous base which is difficult to handle and use, and can cause environmental and safety hazards. Further, most of these processes to synthesize duloxetine also utilize DMSO. DMSO can form dimsyl anion when coupled with sodium hydride, which can cause racemization of the desired (S)-duloxetine product. In addition the combination of sodium hydride with DMSO is particularly dangerous due to the unstable nature of dimsyl anion. The process disclosed above is shown, generally, in Scheme 1.
Scheme 1
[0007] Aimed to overcome the above-described problems, U.S. Patent Application
No. 2007/0167636 A l describes the same process as Scheme 1 but using an organic solvent utilizing less DMSO, utilizing potassium hydroxide as an alternative base, and carrying out the reaction at a temperature of about 85 0C. However, the use of potassium hydroxide involves a number of drawbacks. Potassium hydroxide is not soluble in the reaction solvent, and therefore the reaction may be carried out in a heterogeneous mixture which makes the stirring of the reactants troublesome, consequently affecting the
efficiency of the reaction. Further, the rate of reaction is also adversely affected, given that particles that form solids move much more slowly than those in solution, resulting in a decrease of the frequency of collisions between reactants. Often differences in agitation efficiency between reactors can cause heterogeneous reaction processes to perform irreproducibly when changing scale. Additionally. DMSO can act as a potential oxidizing agent at temperatures higher than 80 0C, which may also cause an important reduction of the arylation reaction rate.
[0008] There is, therefore, a need for an improved process for preparing duloxetine via arylation of compound of Formula II, which may proceed in a homogeneous solution, at a temperature lower than approximately 80 0C, in which chiral integrity is preserved, and neither sodium hydride nor potassium hydroxide is required.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0009] The invention provides an improved process for preparing duloxetine.
[0010] The invention provides an improved process for preparing duloxetine, efficiently and with good reaction rate, which is carried out in a homogeneous mixture, at a temperature lower than 80 0C, in which chiral integrity is preserved, and neither sodium hydride nor potassium hydroxide is required.
[0011] In particular, the invention relates to a process for preparing duloxetine in a homogeneous solution, comprising reacting (S)-3-methylamino-I -(2-thienyl)-l -propanol with a Q-C6 alkoxide salt, and 1-fluoronaphtalene in an organic solvent or a mixture of organic solvents.
[0012] It has been surprisingly observed that the use of a Ci-C6 alkoxide salt as a base overcomes drawbacks of known processes. In particular, the reaction can be carried out efficiently at a temperature lower than approximately 80 0C, thus avoiding the oxidizing reactivity of DMSO. Additionally, because the Ci-C6 alkoxide salt is soluble in organic solvents, the reaction is performed in a homogeneous solution, facilitating the stirring and contact of the reactants.
[0013] The C]-C6 alkoxide salt is preferably a Cs alkoxide salt (amylate salt), and more preferably is sodium /er/-pentoxide (sodium ?er/-amylate).
[0014] The organic solvent is preferably a polar aprotic solvent or mixtures thereof, or a mixture of at least a polar aprotic solvent and at least a non-polar organic solvent.
[0015] The polar aprotic solvent is preferably at least one of dimethyl sulfoxide
(DMSO), dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1.3-dimethγl- 3A5.6-tetrahydro-2( l H)-pyrimidinone (DMPU), N-methyl-2-pyrrolidone (NMP), or mixtures thereof.
[0016] The non-polar organic solvent is preferably at least one of pentane, hexane, heptane, toluene, xylene, or mixtures thereof.
[0017] More preferably, the organic solvent is a mixture of DMSO and toluene.
[0018] The process is preferably carried out at a temperature lower than approximately 80 0C. More preferably, the process is carried out at a temperature of approximately 50 0C.
[0019] Another aspect of the invention includes the process described above further characterized by a product (i.e. (S)-duloxetine) in which the enantiomeric purity is greater than or equal to approximately 96:4 ratio of enantiomers, preferably greater than or equal to approximately 98:2, and more preferably greater than or equal to approximately 99.85:0.15.
[0020] In another aspect, the process of the invention further includes the step of converting the obtained duloxetine into duloxetine hydrochloride by means of conventional methods already known in the art, including those described in WO 2007/096707, the disclosure of which is expressly incorporated herein by reference in its entirety.
[0021] Another aspect of the invention includes a foπnulation including duloxetine hydrochloride obtained according to the process of the invention.
[0022] It will be apparent to those skilled in the art that various modifications and variations can be made in the invention and specific example provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
[0023] The following example is for illustrative purposes only and is not intended, nor should it be interpreted to, limit the scope of the invention.
EXAMPLES [0024] General Experimental Conditions:
[0025] HPLC Chiral Method
[0026] The chromatographic separation was carried out in a Daicel CHIRALCEL
OD-RH, 5 μm, 4.6 x 150 mm column at room temperature (20-25 0C).
[0027] The mobile phase was prepared by mixing 600 mL of acetonitrile with 400 mL of buffer (pH = 2) which was prepared from 18.40 g of hexafluorophosphate dissolved in 1000 mL of water. The pH was adjusted to 2 with phosphoric acid. The mobile phase was mixed and filtered through a 0.22 μm nylon membrane under vacuum.
[0028] The flow rate was 0.5 mL per minute and the chromatograph was recorded at 220 run. Test samples (5 μL) were prepared by dissolving the appropriate amount of sample in the mobile phase in order to obtain 0.5 mg of sample per mL. The chromatogram was run for at least 25 minutes.
[0029] Example 1: Preparation of Duloxetine
[0030] To (S)-3-methylamino-l -(2-thienyl)-l-propanol ( Ig, 5.84 mmol) in DMSO
(10 mL) is added sodium tert-pentoxide (50% sol. in toluene, 1.46 mL, 5.84 mmol), and the mixture heated to 50 0C and stirred for 1 hour. 1-Fluoronaphthalene ( 1.024 g, 7.01 mmol) is added and the mixture stirred at 50 0C for 23 hours. The mixture is cooled and partitioned between water ( 15 mL) and iso-propyl acetate ( 15 mL). The aqueous layer is extracted with iso-propyl acetate, the organic layers are combined, washed with water ( 10 mL) and concentrated to give duloxetine free base as an oil, 1 .25 g (72%). Chiral HPLC shows 92% ee.
[0031] Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the disclosure has been made only by way of example, and that numerous changes in the conditions and order of steps can be resorted to by those skilled in the art without departing from the spirit and scope of the invention.
Claims
1. A process for preparing duloxetine in a homogeneous solution comprising reacting (S)-3-methylamino-l-(2-thienyl)-l-propanol with a Ci-Cβ alkoxide salt and 1- fluoronaphtalene in at least one organic solvent.
2. The process of claim 1, wherein the CI-CO alkoxide salt is a C5 alkoxide salt (amylate salt).
3. The process of claim 1, wherein the CI -CO alkoxide salt is sodium ter/-pentoxide (sodium terr-amylate).
4. The process of claim 1, wherein the at least one organic solvent is at least one of a polar aprotic solvent, a non-polar organic solvent, and mixtures thereof.
5. The process of claim 4, wherein the polar aprotic solvent is at least one of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N.N-dimethylacetamide (DMA), 1, 3 -dimethyl - 3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), N-methyl-2-pyrrolidone (ΝMP), and mixtures thereof.
6. The process of claim 4, wherein the non-polar organic solvent is at least one of pentane, hexane, heptane, toluene, xylene, and mixtures thereof.
7. The process of claim 1 , wherein the at least one organic solvent is a mixture of DMSO and toluene.
8. The process of claim 1, wherein the process is carried out at a temperature lower than approximately 80 0C.
9. The process of claim 1, wherein the process is carried out at a temperature of approximately 50 0C.
10. (S)-duloxetine obtained according to the process of any of claims 1-9.
11. The (S)-duloxetine of claim 10, wherein said (S)-duloxetine has an enantiomeric ratio of greater than or equal to approximately 96:4.
12. The (S)-duloxetine of claim 10, wherein said (S)-duloxetine has an enantiomeric ratio of greater than or equal to approximately 98:2.
13. The (S)-duloxetine of claim 10, wherein said (S)-duloxetine has an enantiomeric ratio of greater than or equal to approximately 99.85:0.15.
14. The process of claim 1 further comprising the step of converting the obtained duloxetine into duloxetine hydrochloride.
15. Duloxetine hydrochloride prepared according to the process of claim 14.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US98588207P | 2007-11-06 | 2007-11-06 | |
| US60/985,882 | 2007-11-06 |
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| Publication Number | Publication Date |
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| WO2009074883A2 true WO2009074883A2 (en) | 2009-06-18 |
| WO2009074883A3 WO2009074883A3 (en) | 2009-08-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2008/003875 WO2009074883A2 (en) | 2007-11-06 | 2008-11-06 | Improved process for preparing duloxetine |
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| Country | Link |
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| WO (1) | WO2009074883A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2386549A1 (en) * | 2010-05-10 | 2011-11-16 | SCI Pharmatech, Inc. | Process for preparing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine by using an optically active methylhydroxylaminopropanol compound as intermediate |
| JP2011236195A (en) * | 2010-05-06 | 2011-11-24 | Sci Pharmatech Inc | Process for preparing (s)-(+)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine using optically active methylhydroxylaminopropanol compound as intermediate |
| WO2013056809A1 (en) | 2011-10-17 | 2013-04-25 | Pharmathen S.A. | Process for the preparation of highly pure duloxetine hydrochloride |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006126213A1 (en) * | 2005-05-24 | 2006-11-30 | Matrix Laboratories Ltd | An improved process for the preparation of duloxetine |
| US7538232B2 (en) * | 2006-01-19 | 2009-05-26 | Eli Lilly And Company | Process for the asymmetric synthesis of duloxetine |
| BRPI0707724A2 (en) * | 2006-02-13 | 2011-05-10 | Teva Pharma | a new process for the preparation of (()) - (+) - n, n-dimethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine), a duloxetine intermediate |
-
2008
- 2008-11-06 WO PCT/IB2008/003875 patent/WO2009074883A2/en active Application Filing
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011236195A (en) * | 2010-05-06 | 2011-11-24 | Sci Pharmatech Inc | Process for preparing (s)-(+)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine using optically active methylhydroxylaminopropanol compound as intermediate |
| EP2386549A1 (en) * | 2010-05-10 | 2011-11-16 | SCI Pharmatech, Inc. | Process for preparing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine by using an optically active methylhydroxylaminopropanol compound as intermediate |
| WO2013056809A1 (en) | 2011-10-17 | 2013-04-25 | Pharmathen S.A. | Process for the preparation of highly pure duloxetine hydrochloride |
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| Publication number | Publication date |
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| WO2009074883A3 (en) | 2009-08-06 |
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