ZA200205023B - Method for preparation of citalopram. - Google Patents
Method for preparation of citalopram. Download PDFInfo
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- ZA200205023B ZA200205023B ZA200205023A ZA200205023A ZA200205023B ZA 200205023 B ZA200205023 B ZA 200205023B ZA 200205023 A ZA200205023 A ZA 200205023A ZA 200205023 A ZA200205023 A ZA 200205023A ZA 200205023 B ZA200205023 B ZA 200205023B
- Authority
- ZA
- South Africa
- Prior art keywords
- isobenzofuran
- reaction
- formula
- nacn
- catalyst
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 12
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 title description 14
- 229960001653 citalopram Drugs 0.000 title description 14
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 14
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 10
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- UBRQBEBBOSKYLQ-UHFFFAOYSA-N 5-chloro-3h-2-benzofuran-1-one Chemical compound ClC1=CC=C2C(=O)OCC2=C1 UBRQBEBBOSKYLQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000002608 ionic liquid Substances 0.000 claims description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims 3
- CQAKANQMFXBJJQ-UHFFFAOYSA-N 5-iodo-3h-2-benzofuran-1-one Chemical compound IC1=CC=C2C(=O)OCC2=C1 CQAKANQMFXBJJQ-UHFFFAOYSA-N 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 2
- 239000007858 starting material Substances 0.000 claims 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 239000011701 zinc Substances 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000000538 analytical sample Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XEEGWTLAFIZLSF-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carbonitrile Chemical compound N#CC1=CC=C2C(=O)OCC2=C1 XEEGWTLAFIZLSF-UHFFFAOYSA-N 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- IUSPXLCLQIZFHL-UHFFFAOYSA-N 5-bromo-3h-2-benzofuran-1-one Chemical compound BrC1=CC=C2C(=O)OCC2=C1 IUSPXLCLQIZFHL-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical group 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WSEQXVZVJXJVFP-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 description 1
- BXRVAIYLQLSKIJ-UHFFFAOYSA-N 3-iodo-3h-2-benzofuran-1-one Chemical compound C1=CC=C2C(I)OC(=O)C2=C1 BXRVAIYLQLSKIJ-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- NOYCNNBKNIAAHS-UHFFFAOYSA-N FC1=CC=C([Mg])C=C1 Chemical compound FC1=CC=C([Mg])C=C1 NOYCNNBKNIAAHS-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
R WO 01/49672 PCT/DK99/00740 : Method for the Preparation of Citalopram
The present invention relates to a method for the preparation of key intermediates in the ‘ process for the preparation of the well known antidepressant drug citalopram, 1-[3- (dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
Citalopram is a well known antidepressant drug that has now been on the market for some years and has the following structure:
NC iy -
CH;
F Formula I
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel, Prog. Neuro-Psychopharmacol. &
Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75 , 478- 486. The compound has further been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580.
Citalopram can be prepared by several disclosed methods. A method and an intermediate for the preparation of citalopram were described in US Patent No 4,650,884. Commercially useful processes are disclosed in International patent application Nos. WO 98019511, WO 98019512 and WO 98019513.
With respect to the above methods for the preparation of citalopram, the process comprising . exchange of the 5-bromo group with cyano proved not to be very convenient in commercial scale, since the yield was rather low, the product was impure and, in particular, since it was i difficult to separate the resulting citalopram from the corresponding 5-bromo compound.
It has now been found that in a new process for the preparation of citalopram, this key intermediate may be obtained in a high yield as a very pure product by a new catalytic
, process in which a halogen or a group of the general formula CF3-(CF,),-SO,- wherein n is any suitable whole number between 0 and 4, situated in the 5-position of a 3-H- isobenzofuran-1-one, is exchanged with a cyanide group. By obtaining the correct cyanide ’ substitution at an early stage of the citalopram synthesis, the extensive work up of the old . 5 cyanide exchange processes of the previous described processes is avoided. The v intermediates of the presently described process are easily purfied and obtained in very high yields. The key intermediate is then subjected to two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N.N-dimethylaminopropyl magnesium halogenide, respectively, whereby citalopram is obtained.
The preparation of the key intermediate of the invention is described earlier in J.Chem. Soc., 1931, 867 and by Tiroflet, J. in Bull. Soc. Sci. Betagne, 26, 35, 1951; The process for preparation of the compound is a three step synthesis starting from 5-nitro-phtalimide with low yields, especially in the last step of the synthesis.
Accordingly, the present invention relates to a novel method for the preparation of an intermediate in the preparation of citalopram comprising reacting a compound of Formula
IV
R' NC jon — jo —— ——> citalopram
O o)
Formula IV wherein R’ 1s Cl, Br, I or a group of the formula CF3-(CF;),-SO5- , wherein n is 0-4, with a cyanide source in the presence or absence of a catalyst, whereby 5-cyano-isobenzofuran-1- one is obtained. This intermediate product can be further reacted to citalopram as described above. .
The reaction of IV til 5-cyanophtalide may be carried out in more convenient solvents, at a
N low temperature and at a minimal excess of CN". The process has environmental advantages in that it only uses small amounts of heavy metals.
X WO 01/49672 3 PCT/DK99/00740 . The cyano sources may conveniently be selected from a group consisting of cyanide sources such as (R’’4;N)CN wherein cach R’’ represents C;.g-alkyl optionally two R”’ together with the nitrogen form a ring structure; NaCN, KCN, Zn(CN), or Cu(CN).
The reaction of the present invention is performed in the presence or absence of a catalyst. y The catalysts are i.e. Ni (0), Pd(0) or Pd(II) catalysts as described by Sakakibara et. al. in
Bull. Chem. Soc. Jpn, 61, 1985-1990, (1988). Preferred catalysts are Ni(PPh;); or
Pd(PPhs)4, or Pd(PPh),Cl,.
In a particularly preferred embodiment, a Nickel(0) complex is prepared in situ before the cyanide exchange reaction by reduction of a Nickel(II) precursor such as NiCl; or NiBr; by a metal, such as zinc, magnesium or mangan in the presence of excess of complex ligands, preferably triphenylphosphin.
The Pd or Ni-catalyst is conveniently used in an amount of 0.5-10, preferably 2-6, most preferably about 4-5 mol%.
Cu’ and Zn** may be added to the reaction mixture in substoichiometric amounts and may function as recycleable cyanide sources, which receives the cyanide from other cyanide sources such as NaCN or KCN. Substoichiometric amounts of Cu” and Zn** , respectively, means 1-20%, preferably 5-10%.
The reactions may be performed in any convenient solvent as described in Sakakibara et. al. in Bull. Chem. Soc. Jpn., 61, 1985-1990, (1988). Preferred solvents are acetonitril, ethylacetat, THF, DMF or NMP;
In one aspect of the invention, a compound of Formula IV wherein R is Cl is reacted with
NaCN in the presence of a N1(PPhj3); which is preferably prepared in situ as described above.
In another aspect of the invention, a compound of formula IV, wherein R is Br or I, is reacted with KCN, NaCN, CuCNor Zn(CN); in the presence of Pd(PPhs)s. In a particular ! aspect of the invention, substoichiometric amounts of Cu(CN) and Zn(CN), are added as recycleable cyanide sources .
In another aspect of same invention, the Cu(CN) is the cyanide source and without catalyst,
In a preferred embodiment of this invention, the reaction is performed at elevated temperature.
In a particular aspect of this invention, the reaction is performed as a neat reaction i.e. without added solvent. -
J
In another aspect of the invention, the reaction is performed in an ionic liquid of the general s formula RyN", X', wherein R are alkyl-groups or two of the R groups together form an ring and X is the counterion. In one embodiment of the invention, RyN"X" represents
GH
N
) ~NY PER
In another particular aspect of this invention, the reaction is conducted with apolar solvents such as benzene, xylene or mesitylene and under the influence of microwaves by using i.e.
Synthewave 1000™ by Prolabo. In a particular aspect of this invention, the reaction is performed without added solvent.
The temperature ranges are dependent upon the reaction type. If no catalyst is present preferred temperatures are in the range of 100-200°C. However, when the reaction is conducted under the influence of microwaves the temperature in the reaction mixture may raise to above 300 °C. More preferred temperature ranges are between 120-170°C. The most preferred range 1s 130-150°C.
If catalyst is present, the preferred temperature range is between 0 and 100°C. More preferred are temperature ranges of 40-90°C. Most preferred temperature ranges are between 60-90°C.
Other reaction conditions, solvents, etc. are conventional conditions for such reactions and may easily be determined by a person skilled in the art.
Examples . The invention is further illustrated by the following examples.
Experimental
Example 1
, N
Br 0 — 0 y © o) ’ A mixture of Zn(CN); (2.4g, 0.02mol) and 5-bromo-3H-isobenzofuran-1-one (4.2g, 0.02mol) In
DMF (80mL) were stirred at room temperature under an atmosphere of argon for 30 minutes. Then 5 dissolved oxygen was removed by bubbling argon through the reaction mixture for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium (0) (1.2g, 0.00096mol,) . Then the reaction was heated at 75 °C for 3 hrs, and then the solvent was removed under reduce pressure and the residue poured into water (150mL). Filtration and followed by drying in vaucco give the crude 3-cvano-3H-isobenzofuran-1-one (2.8 g) (HPLC 95%). An analytical sample was obtained by recrystalisation from acetic acid.
Example 2
A mixture of Zn(CN); (0.3g, 0.00256mol), NaCN (1g, 0,02mol) and 5-bromo-3H-isobenzofuran-1- one (4.2 g, 0.02mol) in DMF (80mL) were stirred at room temperature under an atmosphere of argon for 30 minutes. Then dissolved oxygen was removed by bubbling argon through the reaction mixture for 10 minutes before the addition of tetrakis(triphenylphosphine)pailadium (0) (1.2g, 0.00096mol) . Then the reaction was heated at 75 °C for 3 hrs, and then the solvent was removed under reduce pressure and the residue poured into water (150mL). Filtration and followed by drying in vaucco give the crude 5-cyano-3H-isobenzofuran-1-one (2.7 g) (HPLC 94%). An analytical sample was obtained by recrystalisation from acetic acid.
Example 3
A mixture of 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02mol) and Cu(CN), (2.3g, 0.02mol) in NMP (60mL) were stirred at 140 °C for 3hrs. Then solvent was removed by distilation under reduced pressure and the residue was refluxed in water (150 mL) for 10 minutes and allowed to h cool to room temperature. Filtration and followed by drying in vaucco give the crude 5-cyano- 3H-isobenzofuran-1-one (2.1g) (HPLC 97%). An analytical sample was obtained by recrystalisation from acetic acid.
. N
I
0 o)
Example 4
A mixture of Zn(CN); (2.4g, 0.02mol) and 3-iodo-3H-isobenzofuran-1-one (5.24g. 0.02mol) in
DMF (80mL) were stirred at room temperature under an atmosphere of argon for 30 minutes. Then dissolved oxygen was removed by bubbling argon through the reaction mixture for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium (0) (1.2g, 0.00096mol). Then the reaction was heated at 75 °C for 3 hrs, and then the solvent was removed under reduce pressure and the residue poured into water (150ml). Filtration and followed by drying in vaucco give the crude 5-cyano-3H-isobenzofuran-1-one (2.4 g) (HPLC 93%). An analytical sample was obtained by recrystalisation from acetic acid.
N cl I
O o)
Example 5
Under a nitrogen atmosphere, a mixture of NiCl, (0.2g, 0.0015mol) and triphenylphosphine (1.6g, 0.0061 mol) in acetonitrile (80 mi)was heated at reflux for 45 minutes. After cooling to room temperature. zinic powder was added (0.39 g, 0.006 mol) at stirred for 15 minutes before a solution of 5-chloro-3H-isobenzofuran-1-one (3.4g, 0.02mol) in THF (40 mL) was added.
After stirring for a further 10 minutes, NaCN ( 1.1g, 0.021 mol) was added and the reaction heated at 70 °C for 3hrs. cooled , diluted with acetonitrile (30mL) , and then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was was refluxed § in water (150 mL) for 10 minutes and allowed 10 cool to room temperature. Filtration and followed by drying in vaucco give the crude 5-cvano-3H-isobenzofuran-1-one (2.5 g). An analytical sample was obtained by recrystalisation from acetic acid.
Claims (15)
1. A method for the preparation of a compound of the formula :
N . NC . N . Te | | 0 Co comprising reacting an isobenzofuran-1-one of the formula Co R' ’ Oo ~ wooo ow = - Wherein R? represents a halogen or a group of the formula CF,-(CF,),-SO,- , wherein nis 0-7, with a cyanide source optionally in the presence of a catalyst.
2. The method of claim 1 wherein the starting material is an isobenzofuran-1-one with a Cl, Br or I in position 5.
3. The method of claim 1 wherein the starting material is an isobenzofuran-1-one with a triflate group of the formula CF3-(CF2),-SO;-, wherein nis 0, 1, 2, 3 or 4, in position 5.
4. The method of claims 1-3 wherein the cyanide source is selected from (R” ;N)CN wherein each R” represents C,.s-alkyl optionally two R” together with the nitrogen form a ring structure; KCN, NaCN, Zn(CN), or CuCN or combinations thereof,
5. The method of claims 1-4 wherein Zn®*" or Cu" are added in substoichiometric amounts in combination with another cyanide source. :
6. The method of claims 1-4 wherein the catalyst is selected from Ni(PPhs);, Pd(PPhs)4, Pd(dba); or Pd(PPh),Cl,.
7. The process of claims 1, 2 and 4 wherein a 5-chloro-isobenzofuran-1-one is subjected to NaCN in the presence of Ni-catalyst.
8. The method of claim 7 wherein the Ni-catalyst is Ni(PPh;); prepared in situ by subjecting NiCl; to a reducing agent in the presence of PPh;. Amended Sheet 17/04/2003
A 8
9. The method of claim 8 wherein the reducing agent is Zn.
10. The method of claim 1, 2 and 4 wherein a 5-bromo- or 5-iodo-isobenzofuran-1-one is subjected to KCN, NaCN, Zn(CN),, or CuCN or combinations thereof in the presence of Pd(PPhs;)s,.
11. The method according to claim 1, 2 and 4 wherein a 5-bromo- or 5-iodo- isobenzofuran-1-one is subjected to KCN, NaCN, Zn(CN),, or CuCN or combinations thereof and the process is performed without catalysts. oo TTT" T
12. The method of claim 11 wherein the reaction is performed in an ionic liquid of the general formula R;N"X wherein each R represents C,.g-alkyl optionally two R” together with the nitrogen form a ring.
13. The method of claim 11 wherein the reaction is performed under the influence of microwaves in an apolar solvent.
14. The method according to claim 11 or claim 13 wherein the reaction is performed as a neat reaction.
15. A method according to claim 1 substantially as herein described with reference to any one of the illustrative examples. Amended Sheet 17/04/2003
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ZA200205023A ZA200205023B (en) | 2002-06-21 | 2002-06-21 | Method for preparation of citalopram. |
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ZA200205023A ZA200205023B (en) | 2002-06-21 | 2002-06-21 | Method for preparation of citalopram. |
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2002
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